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Final Version of 2009 AJCC Melanoma Staging and Classification
Abstract
To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database.
The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria.
Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level.
Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.
... LDH leakage into the serum is believed to occur when melanoma cells outgrow their blood supply. The escalation of LDH levels emerges as an adverse prognostic marker, irrespective of metastasis site or number, strongly correlating with reduced survival rates in advanced disease [18,19]. The American Joint Committee on Cancer's staging system uses elevated LDH levels alongside any distant metastasis to classify patients into stage IV [18]. ...
... A recent randomized study exploring the efficacy of dacarbazine with and without oblimersen in advanced melanoma patients found that supplementing with oblimersen resulted in improved overall response rates and survival. Notably, LDH emerged as a highly predictive factor for the effects of oblimersen [18][19][20][21][22][23]. This discovery bears significance for clinical trials, emphasizing the importance of stratifying patients based on LDH levels to prevent high baseline LDH levels from masking treatment effects [18][19][20][21][22][23]. ...
... Notably, LDH emerged as a highly predictive factor for the effects of oblimersen [18][19][20][21][22][23]. This discovery bears significance for clinical trials, emphasizing the importance of stratifying patients based on LDH levels to prevent high baseline LDH levels from masking treatment effects [18][19][20][21][22][23]. ...
Melanoma, a malignant neoplasm originating from melanocytes, stands as one of the most prevalent cancers globally, ranking fifth in terms of estimated new cases in recent years. Its aggressive nature and propensity for metastasis pose significant challenges in oncology. Recent advancements have led to a notable shift towards targeted therapies, driven by a deeper understanding of cutaneous tumor pathogenesis. Immunotherapy and tyrosine kinase inhibitors have emerged as promising strategies, demonstrating the potential to improve clinical outcomes across all disease stages, including neoadjuvant, adjuvant, and metastatic settings. Notably, there has been a groundbreaking development in the treatment of brain metastasis, historically associated with poor prognosis in oncology but showcasing impressive results in melanoma patients. This review article provides a comprehensive synthesis of the most recent knowledge on staging and prognostic factors while highlighting emerging therapeutic modalities, with a particular focus on neoadjuvant and adjuvant strategies, notably immunotherapy and targeted therapies, including the ongoing trials.
... 8 Further, we included data on melanoma incidence from the Swiss National Cancer Registry from 2013 to 2015, from Hungary from 2019, from National Health Service England from 2015 to 2017, 9 and from Public Health Wales from 2016 to 2017. 10 Indirect treatment costs and melanoma numbers were collected from the Belgian Cancer Registry from 2009 to 2011. 5 We included patients aged 18 years and older with invasive primary cutaneous melanomas stages I to IV, according to the AJCC seventh and eighth editions, including melanomas of unknown primary (T0). [11][12][13] Additional information is provided in eTable 1 and eTable 4 in Supplement 1. ...
... The variation in estimated rates was not more than 0.5 percentage points (eTable 6 in Supplement 1). Since the published DALY calculations are based on the AJCC seventh edition, 5 we used AJCC seventh edition 11 staging for data used in the primary modeling. ...
... Melanomas are differentiated into 4 stages in the AJCC seventh edition, I through IV. 11 As outlined in Figure 3A and B and eTables 1 to 4 in Supplement 1, most melanomas were detected at an early stage (eg, for stage I, 66%; stage II, 24%; stage III, 7%; stage IV, 3%; according to National ...
Importance
The COVID-19 pandemic resulted in delayed access to medical care. Restrictions to health care specialists, staff shortages, and fear of SARS-CoV-2 infection led to interruptions in routine care, such as early melanoma detection; however, premature mortality and economic burden associated with this postponement have not been studied yet.
Objective
To determine the premature mortality and economic costs associated with suspended melanoma screenings during COVID-19 pandemic lockdowns by estimating the total burden of delayed melanoma diagnoses for Europe.
Design, Setting, and Participants
This multicenter economic evaluation used population-based data from patients aged at least 18 years with invasive primary cutaneous melanomas stages I to IV according to the American Joint Committee on Cancer (AJCC) seventh and eighth editions, including melanomas of unknown primary (T0). Data were collected from January 2017 to December 2021 in Switzerland and from January 2019 to December 2021 in Hungary. Data were used to develop an estimation of melanoma upstaging rates in AJCC stages, which was verified with peripandemic data. Years of life lost (YLL) were calculated and were, together with cost data, used for financial estimations. The total financial burden was assessed through direct and indirect treatment costs. Models were building using data from 50 072 patients aged 18 years and older with invasive primary cutaneous melanomas stages I to IV according to the AJCC seventh and eighth edition, including melanomas of unknown primary (T0) from 2 European tertiary centers. Data from European cancer registries included patient-based direct and indirect cost data, country-level economic indicators, melanoma incidence, and population rates per country. Data were analyzed from July 2021 to September 2022.
Exposure
COVID-19 lockdown-related delay of melanoma detection and consecutive public health and economic burden. As lockdown restrictions varied by country, lockdown scenario was defined as elimination of routine medical examinations and severely restricted access to follow-up examinations for at least 4 weeks.
Main Outcomes and Measures
Primary outcomes were the total burden of a delay in melanoma diagnosis during COVID-19 lockdown periods, measured using the direct (in US$) and indirect (calculated as YLL plus years lost due to disability [YLD] and disability-adjusted life-years [DALYs]) costs for Europe. Secondary outcomes included estimation of upstaging rate, estimated YLD, YLL, and DALY for each European country, absolute direct and indirect treatment costs per European country, proportion of the relative direct and indirect treatment costs for the countries, and European health expenditure.
Results
There were an estimated 111 464 (range, 52 454-295 051) YLL due to pandemic-associated delay in melanoma diagnosis in Europe, and estimated total additional costs were $7.65 (range, $3.60 to $20.25) billion. Indirect treatment costs were the main cost driver, accounting for 94.5% of total costs. Estimates for YLD in Europe resulted in 15 360 years for the 17% upstaging model, ranging from 7228 years (8% upstaging model) to 40 660 years (45% upstaging model). Together, YLL and YLD constitute the overall disease burden, ranging from 59 682 DALYs (8% upstaging model) to 335 711 DALYs (45% upstaging model), with 126 824 DALYs for the real-world 17% scenario.
Conclusions and Relevance
This economic analysis emphasizes the importance of continuing secondary skin cancer prevention measures during pandemics. Beyond the personal outcomes of a delayed melanoma diagnosis, the additional economic and public health consequences are underscored, emphasizing the need to include indirect economic costs in future decision-making processes. These estimates on DALYs and the associated financial losses complement previous studies highlighting the cost-effectiveness of screening for melanoma.
... Locoregional stage III melanoma is treated with surgical resection with curative intent. Unfortunately, despite complete surgical resection patients have a high risk of recurrence, resulting in 5-year OS rates between 78% and 40% 16 . Therefore, effective adjuvant therapy for this group of patients is warranted. ...
... The MIND-DC study is a double-blind, randomized, placebo-controlled phase 3 study performed in two centers in the Netherlands (Radboud university medical center, Nijmegen and Isala, Zwolle). Eligible patients were at least 18 years of age and had histologically confirmed stage IIIB or IIIC cutaneous melanoma as defined according to the American Joint Committee on Cancer 2009 classification, 7th edition 16 . Patients with an unknown primary tumor were also eligible. ...
Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88−1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73−2.38; p = 0.44). Grade 3−4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.
... For localized melanoma (stage 0-stage I), the 5-year survival rate is around 97%. However, for stage IV melanoma, the five-year survival rate drops to 4% (7,8). Detecting melanoma in its early stages is crucial for its survival rate as it allows timely intervention and treatment, significantly improving the chances of successful outcome and reducing the risk of severe complications (7,8). ...
... However, for stage IV melanoma, the five-year survival rate drops to 4% (7,8). Detecting melanoma in its early stages is crucial for its survival rate as it allows timely intervention and treatment, significantly improving the chances of successful outcome and reducing the risk of severe complications (7,8). ...
Background
The COVID-19 pandemic disrupted the healthcare system and negatively affected the diagnosis and management of melanoma worldwide. The purpose of this study is to investigate the long-term effects of the COVID-19 pandemic on the diagnosis and prognosis of melanoma.
Materials and methods
This retrospective cohort study included histopathologically confirmed melanoma cases from March 2019 to February 2023 in Cluj and Bihor counties. Data from the post-COVID-19 period (March 2021 to February 2023) were compared to the pre-COVID-19 period (March 2019 to February 2020) and the COVID-19 period (March 2020 to February 2021). Patient characteristics, monthly diagnostics, histological subtypes, and key histological features were analyzed using statistical tests.
Results
The number of melanoma cases diagnosed annually decreased by 31.37 and 23.75% in the first and second post-pandemic years, respectively, compared to pre-pandemic numbers. Diagnostic rates also decreased by 14.9 and 5.4% in the first and second post-pandemic years, respectively, compared to the pandemic period. Prognostic factors worsened in the post-pandemic period, with higher Breslow index and mitotic rate, and increased ulceration and thick melanomas compared to the pre-pandemic period.
Conclusion
The COVID-19 pandemic had a long-lasting impact on the diagnosis of melanoma in Romania, resulting in advanced stages and unfavorable prognostic factors. Larger global studies are needed to comprehensively understand the pandemic’s long-term effects on the diagnosis of melanoma.
... Until 2010, less than 5% of the patients with stage IV melanoma survived 5 years (Manola et al. 2000;Tsao et al. 2004;Balch et al. 2009). With the approval of the immune checkpoint inhibitors (ICI) ipilimumab in 2011 (Hodi et al. 2010;Tsao et al. 2004), nivolumab and pembrolizumab in 2015 and the combination of ipilimumab and nivolumab in 2016, overall survival (OS) increased markedly and complete remissions are no longer rarities (Balch et al. 2009;Rockberg et al. 2016;Tichanek et al. 2023;van Zeijl et al. 2021). ...
... Until 2010, less than 5% of the patients with stage IV melanoma survived 5 years (Manola et al. 2000;Tsao et al. 2004;Balch et al. 2009). With the approval of the immune checkpoint inhibitors (ICI) ipilimumab in 2011 (Hodi et al. 2010;Tsao et al. 2004), nivolumab and pembrolizumab in 2015 and the combination of ipilimumab and nivolumab in 2016, overall survival (OS) increased markedly and complete remissions are no longer rarities (Balch et al. 2009;Rockberg et al. 2016;Tichanek et al. 2023;van Zeijl et al. 2021). For patients with BRAF V600 mutant melanoma, BRAF and MEK inhibitors offer likewise excellent treatment options (McArthur et al. 2014;Hauschild et al. 2012;Rogiers et al. 2019;Long et al. 2017Long et al. , 2014. ...
Purpose
Since the introduction of immune checkpoint inhibitors (ICI) and targeted therapies (TT), survival rates of metastatic melanoma patients have increased significantly and complete remissions are no longer rarities. Consequently, there is an increasing number of long-term survivors who have not yet been comprehensively characterized.
Methods
We included melanoma patients who entered stage IV between 2014 and 2017 and survived at least 5 years after entering stage IV. Descriptive statistics were performed to characterize the applied systemic therapies, response rates and to report which of these patients are still alive today.
Results
640 patients entered stage IV at the University Hospital Tuebingen. Of these, 207 patients (32%) were still alive at least 5 years after entering stage IV. Details of applied therapies and response rates were available in 176 patients (85%). About 90% of patients (n = 159) were still alive at the time of analysis. Median survival since first stage IV diagnosis was 6.0 years (range 5–9 years). An impressive majority of patients (n = 146, 83%) were no longer receiving systemic therapy at the time of evaluation. Complete remission under first line systemic therapy was seen in 36% of the patients.
Conclusion
This dataset comprises the largest available cohort of long-term surviving stage IV melanoma patients. Since 90% of patients in our cohort are still alive today, we expect an increasing number of long-term survivors in the future. Our data indicate the need for specific follow-up programs addressing the needs of long-term survivors.
... Especially noteworthy is the increase in the 5-year survival rate for patients with advanced, inoperable melanoma. For example, the 5-year survival rate was around 10% in 2009 [8], but with the use of checkpoint inhibitors and BRAF and MEK kinase inhibitors, it now ranges from 34 to 52% [9][10][11]. This highlights the remarkable progress in melanoma treatment and its impact on managing this aggressive form of cancer. ...
In recent decades, the field of systemic cancer treatment has seen remarkable changes due to advancements in the understanding of cancer’s biology, immunology, and genetic makeup. As a result, individuals with late-stage cancers are now achieving survival rates that were previously unattainable. The goal of personalized cancer therapy is to enhance clinical outcomes by customizing drug treatments to suit the unique genetic and/or epigenetic profiles of each patient’s tumor. This approach aims to reduce the side effects commonly associated with ineffective treatments. Advances in genetic sequencing and molecular cytogenetics have been instrumental in identifying cancer-driving mutations and epigenetic irregularities, leading to the development of specific molecular therapies. This review article highlights the progress and success of targeted molecular therapies in treating malignant melanoma, illustrating the concept of personalized cancer treatment.
... Regarding visceral metastasis, even though it is the third most common source of brain metastasis, it has the highest tendency to metastasize [16], the mortality being related to the metastatic visceral spread to different organs. Moreover, studying the pathogenesis of this disease, researchers heeded that tumor progression is favored by a complex interaction between tumor cells and the host's immune response [17], deeming malignant melanoma an immunogenic tumor that quickly stimulates immune reactions in the host's organism [18][19][20]. In addition, melanoma was pinpointed as having the highest mutational load of all malignant tumors [21,22]. ...
Since transcription factor Forkhead Box P3 (FoxP3) was identified as a specific regulatory T cell (Treg) marker, researchers have scrutinized its value as a potential novel therapeutic target or a prognostic factor in various types of cancer with inconsistent results. The present analysis was performed to assess the influence of Treg FoxP3 expression on the prognosis of primary melanoma and to evaluate the correlations with various clinicopathological prognostic factors. We analyzed all eligible patients with stage pT3 primary malignant melanomas treated in a tertiary cancer center. Immunohistochemical staining for Treg FoxP3 expression was performed on retrospectively identified paraffin blocks and subsequently correlated with the outcomes of the patients. A total of 81% of the patients presented a positive Treg FoxP3 expression, being correlated with a higher risk of lymph node metastasis, tumor relapse, and death. Moreover, positive expression was statistically associated with a shorter OS. The tumor relapse rate was estimated at 36.7%. A positive expression of Treg FoxP3 and lymph node metastasis were associated with a higher risk of death based on multivariate analysis. Treg FoxP3 expression may be used as an independent prognostic factor in patients with malignant melanoma to evaluate tumor progression and survival.
... While there have been differing opinions on the socio-economic cost of skin cancer screenings and overtreatment of malignant melanoma, studies support the potential benefit of screening 35 . Not only is an early diagnosis of melanoma crucial for therapy as it is decisive for TNM staging and corresponding survival rates 36 , but the rising cost of skin cancer treatment is an economic burden that highlights the need for early detection and skin cancer prevention 13 . Additionally, UV radiation is not only a main contributor in the development of melanoma and non melanoma skin cancer, but also a known trigger and hypothesized to be crucial to rosacea pathogenesis 37,38 . ...
Rosacea is often considered a cosmetic problem but is known to be associated with a variety of comorbidities. To identify such risks, we generated two age- and sex-matched real-world cohorts of 122,444 patients each with and without rosacea. In contrast to earlier studies, we found significant associations with malignant melanoma (OR 6.02, 95% CI 5.76–6.32). This association does not exist for an Asian sub-cohort, which could explain previous inconclusive or conflicting reports. Several strongly associated comorbidities like visual disturbances (ICD-10: H53–H54; OR 4.80, 4.68–4.92), metabolic disorders (E73–E79; OR 3.17, 3.11–3.22), joint problems (M25; OR 4.16, 4.08–4.25) and type 2 diabetes (E11; OR 1.62, 1.58–1.65) should be watched as a risk for rosacea patients. Rosacea is associated with some comorbidities and ethnicity may be a risk factor in melanoma development. The retrospective nature of this study and the sole use of ICD-10 code based filtering calls for future validation of our findings. Additionally, confounding factors such as skin type and previous UV exposure should be included in future studies.
... Up to 10% of patients with highrisk early-stage cutaneous melanoma will develop in-transit metastases (ITM), most often localized to the limbs, characterized by tumor nodules that spread along lymphatics in the subcutaneous or dermal layers between the primary lesion and regional nodal basin [3,4]. ITM without regional node involvement has been associated with 5-year survival rates of 60-69%, and ITM with regional node involvement has been associated with 5-year survival rates of 36-46% [3,5,6]. For patients with uveal melanoma who develop metastatic disease, approximately 90% will develop isolated liver metastases, with the liver being the predominant site of metastases in the majority of patients [4]. ...
Simple Summary
Many novel therapeutic options have emerged in recent years for patients with locoregionally advanced and metastatic melanoma. For in-transit melanoma with metastatic tumor spread between the primary tumor site and the regional lymph node basin, treatment options include intralesional tumor injections and an isolated infusion of the affected extremity. Notably, for ocular melanoma with metastatic disease to the liver, recent FDA approval of percutaneous hepatic perfusion, a minimally invasive method of isolated infusion of the liver, has become an approved treatment option. This article aims to review the current updates and efficacy on intralesional and infusional therapies for locoregionally advanced and metastatic melanoma.
Abstract
Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of advanced melanoma, followed by the utilization of isolated extremity perfusion (ILP). Following this, intralesional oncolytic viruses, xanthene dyes, and cytokines were introduced for the management of in-transit metastases as well as unresectable, advanced melanoma. In 2015, the Food and Drug Administration (FDA) approved the first oncolytic intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of advanced melanoma. Additionally, immune checkpoint inhibition has demonstrated efficacy in the management of advanced melanomas, and this improvement in outcomes has been extrapolated to aid in the management of in-transit metastatic disease. Finally, percutaneous hepatic perfusion (PHP), also approved by the FDA, has been reported to have a significant impact on the treatment of hepatic disease in uveal melanoma. While some of these treatments have less utility due to inferior outcomes as well as higher toxicity profiles, there are selective patient profiles for which these therapies carry a role. This review highlights intralesional and infusional therapies for the management of metastatic melanoma.
... Melanoma, an aggressive form of skin cancer originating from melanocytes [1], poses a significant challenge with its escalating incidence and bleak prognosis upon metastasis [2][3][4][5]. Despite available therapies like molecular-targeted and immunotherapies, treatment efficacy is hampered by drug resistance and suboptimal patient response [1,6,7]. ...
Malignant melanoma represents a form of skin cancer characterized by a bleak prognosis and heightened resistance to traditional therapies. Quercetin has demonstrated notable anti-carcinogenic, anti-inflammatory, anti-oxidant, and pharmacological effects across various cancer types. However, the intricate relationship between quercetin’s anti-cancer properties and ganglioside expression in melanoma remains incompletely understood. In this study, quercetin manifests specific anti-proliferative, anti-migratory, and cell-cycle arrest effects, inducing mitochondrial dysfunction and apoptosis in two melanoma cancer cell lines. This positions quercetin as a promising candidate for treating malignant melanoma. Moreover, our investigation indicates that quercetin significantly reduces the expression levels of ganglioside GD3 and its synthetic enzyme. Notably, this reduction is achieved through the inhibition of the FAK/paxillin/Akt signaling pathway, which plays a crucial role in cancer development. Taken together, our findings suggest that quercetin may be a potent anti-cancer drug candidate for the treatment of malignant melanoma.
... Traditional diagnostic methods, including visual inspection and biopsy, have long been the mainstay; however, their subjectivity and limitations in achieving early detection have paved the way for the exploration of cutting-edge technologies, notably artificial intelligence (AI), in dermatology. 3 Dermatologists conventionally rely on visual examination, dermoscopy, and biopsy for skin cancer diagnosis. While these methods are valuable, their efficacy is often contingent on the clinician's expertise and may involve inherent subjectivity. ...
This Review explores the transformative impact of artificial intelligence (AI) on the early detection of skin cancer, with a specific focus on melanoma, a potentially lethal form of the disease. Beginning with an overview of traditional diagnostic methods and their limitations, this paper delves into the evolution of AI within dermatology, emphasizing its application in image analysis and pattern recognition. A comprehensive examination of AI algorithms for melanoma detection, including machine learning and deep learning models, is provided. This Review critically assesses the performance metrics, training datasets, and comparative analyses with traditional methods. Addressing challenges such as data quality, interpretability, and ethical considerations, this paper outlines future directions, emphasizing ongoing research, algorithm improvements, and integration with clinical practices. Case studies and success stories highlight the real-world impact of AI in dermatology. This Review concludes by summarizing key findings and underlining the pivotal role of AI in revolutionizing early melanoma detection, with implications for personalized medicine and enhanced patient outcomes.
... The incidence of melanoma in adolescents and young adults (AYAs) is disproportionately high, especially in western countries where it is the most frequent cancer diagnosis in those under 40 years of age 1,2 . The advent of immune checkpoint inhibitor (ICI) therapies has brought substantial improvements in patient outcome, where the overall survival (OS) for metastatic melanoma patients has improved from 10% to 50% with anti-PD-1-based immunotherapies when compared with traditional treatments [3][4][5][6][7] . However, the benefits of ICI therapies are highly variable and there are currently no reliable biological or clinical biomarkers that can predict treatment response. ...
The biological underpinnings of therapeutic resistance to immune checkpoint inhibitors (ICI) in adolescent and young adult (AYA) melanoma patients are incompletely understood. Here, we characterize the immunogenomic profile and spatial architecture of the tumor microenvironment (TME) in AYA (aged ≤ 30 years) and older adult (aged 31–84 years) patients with melanoma, to determine the AYA-specific features associated with ICI treatment outcomes. We identify two ICI-resistant spatiotypes in AYA patients with melanoma showing stroma-infiltrating lymphocytes (SILs) that are distinct from the adult TME. The SILhigh subtype was enriched in regulatory T cells in the peritumoral space and showed upregulated expression of immune checkpoint molecules, while the SILlow subtype showed a lack of immune activation. We establish a young immunosuppressive melanoma score that can predict ICI responsiveness in AYA patients and propose personalized therapeutic strategies for the ICI-resistant subgroups. These findings highlight the distinct immunogenomic profile of AYA patients, and individualized TME features in ICI-resistant AYA melanoma that require patient-specific treatment strategies.
... These metastases can be local (satellite lesions), regional (in-transit), or distant lesions typically seen on imaging as they are easily differentiated from local subcutaneous adipose tissue [2]. Satellite lesions are defined as secondary lesions in the skin or subcutaneous tissue within 2 cm of the primary tumor [17]. Satellite lesions are clearly separated by the normal dermis and are considered intralymphatic extensions of the primary mass. ...
This case describes a unique presentation of a rare malignancy: giant melanoma. Due to the accessibility of healthcare in the United States, it is unusual for melanomas to grow to massive sizes without clinical intervention. In fact, an in-depth literature review elicited only a handful of similar cases. Giant malignant melanomas are typically defined by a cutoff size of no less than 10 cm in diameter. They often present with distant metastases and are highly invasive. Due to limited yet highly variable presentations, there is no standardized approach to treating this class of melanomas. We present a case with unique features not previously documented in similar cases that was ultimately treated with a novel approach.
... Among skin cancers, melanoma is the most fatal, as it can rapidly metastasize throughout the body and lead to a painful death. The five-year survival rate of melanoma can be improved to 95% if it is treated at an early stage [3]. However, early prevention of melanoma is hindered by a large number of patients with skin diseases and a shortage of experienced dermatologists. ...
In this study, we introduce a multi-modal approach that efficiently integrates multi-scale clinical and der-moscopy features within a single network for skin lesion classification , thereby substantially reducing model parameters. The proposed method includes three novel fusion schemes. First, unlike current methods that usually employ two individual models for clinical and dermoscopy modalities, we verified that multi-modal features can be learned by sharing the parameters of the encoder while leaving the individual modal-specific classifiers apart. Second, the shared cross-attention module can replace the individual one to efficiently interact between two modalities at multiple layers. Third, different from current methods that optimize dermoscopy and clinical branches equally, inspired by the prior knowledge that dermoscopy images play a more significant role than clinical images, we propose a novel biased loss. This loss guides the single shared network to prioritize dermoscopy information over clinical information, implicitly learning a better joint feature representation for the modal-specific task. Extensive experiments on the well-recognized Seven-Point Checklist (SPC) dataset and the collected ISIC dataset demonstrate the effectiveness of our method using both CNN or Transformer structures. Furthermore, our method exhibits superiority in both accuracy and model complexity compared to current advanced methods. The code will be publicly available.
... In comparison with results reported in the chemotherapy era of melanoma treatment, in which dacarbazine and paclitaxel + carboplatin regimens were staples of treatment in stage IV melanoma, a marked improvement can be noticed. Chemotherapy treatments in this scenario reported a median survival time of 7-9 months [24][25][26] and a one-year overall survival ranging between 30% and 65%, varying greatly based on the site of metastasis and LDH levels at diagnosis [27]. Meanwhile, our results reported an OS of 346 days with 17% of patients having CNS involvement and 30.2% of patients having high LDH levels at diagnosis. ...
Background: This retrospective study evaluates patients with stage IV melanoma treated with nivolumab and ipilimumab combination therapy from two regional oncology centers in Romania from the year 2019 to the end of 2022. Methods: The data were analyzed in SAS for Windows, V9.4. LDH means were stratified by the number of metastatic sites before treatment and compared using an independent sample T-test. The survival curves were estimated using the Kaplan–Meier method, and the survival distributions were compared with the log-rank test. The effects of the main clinical and pathological variables on OS and PFS were investigated with Cox regression. Results: The LDH mean for patients with three or more metastases before treatment was significantly higher than that for patients with only one metastatic site. The Kaplan–Meier curve of OS in all evaluable patients enrolled in the study resulted in a median OS of 346 days (95% CI: 150) and a median PFS of 211 days (95% CI: 113–430). A total of 45.3% of the patients experienced adverse events during the nivolumab + ipilimumab treatment, with some of them having multiple organ systems involved. Discussion: The OS values were lower than those reported in approved clinical trials, but the results show a marked improvement when compared to the results obtained by chemotherapy regimens previously used in these scenarios. Conclusion: This study provides real-world insights into the survival data and safety profiles of combination therapy with anti-PD-1 antibodies and anti-CTLA-4 antibodies.
... Tumor staging was performed manually and according to the eighth edition of the American Joint Committee on Cancer (AJCC) cancer staging. 18 While adjuvant therapy in the form of adjuvant radiation, immunotherapy, and/or interferon therapy was administered based on the recommendation of a multidisciplinary tumor board, only adjuvant interferon therapy was included in multivariable analysis. Patient data were encoded via pseudonymized numbers, justifying this analysis as nonhuman subject research. ...
Background: In melanoma treatment, complete lymph node dissection (CLND) has been considered the therapeutic gold standard in patients with positive sentinel lymph node biopsy (SLNB). This long-held approach was revised in 2017, with recent evidence questioning the therapeutic benefit of CLND in malignant melanoma (MM) therapy. In this study, we aimed to fill this knowledge gap by retrospectively analyzing the impact of CLND on MM patients' survival. Methods: We retrospectively analyzed the multi-center population-based Clinical Cancer Registry at the Tumor Center Regensburg (TUDOK) database (2004-2020) to identify patients who had been diagnosed with SLN-positive MM and underwent (non)invasive management thereof. Patient cohorts were subdivided according to the treatment received (CLND and waiving CLND). Primary outcomes included overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rate. Results: We identified 1,143 MM patients, of whom 126 (11.0%) had positive SLN status. CLND was waived in the majority of SLN-positive MM cases (n=71; 56.3%), with 55 (43.7%) patients undergoing CLND. Univariable and multivariable Cox regression revealed no significant advantage for CLND patients compared to non-CLND patients in OS (HR=0.970, p=0.915 and HR=1.295, p=0.479, respectively), RFS (HR=1.050, p=0.849 and HR=1.220, p=0.544, respectively), and cumulative recurrence rate (HR=1.234, p=0.441 and HR=1.220, p=0.544), respectively). Conclusion: We found that CLND had no significant impact on patient survival and MM recurrence rate, thus corroborating the validity of current clinical guidelines.
... The sole study that did not elaborate in depth on C2 as a positive predictive factor in hepatocellular carcinoma was consistent with the results of the present pan-cancer analysis [29]. Moreover, ulceration, a predictive tissue biomarker for melanoma in tissue [30], has been incorporated into the current American Joint Committee on Cancer system [31]. Ulceration indicates a poorer prognosis and higher tumor stage. ...
Simple Summary
Melanoma is an immunogenic tumor, so its outcomes and the efficacy of immunotherapy must be linked to the immune component. In this study, we aimed to find indicators that would allow us to monitor both the prognosis of patients and the efficacy of immunotherapy. We found that complement C2 tended to be upregulated in patients after effective anti-PD-1 therapy, and the high expression group achieved longer survival. Tumor tissues with C2 expression were infiltrated with more M1-type macrophages and tertiary lymphoid structures, and this favorable immune status may be responsible for the favorable outcome. Our findings provide valuable insights into the functional role of C2 in melanoma and its potential implications for clinical therapy.
Abstract
Immunotherapy is an essential therapy for individuals with advanced melanoma. However, not all patients respond to such treatment due to individual differences. We conducted a multidimensional analysis using transcriptome data from our center, as well as publicly available databases. We found that effective nivolumab treatment led to an upregulation of C2 levels, and higher levels following treatment are indicative of a good outcome. Through bioinformatics analyses and immunofluorescence, we identified a correlation between C2 and M1 macrophages. To further investigate the role of C2 in melanoma, we constructed subcutaneous tumorigenic models in C57BL/6 mice. The tumors in the C2 overexpression group exhibited significantly smaller sizes. Flow cytometric analysis of the mouse tumors demonstrated enhanced recruitment of macrophages, particularly of the M1 subtype, in the overexpression group. Moreover, single-cell RNA sequencing analysis revealed that C2-positive tumor cells exhibited enhanced communication with immune cells. We co-cultured tumor cell supernatants with macrophages in vitro and observed the induction of M1 subtype polarization. In addition, we discovered a close correlation between C2 and tertiary lymphoid structures. C2 has been demonstrated to exert a protective effect, mediated by its ability to modulate the tumor microenvironment. C2 serves as a prognostic marker for melanoma and can be employed to monitor the efficacy of immunotherapy.
... Consequently, these parameters are associated with poor prognostic outcomes in early-stage melanoma. 11 The risk of developing systemic metastatic disease in patients with regional lymph node metastasis is further correlated with whether the metastasis is microscopic or palpable, as well as the number of positive nodes 12 . However, the most significant factor determining prognosis, as observed in our study, remains lymph node metastasis. ...
Our aim was to assess the efficacy of adjuvant programmed cell death protein-1 (PD-1) inhibitors and compare the other adjuvant treatments in patients with surgically resected stage III or IV acral melanoma. This study is a multicenter, retrospective analysis. We included 114 patients with stage III or IV acral malignant melanoma who underwent surgery within the past 10 years. We analyzed the effect of adjuvant programmed cell death protein-1 inhibitors on disease-free survival (DFS). The mean follow-up was 40 months, during which 69 (59.5%) patients experienced recurrence. Among the participants, 64 (56.1%) received systemic adjuvant therapy. Specifically, 48.4% received anti–PD-1 therapy, 29.7% received interferon, 14.1% received tezozolomide, and 7.8% received B-Raf proto-oncogene/mitogen-activated protein kinase inhibitors. Patients who received adjuvant therapy had a median DFS of 24 (10.9–37.2) months, whereas those who did not receive adjuvant therapy had a median DFS of 15 (9.8–20.2) months. Multivariate analysis for DFS revealed that the receipt of adjuvant therapy and lymph node metastasis stage were independent significant parameters ( P = 0.021, P = 0.018, respectively). No statistically significant difference was observed for DFS between programmed cell death protein-1 inhibitor treatment and other adjuvant treatments. Regarding overall survival (OS), patients who received adjuvant treatment had a median OS of 71 (30.4–111.7) months, whereas those who did not receive adjuvant treatment had a median OS of 38 (16.7–59.3; P = 0.023) months. In addition, there were no significant differences in OS observed between various adjuvant treatment agents ( P = 0.122). In our study, we have shown that adjuvant therapy had a positive effect on both DFS and OS in patients with stages III–IV acral melanoma who underwent curative intent surgery. Notably, we found no significant differences between anti–PD-1 therapy and other adjuvant therapies.
... Multivariate Cox regression analysis was carried out with American Joint Committee on Cancer (AJCC) staging version 7 (Balch et al., 2009), age, sex and melanoma site (limbs vs. rest) as possible confounding factors. The multivariate Cox proportional-hazards model can be represented as: ...
... Melanoma survival is strongly inversely associated with lesion thickness; thus, thin lesions have a better prognosis than thicker ones. Thick melanomas (>4 mm) have a 20-year survival rate of approximately 50% [5]. Ulceration is a relevant factor as well, since studies consistently report that melanomas with ulceration present a significantly lower survival rate compared to non-ulcerated ones [6]. ...
Simple Summary
We aimed to study whether the burden of disease (incidence and mortality) of thin melanomas (i.e., melanomas thinner than 1 mm at diagnosis) increased in recent decades in Italy as observed in other world countries (e.g., Australia, the USA, and Scandinavian countries). We used data from a population-based cancer registry in Tuscany (Central Italy) and found that, while the incidence of thin melanomas has indeed been increasing steadily in recent years (much more than thick melanomas), the contribution of thin melanomas to mortality has not changed substantially. Moreover, we detected differences between sexes and across age groups in the way the epidemiology of melanoma, and especially thin melanomas, has changed in recent years. These findings likely reflect parallel changes in exposure to UV radiation (the most important environmental risk factor for melanoma) and possibly early diagnosis practices, and they represent a valuable piece of information for informing effective prevention interventions.
Abstract
A steady increase in the incidence and mortality burden correlated to thin melanomas (≤1 mm) has been reported in recent years in some international studies, but there is currently a paucity of data from the Mediterranean area. We aimed to describe the epidemiological characteristics of thin melanoma in Tuscany, Central Italy. A total of 6002 first cutaneous invasive melanomas occurring from 1985 to 2017 were selected for analysis; data were retrieved from the local population-based cancer registry. The standardized incidence rate was 15.0 per 100,000 in the population, higher among men than women (16.5 vs. 14.1). Incidence rates tended to increase over time across all age group-specific population strata, with annual percent changes moderately higher among men (+8.0%) than women (+6.9%), especially among the elderly. Among both sexes and in each age group, the trend toward increasing incidence rates was particularly strong for thin melanomas. Survival was better among women than men across all categories of thickness. Approximately 15% of deaths occurred among patients with thin lesions, with no major temporal changes in recent years. This study contributes to an improved understanding of melanoma epidemiology in Tuscany and underscores the need for primary prevention strategies tackling the growing burden of thin melanomas.
... Due to limited awareness of melanoma, lesions are frequently misdiagnosed as benign, leading to delayed diagnoses. Ulceration is recognized as a negative prognostic factor in melanoma 31,32 , often used in conjunction with tumor thickness to guide treatment decisions and predict outcomes. These factors are fundamental elements of the AJCC melanoma staging system 18 . ...
Introdução: O melanoma acral (MA) está associado à alta mortalidade e à baixa sobrevida, e seu prognóstico é pior em comparação com os outros subtipos de melanoma. Objetivo: Analisar o poder preditivo de aspectos demográficos e clinicopatológicos em pacientes com MA. Método: Estudo retrospectivo com pacientes diagnosticados com MA entre janeiro de 2001 e dezembro de 2015. Foram coletadas características demográficas e clinicopatológicas. O desfecho foi a sobrevida global (SG) em cinco anos. Foram utilizados curvas de Kaplan-Meier, teste de log-rank e análise de regressão de Cox. Resultados: Foram identificados 394 pacientes com MA. A taxa de sobrevida em cinco anos para pacientes com MA foi de 45,6%. Os fatores preditivos da SG incluíram espessura de Breslow [hazard ratio (HR): 1,02, intervalo de confiança (IC) de 95%: 1,01-1,03], ulceração (HR: 4,06, IC 95%: 2,18-7,57) e invasão linfovascular (ILV) (HR: 2,12, IC 95%: 1,12-4,00). Conclusão: Tais achados destacam o prognóstico desfavorável do MA e o poder preditivo da espessura de Breslow, ulceração e ILV.
... [8] The site of metastasis of a melanoma is important prognostically, because cutaneous/subcutaneous involvement has better prognosis as compared to visceral metastases. [9] Dermal melanoma is limited to the dermis and/or subcutis without involving the epidermis. Clinically, it can often mislead the clinician. ...
Malignant melanoma is most lethal skin malignancy accounting for 4% of all cutaneous cancers. It is usually seen in sun exposed areas but can occur anywhere in the body involving mucosal surfaces and internal organs as well. Rarely cases can present with metastases as the first manifestation of the disease, sometimes with unknown primary. Dermal melanomas are rarer which characteristically show lack of epidermotropism and thus enter as a close differential of metastatic melanomas that are exclusively dermal based. Amelanotic melanomas pose diagnostic difficulty clinically as well as on histopathology as the absence of pigments may simulate soft tissue tumors. In our study, we report a case of an elderly female presenting with a mass on the leg since 1 year, which on histopathology looked like a malignant soft tissue tumor with mixed epithelioid and spindle cells but on immunohistochemistry, it turned out to be an amelanotic melanoma that was completely based in the dermis. Following this, extensive serial sectioning of the remaining tissue specimen was done and two foci of lymphovascular invasion were detected favoring a diagnosis of a metastatic melanoma rather than a dermal melanoma. No obvious primary was found even after thorough work up. We are presenting this case to throw light on the difficulties encountered by pathologists in diagnosing melanomas that show lack of melanin and epidermotropism, both are considered to be the most reliable features in clinching the diagnosis and how this tricky presentation should be worked up to render a correct report.
... The histological examination allows for a detailed evaluation of the tumor's characteristics, including its architectural features, cell type, mitotic rate, and, importantly, the Breslow depth. These factors play a significant role in determining the accurate stage of melanoma and enabling healthcare professionals to make informed decisions regarding the most appropriate treatment approach [10][11][12]. Although non-invasive imaging techniques can offer valuable insights, they are limited in determining the histological parameters necessary for accurate staging [10,11]. ...
Simple Summary
In this study, we focused on melanoma, a highly aggressive form of skin cancer with a rising global incidence. Melanoma’s staging and treatment depend on Breslow thickness, which is usually unavailable at the initial diagnosis. We aimed to compare two novel imaging techniques, optically guided high-frequency ultrasound (OG-HFUS) and multispectral imaging (MSI), to estimate Breslow thickness and improve preoperative staging. We enrolled 101 patients with confirmed primary melanoma, categorized by tumor thickness, and utilized these imaging methods. Our findings revealed that OG-HFUS was superior compared to MSI in estimating Breslow thickness, making it a valuable tool for melanoma diagnosis and patient care. This research may enhance preoperative staging and treatment decisions in the field of melanoma, offering promising implications for patient outcomes.
Abstract
Melanoma is the most aggressive form of skin cancer that is known for its metastatic potential and has an increasing incidence worldwide. Breslow thickness, which determines the staging and surgical margin of the tumor, is unavailable at initial diagnosis. Novel imaging techniques for assessing Breslow thickness lack comparative data. This study evaluates optically guided high-frequency ultrasound (OG-HFUS) and multispectral imaging (MSI) for preoperative estimation of Breslow thickness and staging. We enrolled 101 patients with histologically confirmed primary melanoma and categorized them based on tumor thickness. Optically guided 33 MHz HFUS and MSI were utilized for the assessment. Our MSI-based algorithm categorized melanomas into three subgroups with a sensitivity of 62.6%, specificity of 81.3%, and fair agreement (κ = 0.440, CI: 0.298–0.583). In contrast, OG-HFUS demonstrated a sensitivity of 91.8%, specificity of 96.0%, and almost perfect agreement (κ = 0.858, CI: 0.763–0.952). OG-HFUS performed better than MSI in estimating Breslow thickness, emphasizing its potential as a valuable tool for melanoma diagnosis and patient management. OG-HFUS holds promise for enhancing preoperative staging and treatment decision-making in melanoma.
... Early metastases are those that typically develop within 3 years after diagnosis, but late metastases can also occur, even after 10 or more years of asymptomatic disease [5]. Primary tumor thickness (using the Breslow score) and the presence or absence of ulceration are the two main histological prognostic parameters [6]. While awareness campaigns and advancements in therapy have led to improvements in melanoma survival [7], there still exist unmet medical needs. ...
The early detection of melanoma relapse can improve patient survival; thus, there is a great need for easily accessible biomarkers that facilitate the diagnosis of metastatic disease. We investigated the diagnostic effect of blood biomarkers such as lactate dehydrogenase (LDH), S100B, and osteopontin in the detection of metastases. Clinical data and peripheral blood samples of 206 melanoma patients were collected (no metastasis, N = 120; metastasis, N = 86). The discriminative power of blood biomarkers, patient demographics, and clinicopathological parameters of primary melanomas were evaluated using univariate and multivariate logistic regression models and receiver operating characteristic (ROC) analysis to determine the area under the curve (AUC). Plasma osteopontin levels showed a significant and independent effect on the probability of metastasis, similar to serum S100B levels. In addition, the location of the primary tumor on the lower extremities and the American Joint Committee on Cancer (AJCC) categories pT2b-3a, pT3b-4a, and pT4b were associated with the diagnosis of metastasis. Importantly, the combination of the three blood biomarkers and primary tumor localization and AJCC pT category yielded excellent discrimination (AUC: training set: 0.803; validation set: 0.822). In conclusion, plasma osteopontin can be classified as a melanoma biomarker; moreover, by combining clinicopathological prognostic variables, the diagnostic effect of blood biomarkers in the detection of metastatic melanoma can be improved.
Objective
Stage 3 patients with clinically positive nodal metastasis are treated with therapeutic neck dissection and adjuvant systemic therapy. The aim of our study was to examined the predictability of pre‐operative CT as a nodal drainage assessment tool.
Methods
Retrospective review of all patients with clinically positive head and neck cutaneous melanoma between 2010 and 2019. Clinical disease was diagnosed as radiological suspicious, biopsy‐proven node. A pre‐operative CT evaluation for nodal metastasis was compared to pathology report.
Results
A total of 53 patients were included. Forty patients (75.5%) were males with a mean age of 59 (SD 15.52). The majority of patients (26.4%) had an unknown primary site. The most common sites for primary were the cheek in eight patients (15.1%) followed by forehead (9.4%) and lateral neck (9.4%). Preoperative CT predicted nodal disease in 84.6% of cases. The primary region that mainly failed from the previously described clinical prediction was the upper anterior neck with 83.3% parotid involvement. A total of 10 patients (18.9%) were diagnosis with non‐clinical nodes on pathology with a median non‐clinical node of 1 (range 1–2). Of them, 9 (90%) were in the same clinical levels detected by CT. Pre‐operative CT was associated with a neck level accuracy of 98.1%.
Conclusion
Stage 3 head and neck melanoma with clinically positive nodal metastasis that are eligible for an adjuvant systemic treatment, may benefit from a highly selective neck dissection according to their pre‐operative imaging studies. This should be further evaluated in a large‐scale clinical trial.
Level of Evidence
3 Laryngoscope , 2024
Zusammenfassung
Hintergrund
Die psychosoziale Versorgung von Krebspatienten nimmt über den gesamten Verlauf der onkologischen Behandlung einen wichtigen Stellenwert ein. Seit 2015 ist das psychosoziale Screening in den Ambulanzen des Hauttumorzentrums in Freiburg implementiert. Wir präsentieren hier eine Post-hoc-Analyse im Rahmen der Qualitätssicherung.
Fragestellung
Akzeptanz, psychosoziale Belastung und Inanspruchnahme wurden evaluiert. Explorativ untersuchten wir, welche Patienten- und Krankheitsmerkmale mit einer erhöhten subjektiven Belastung zusammenhängen.
Material und Methoden
In einer Vollerhebung von 06/2015 bis 12/2015 wurden die Akzeptanz, die psychosoziale Belastung mittels Distress-Thermometer (DT) und der Beratungswunsch ausgewertet.
Ergebnisse
Von 753 Patienten haben 345 (45,8 %) am psychosozialen Screening teilgenommen und Daten von 310 (m:w 174:136; 89,7 % Melanompatienten, mittlere Zeit seit Erstdiagnose 4,7 ± 3,9 Jahre) konnten ausgewertet werden. Die mittlere Belastung auf dem DT betrug 2,97 ± 2,83 (Median 2, Range 0 bis 10). Eine überschwellige Belastung (DT ≥ 5) wurde von 84 Patienten (28,8 %) angegeben; 34 Patienten (11 %) gaben einen Beratungswunsch an, und 23 Patienten nahmen das Beratungsangebot in Anspruch. Patienten mit überschwelliger Belastung waren jünger, befanden sich häufiger unter laufender oder kürzlich abgeschlossener medikamentöser Therapie und hatten häufiger einen Beratungswunsch.
Diskussion
Neben der Erhebung der Belastung mit validierten Screeninginstrumenten stellt die Erhebung des subjektiven Betreuungswunsches einen wichtigen Parameter zur Identifikation von betreuungsbedürftigen Patienten dar. Junge Patienten und Patienten unter Systemtherapie sollten in den Fokus der Aufmerksamkeit rücken.
In 4%–11% of cases, melanoma recurrences present as in-transit (IT) metastases, and their prognosis is quite poor. Consequently, an early diagnosis and treatment of IT metastasis assume paramount significance. Despite this, the diagnosis of cutaneous IT metastases persistently presents a formidable challenge due to the diversity in clinical and dermoscopic characteristics. We provide a novel melanoma IT metastases pattern with interesting dermoscopic features and magnetic resonance imaging via presenting an unusual case characterized by diffuse subcutaneous intravascular lesions to supplement the understanding of cutaneous melanoma IT metastases.
Systemic therapy for melanoma patients has dramatically improved over the past decade. New treatment strategies have significantly ameliorated survival and prognosis of affected patients. The indication for immune directed and targeted therapies has expanded and can be considered for both very early melanoma stages as well as advanced disease. Ongoing challenges deal with reducing development of primary and secondary resistance to antitumoural drugs and identifying useful biomarkers as well as improving quality of life of affected patients. Overall, the aim to cure metastatic melanoma has become more tangible than ever before.
Terahertz (THz) imaging has long held promise for skin cancer detection but has been hampered by the lack of practical technological implementation. In this article, we introduce a technique for discriminating several skin pathologies using a coherent THz confocal system based on a THz quantum cascade laser. High resolution in vivo THz images (with diffraction limited to the order of 100 μm) of several different lesion types were acquired and compared against one another using the amplitude and phase values. Our system successfully separated pathologies using a combination of phase and amplitude information and their respective surface textures. The large scan field (50 × 40 mm) of the system allows macroscopic visualization of several skin lesions in a single frame. Utilizing THz imaging for dermatological assessment of skin lesions offers substantial additional diagnostic value for clinicians. THz images contain information complementary to the information contained in the conventional digital images.
An increase in the incidence of melanoma has been observed in recent decades, which poses a significant challenge due to its poor prognosis in the advanced and metastatic stages. Previously, chemotherapy and high doses of interleukin-2 were available treatments for melanoma; however, they offered limited survival benefits and were associated with severe toxicities. The treatment of metastatic melanoma has been transformed by new developments in immunotherapy. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligand, PDL-1, have emerged as promising therapeutic options. Commonly used ICIs, such as ipilimumab, nivolumab and pembrolizumab, have been found to be associated with an improved median overall survival, recurrence-free survival and response rates compared to traditional chemotherapies. Combination therapies involving different types of ICIs, such as anti-PD1 with anti-CTLA-4, have further enhanced the overall survival and response rates by targeting various phases of T-cell activation. Additionally, the development of novel biomarkers has facilitated the assessment of responses to ICI therapy, with tissue and serum-based prognostic and predictive biomarkers now available. The increased response observed with ICIs also provides potential for immune-related adverse effects on various organ systems. Further research is required to evaluate the efficacy and safety of various combinations of ICIs, while ongoing clinical trials explore the potential of newer ICIs. Concerns regarding the development of resistance to ICIs also warrant attention. The present review summarizes and discusses the advent of ICIs with a marked significant breakthrough in the treatment of metastatic mela-noma, providing improved outcomes compared to traditional therapies.
Skin diseases have a widespread impact on people’s lives, making their identification crucial in medical data analysis. Convolutional neural networks (CNNs) are widely used for skin disease recognition, yielding success. However, the current research overlooks the crucial issue of compressing label-independent information. Key information in skin disease images exists in small symptomatic patches, while the rest is extraneous. Regrettably, prevailing CNNs-based methods embed redundancy in skin disease features across convolutional layers, reducing accuracy. This paper introduces an Information Bottleneck theory-based algorithm for selective information propagation. The Hilbert-Schmidt independence criterion (HSIC) is used to calculate the dependency between variables in the algorithm. This algorithm enhances the independence of CNN’s convolutional layers and the input features of the skin disease image during training while improving the dependence of convolutional layers and the label value of the image. This confines superfluous data spread and boosts vital information propagation. Experiments conducted on both a self-collected hypopigmentation dataset and the publicly available ISIC2018 dataset, utilizing ResNet-50, DenseNet-169, Inception-v4, and ConvNeXt-B, confirm the effectiveness of the algorithm. The experimental results demonstrate significant enhancements in accuracy following the application of the algorithm. These four CNNs achieve accuracy improvements of 2.68%, 7.63%, 4.20%, and 3.44% on hypopigmentation dataset, and 0.86%, 0.33%, 2.84%, and 1.19% on ISIC2018 dataset. Thus, this algorithm effectively compresses label-independent information, enhancing skin disease recognition.
Background
We aimed to develop tools that could predict the occurrence of distant metastases in melanoma and its prognosis based on clinical and pathological characteristics.
Materials and methods
We obtained data from the Surveillance, Epidemiology, and End Results (SEER) database of melanoma patients diagnosed between 2010 and 2019. Logistic analyses were performed to identify independent risk factors associated with distant metastasis. Additionally, multivariate Cox analyses were conducted to determine independent prognostic factors for patients with distant metastasis. Two nomograms were established and evaluated with the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Furthermore, we performed a retrospective analysis of melanoma with distant metastasis from our institute between March 2018 and June 2022.
Results
Of the total 19 396 melanoma patients, 352 (1.8%) had distant metastases at the time of diagnosis. The following clinical and pathological characteristics were identified as independent risk factors for distant metastasis in melanoma: N stage, tumor size, ulceration, mitosis, primary tumor site, and pathological subtype. Furthermore, tumor size, pathological subtype, and radiotherapy were identified as independent prognostic factors. The results of the training and validation cohorts’ ROC curves, calibration, DCA, and Kaplan–Meier survival curves demonstrate the effectiveness of the two nomograms. The retrospective study results from our center supported the results from the SEER database.
Conclusion
The clinical and pathological characteristics of melanoma can predict a patient’s risk of metastasis and prognosis, and the two nomograms are expected to be effective tools to guide therapy decisions.
Invasive melanoma accounts for only 1% of skin cancer diagnosed but causes most fatalities. It is the most prevalent malignancy diagnosed in the United States. Scientific databases like Pubmed, ScienceDirect, Scopus, and Google Scholar were used to retrieve information on the cytotoxic activity of botanicals and phytochemicals from the flora of Africa toward drug-sensitive and multidrug-resistant (MDR) melanoma cancer cells. This information was further compiled. As a result, botanicals from Piper capense and Callicarpa longissimi as well as 8,8-bis-(dihydroconiferyl)-diferulate (1), licarin A (2), and soyauxinium chloride (3) were the more suitable samples that could be helpful to combat the multidrug resistance of melanoma cell lines. Extensive preclinical and clinical studies on these natural products are required, to develop novel anti-melanoma drugs.
Background
Cutaneous melanoma is characterized by a high risk of metastasis to distant organs and a substantial mortality rate. For planning treatment and assessing outcomes, the Breslow micrometric measurement is critical. The tumor macroscopic dimension is not considered a prognostic parameter in cutaneous melanoma, although there are studies showing that tumor size is an independent prognostic factor for melanoma‐specific survival. Therefore, this study aimed to evaluate the macroscopic dimension of melanoma and other known prognostic factors (i.e., Breslow index, mitoses, regression, and ulceration) as predictors of sentinel lymph node outcome and survival outcome.
Methods
We performed a retrospective cross‐sectional study of 227 melanoma lesions subjected to sentinel lymph node biopsy at two Brazilian referral centers.
Results
On univariate analysis, there was a statistically significant correlation between the largest macroscopic tumor dimension and the sentinel lymph node result ( P = 0.001); however, on multivariate analysis considering all evaluated parameters, there was no significant difference between the sentinel lymph node result and the tumor macroscopic dimension ( P = 0.2689). Regarding melanoma‐specific survival, the macroscopic dimension showed no significant correlation ( P = 0.4632) in contrast to Breslow's dimension ( P < 0.0001).
Conclusion
The Breslow thickness was the only significant factor related to both the sentinel lymph node outcome and melanoma specific survival among the evaluated variables.
Background:
Malignant melanoma (MM) is a highly aggressive form of skin cancer whose incidence continues to rise worldwide. If diagnosed at an early stage of disease, it has an excellent prognosis, but the mortality increases significantly at advanced stages after distant spread. Unfortunately, early detection of aggressive melanoma remains a challenge to improve patient survival.
Objectives:
To identify novel blood-circulating biomarkers that may be useful for the diagnosis of MM to guide patient counselling and appropriate disease management.
Methods:
In this study, a total of 105 serum samples from 26 healthy patients (HC) and 79 MM patients (MMP) were analysed using an untargeted approach by liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) to compare the metabolomic profile of both conditions. Resulting data were subjected to both univariate (UVA) and multivariate (MVA) statistical analysis to select robust biomarkers. The classification model obtained from this analysis was further validated with an independent cohort of 12 stage I MMP.
Results:
The study successfully identified several lipidic metabolites differentially expressed in Stage I MM patients in comparison to HC. Three of these metabolites were utilized to develop a classification model, which exhibited exceptional precision (0.92) and accuracy (0.94) when validated on an independent sample.
Conclusions:
These results demonstrate that metabolomics using LC-HRMS is a powerful tool to identify and quantify metabolites in body fluids that could serve as potential early diagnostic markers for MM.
A multifactorial analysis of 200 cutaneous melanoma patients with distant metastasis (stage III) was performed on 13 clinical and pathological factors using the Cox regression analysis. There were only three dominant prognostic variables that independently predicted the patient's clinical course: (1) number of metastatic sites (1 vs. 2 vs. greater than or equal to 3, p less than 0.00001), (2) remission duration (less than 12 mo vs. greater than or equal to 12 mo, p = 0.0186), and (3) the location of the metastases (visceral vs. nonvisceral vs. combined, p = 0.0192). Factors that were not significant in the multifactorial analysis included the patients' age and sex, the site of the primary melanoma, the sequence of metastases, and all histopathological features of the primary melanoma (thickness, level of invasion, ulceration, growth pattern, pigmentation, and lymphocyte infiltration). For a single metastatic site, the 1-yr survival rate was 36%, while it was only 13% for 2 sites, and 0% for greater than or equal to 3 sites (p less than 0.00001). The 1-yr survival for patients was 40% for nonvisceral sites (skin, subcutaneous, distant lymph nodes) compared to only 11% for visceral metastases and 8% for combined sites (p less than 0.00001). Pulmonary metastases were associated with a significantly higher survival rate than metastatic melanoma in any other visceral site. The most common first site of distant metastases (either alone or in combination) was skin (38%), lung (36%), liver (20%), and brain (20%). The skin, subcutaneous and distant lymph node group was the first site of metastases in 59% of patients. This finding emphasizes the importance of careful physical exams in routine metastatic evaluations. Only a minority (25%) of stage I patients progressed to stage III disease after a median interval of 2.8 years. In contrast, the majority (75%) of melanoma patients with nodal metastases (stage II) progressed to stage III disease after a median duration of only 11 mo. Of the patients who eventually developed stage III disease, 95% of those who initially presented with stage II disease progressed within 3 yr, while stage I patients who progressed to stage III did not reach a 95% cumulative incidence until 8 yr.
We report the experience of the World Health Organization (WHO) Melanoma Program concerning sentinel lymph node (SLN) biopsy for detecting patients with occult regional nodal metastases to submit to selective regional node dissection.
From February 1994 to August 1998, in 12 centers of the WHO Melanoma Program, 892 SLN biopsies were performed in 829 patients with clinical stage I melanoma (male: 370; female: 459; median age: 50 years old). The location of the primary melanoma was as follows: trunk 35%; lower limbs, 45%; upper limbs, 18%; and head and neck, 2%. Blue dye injection for SLN identification was performed in all cases; preoperative lymphoscintigraphy was done in 440 patients, and an intra-operative probe for a radio-guided biopsy was used in 141 cases. Overall, the SLN identification rate was 88%. In 68% of the patients, only one SLN was identified, whereas two and three or more SLN were detected in 24% and 8% of the remaining cases, respectively.
Overall SLN positivity rate was 18%. Intra-operative frozen section examination was performed in 39% of the cases and was helpful in detecting occult localizations only in 47% of the positive SLNs. Distribution of positive cases by primary thickness was as follows: < 1mm: 2%; 1-1.99 mm: 7%; 2-2.99 mm: 13%; and > or = 3 mm: 31%. Positive nonsentinel lymph nodes were found in 22% of cases with positive SLN submitted for selective dissection. No complications due to the procedure were registered. Of 710 patients who were evaluated, 40 (6%) presented a regional nodal relapse after a negative SLN biopsy and underwent a delayed therapeutic dissection. From the 710 enrolled cases, 638 (88.5%) were alive without evidence of disease at the time of this writing. A multivariate analysis showed SLN status as one of the most significant prognostic factors (P = .000) along with thickness (P = .001) and ulceration (P = .015) of primary tumor.
These data confirm the feasibility and safety of the SLN technique for selecting patients to submit to a radical node dissection. The data represent the basis for a future trial by the WHO Melanoma Program in this field to evaluate the most appropriate surgical approach for treating patients with occult regional nodal metastases.
To evaluate the prognostic significance of sentinel node biopsy in the management of stage IB and II melanoma patients, and to evaluate the status of nonsentinel nodes as a "second step key factor" to assess the prognosis of these patients.
We conducted an analysis of data collected in a prospective database.
From February 1994 to June 2005, 1,108 consecutive patients with stage IB and II melanoma were submitted to sentinel node biopsy; 176 patients (15.9%) had occult node metastases. The frequency of positive nodes increased with increasing Breslow's thickness. The largest diameter of metastatic foci and their localization within the lymph node were associated with the risk of nonsentinel node metastases only. The 5-year survival of patients with positive sentinel nodes was 81.4% in patients with one positive node and 39.6% in patients with two positive nodes (P = .056). Multivariate analysis indicated that status of sentinel nodes is a key factor and that sex and Breslow's thickness maintain statistically significant relevance. Ulceration, which was associated with survival when considered as single factor (P < .001) had no impact on survival in the multivariate analysis (P = .10). To evaluate the relevance of metastases to nonsentinel nodes, we identified four groups of patients.
Evaluation of the sentinel node is a useful procedure to identify patients to be submitted for complete lymph node dissection. The procedure makes it possible to assess the best prognosis of patients.
In this issue of the Journal, Morton and colleagues report the largest and most important trial of sentinel-lymph-node biopsy for melanoma conducted to date.1 In the trial, 1269 patients with intermediate-thickness (1.2 to 3.5 mm) melanoma were randomly assigned to immediate sentinel-node biopsy or to observation for clinically detectable (palpable) lymph nodes draining the site of the melanoma. If the biopsy showed microscopical metastases, patients underwent immediate radical lymphadenectomy. In the observation group, lymphadenectomy was performed only after palpable lymph nodes were detected. The trial clearly demonstrates that sentinel-node biopsy provides important prognostic information and identifies patients with nodal metastases . . .
Most patients with melanoma have microscopically thin (< or = 1 mm) primary lesions and are cured with excision. However, some develop metastatic disease that is often fatal. We evaluated established prognostic factors to develop classification schemes with better discrimination than current American Joint Committee on Cancer (AJCC) staging.
We studied patients with thin melanomas from the US population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry (1988 to 2001; n = 26,291) and those seen by the University of Pennsylvania's Pigmented Lesion Group (PLG; 1972 to 2001; n = 2,389; Philadelphia, PA). AJCC prognostic factors were thickness, anatomic level, ulceration, site, sex, and age; PLG prognostic factors also included a set of biologically based candidate prognostic factors. Recursive partitioning was used to develop a SEER-based classification tree that was validated using PLG data. Next, a new PLG-based classification tree was developed using the expanded set of prognostic factors.
The SEER-based classification tree identified additional criteria to explain survival heterogeneity among patients with thin, nonulcerated lesions; 10-year survival rates ranged from 89.1% to 99%. The new PLG-based tree identified groups using level, tumor cell mitotic rate, and sex. With survival rates from 83.4% to 100%, it had better discrimination.
Prognostication and related clinical decision making in the majority of patients with melanoma can be improved now using the validated, SEER-based classification. Tumor cell mitotic rate should be incorporated into the next iteration of AJCC staging.
PURPOSE: To identify factors that are prognostic for survival in patients with metastatic melanoma treated in eight Eastern Cooperative Oncology Group (ECOG) trials conducted over the past 25 years.
METHODS: We identified common, significant patient characteristics collected at baseline on 1,362 eligible patients for inclusion in a pooled analysis. Proportional hazards models were used to examine simultaneously the effects of multiple covariates on survival.
RESULTS: Median survival was 6.4 months (95% confidence interval, 6.1 to 6.9 months.) Factors conferring the greatest increased risk of death included number of metastatic sites (relative risk [RR] = 1.12), ECOG performance status of 1 or more (RR = 1.49), or metastatic disease in the gastrointestinal (GI) tract (RR = 1.49), liver (RR = 1.44), pleura (RR = 1.35), or lung (RR = 1.19). Prior immunotherapy (RR = 0.84) and female sex (RR = 0.87) were associated with prolonged survival. Although only 12% of patients responded to protocol treatment, landmark analysis showed this to be a significant prognostic factor (RR = 0.57). A model based on three recent studies in which baseline values for alkaline phosphatase, lactate dehydrogenase (LDH), and platelets were available identified an increased number of sites of metastasis (RR = 1.30), abnormal LDH (RR = 1.89), abnormal alkaline phosphatase (RR = 1.76), abnormal platelets (RR = 1.63), and GI metastases (RR = 1.66) as prognostic for poorer survival. Response to treatment, when examined by landmark analysis of studies with laboratory parameters, was associated with decreased risk of death (RR = 0.47).
CONCLUSION: This study demonstrates the importance and utility of laboratory parameters as prognostic factors for survival and confirmed the deleterious effects of multiple metastatic sites. Prior immunotherapy and female sex were associated with improved prognosis. Prognostic factors identified in this analysis are consistent with the findings of prior published studies and argue for the adoption of laboratory findings in the staging systems that are used for entry and stratification of clinical trials in the future.
PURPOSE: To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma.
PATIENTS AND METHODS: We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival.
RESULTS: In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients.
CONCLUSION: Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.
Background: Elective lymph node dissection ELND may contribute to a survival benefit in certain stratified subsets of melanoma patients. We hypothesized that lymphatic mapping and sentinel lymph node SLN biopsy with complete node dissection if metastases are present may improve both staging and survival of patients with clinically negative nodes, without subjecting all patients to the morbidity associated with complete ELND.
The aim of this study was to define prognostic factors for survival, and especially for long-term survival in a mature data-set of patients with stage IV melanoma treated within a randomised trial of cytokine-based protocols. Long-term follow-up data on patients enrolled into a European Organization for Research and Treatment of Cancer (EORTC) trial comparing interferon-α (IFNα) plus interleukin-2 (IL-2) with or without cisplatin were collected. Univariate and multivariate Cox regression analyses wereperformed to define prognostic factors for survival. The characteristics of patients alive at 2 and 5 years after randomisation were compared with the entire cohort using the χ2 test. The minimum potential follow-up of the 131 evaluable patients was 5 years. 18 patients (14%) were alive 2 years after randomisation, and 11 (8%) 5 years after randomisation. Pretreatment performance status (PS), serum lactate dehydrogenase (LDH) and tumour mass were significant predictors for survival, whereas site of metastases and number of sites were non-significant. PS and LDH were the only independent prognostic factors. All except 1 patient alive at 2 and 5 years had a pretreatment PS of 100%, and only three long-term survivors had elevated pretreatment LDH. There was no association between the site of metastases and long-term survival. Response to treatment was a major predictor for long-term survival, whereas addition of cisplatin did not impact upon overall survival probability or on long-term survival. The probability of long-term survival in stage IV melanoma patients after IL-2-based treatments is governed by pretreatment PS, serum LDH and response to treatment. Site of metastases, the basis for the M-subcategories of the new AJCC staging system, was not informative in this study.
An international panel was convened by the organizing committee of the International Sentinel Node (SN) Society (ISNS) at their meeting in Sydney, Australia, on February 21, 2008, to address questions about SN biopsy (SNB) for melanoma. The panelists subsequently wrote this consensus statement, based on their interpretation of current evidence, as a guide to clinical treatment of patients with clinically localized melanoma. The panel comprised a cross section of expert melanoma surgeons who have contributed data and leadership to investigations of SNB.
Microscopic satellitosis in melanoma is uncommon. The role of regional basin staging/therapy in patients with this high-risk feature has not been well defined.
Patients presenting from 1996 to 2005 with clinically localized melanoma containing microscopic satellitosis were identified from a prospective, single-institution database. Multiple factors were analyzed to determine their predictive value for recurrence. The management of the draining nodal basin was evaluated to determine its impact on recurrence and survival.
Thirty-eight patients presented to our institution during this time period with clinically localized melanoma containing microscopic satellitosis. The 5-year overall and disease-free survivals in these patients were 34% and 18%, respectively. Sixty-eight percent had pathologically involved regional nodal metastases. With median follow-up of 21 months, 68% recurred, with a median time to recurrence of 9 months. Lymphovascular invasion (LVI) (p = 0.01), tumor regression (p = 0.04), and positive regional lymph nodes (p = 0.02) were associated with an increased risk of recurrence. Of the 31 patients who underwent sentinel lymph node (SLN) biopsy, 22 had metastasis in the SLN (71%). Fifteen of these patients underwent completion lymphadenectomy (CLND) and seven were observed. There was no difference in disease-free survival (DFS), disease-specific survival (DSS), or overall survival (OS) between these groups (p = 0.42).
Pathological lymph node metastases were more prevalent (68%) than in any group previously defined. Regional nodal status predicted recurrence but not nodal recurrence. In SLN-positive patients, CLND did not improve DFS, DSS, or OS, although the number of patients was small. Further studies are needed to determine the utility of regional nodal staging/therapy in these high-risk patients.
Although over 7,000 people die from malignant melanoma each year, there are limited prognostic data for patients with metastatic disease. A retrospective analysis was undertaken to identify variables that accurately predict outcome and to determine if the survival rate of patients with melanoma treated for distant metastases (American Joint Committee on Cancer [AJCC] stage IV disease) at the authors' institution changed between 1971 and 1993.
Data for 1,521 patients with AJCC stage IV melanoma treated by the staff of the John Wayne Cancer Institute were reviewed, and a univariate and multivariate survival analysis against ten clinical and pathological variables was performed using the Cox proportional hazard regression model.
The median survival time of the 1,521 patients was 7.5 months; the estimated five-year survival rate was 6 percent. Three independent variables predicted survival: initial site of metastases (p < 0.0001); disease-free interval before distant metastases (p = 0.0001); and stage of disease preceding distant metastases (p = 0.0001). Patients could be divided into three distinct prognostic groups based on the initial site of metastases: cutaneous, nodal, or gastrointestinal metastases (median survival of 12.5 months; estimated five-year survival rate 14 percent); pulmonary metastases (median survival of 8.3 months; estimated five-year survival rate 4 percent); and metastases to the liver, brain, or bone (median survival of 4.4 months; estimated five-year survival rate 3 percent). There was no significant change in the survival rate of patients with AJCC stage IV melanoma during the 22-year review period.
Despite new treatment options, the survival rate of patients with metastatic melanoma has not changed significantly over the last 22 years; their prognosis remains dismal. The three prognostic variables identified in this study should be considered in the design of future clinical trials.
To critically review the accuracy of the current American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma and propose a more useful staging system.
Retrospective evaluation of the published data as well as a reanalysis of the University of Alabama and Sydney Melanoma Unit (UAB/SMU) data bases (n = 4,568) for patients with primary melanoma was performed to examine specifically the impact of level of invasion and ulceration on the prognostic value of tumor thickness. In addition, an overlay graphic technique was used to compare the Kaplan-Meier survival curves of patients with local recurrences, satellites, in-transit metastases, and nodal metastases reported in the literature.
Tumor thickness and ulceration remained the most powerful prognostic indicators in patients with stage I and II disease. Level of invasion provided statistically significant prognostic information only in the subgroup of patients with tumor thickness < or = 1 mm, but the absolute 10-year survival differences were small and inconsistent (level II, 95%; level III, 85%; level IV, 89%). The best statistical fit for tumor thickness cutoffs was at 1 versus 2 versus 4 mm. The overlay graphic technique showed that patients who developed satellite lesions or local recurrence had prognoses similar to those of patients with stage III disease. The most important prognostic factor for patients with nodal metastases was number of involved nodes rather than size.
Our analysis showed that the current AJCC staging system has many inaccuracies that should be modified to conform to published data. On the basis of our analysis and review of the literature, we propose a new and more accurate staging system.
To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma.
We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival.
In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients.
Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.
The Melanoma Staging Committee of the AJCC has proposed major revisions of the melanoma TNM and stage grouping criteria. The committee members represent most of the major cooperative groups and cancer centers worldwide with a special interest in melanoma; the committee also collectively has had clinical experience with over 40,000 patients. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion, to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 4) an upstaging of all patients with Stage I,II, and III disease when a primary melanoma is ulcerated; 5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into Stage III disease; and 6) a new convention for defining clinical and pathologic staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. The AJC Melanoma Staging Committee invites comments and suggestions regarding this proposed staging system before a final recommendation is made.
Historically, patients with thick (> or =4 mm) primary melanoma have not been considered candidates for elective lymph node dissection, because their risk for occult distant disease is significant. Sentinel lymph node (SLN) biopsy offers an alternative approach to assess disease in the regional nodal basin, but no studies have specifically addressed the role for this technique in patients with thick melanoma. Although adjuvant therapy benefits patients who develop nodal metastases, data that supports its routine use in all patients with thick melanoma is both limited and controversial. This study was performed to determine whether pathological status of the SLN is an important risk factor in this heterogeneous group and, thus, provides a rationale for SLN biopsy.
The records of 131 patients with primary cutaneous melanoma whose primary tumors were at least 4 mm thick and who underwent lymphatic mapping and SLN biopsy were reviewed. Several known prognostic factors, i.e., tumor thickness, ulceration, Clark level, location, sex, as well as SLN pathological status were analyzed with respect to disease-free and overall survival.
Lymphatic mapping and SLN biopsy was successful in 126 (96%) of 131 patients who underwent the procedure. In 49 patients (39%), the SLN biopsy was positive by conventional histology, although it was negative in 77 patients (61%). The median follow-up was 3 years. Although presence of ulceration and SLN status were independent prognostic factors with respect to disease-free and overall survival, SLN status was the most powerful predictor of overall survival by univariate and multivariate analyses.
Lymphatic mapping and SLN biopsy is a highly accurate method of staging lymph node basins at risk for regional metastases in patients with thick melanoma and identifies those patients who may benefit from earlier lymphadenectomy as well as patients with a more favorable prognosis. Pathological status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for survival and is essential to establish stratification criteria for future adjuvant trials in this high-risk group.
To identify factors that are prognostic for survival in patients with metastatic melanoma treated in eight Eastern Cooperative Oncology Group (ECOG) trials conducted over the past 25 years.
We identified common, significant patient characteristics collected at baseline on 1,362 eligible patients for inclusion in a pooled analysis. Proportional hazards models were used to examine simultaneously the effects of multiple covariates on survival.
Median survival was 6.4 months (95% confidence interval, 6.1 to 6.9 months.) Factors conferring the greatest increased risk of death included number of metastatic sites (relative risk [RR] = 1.12), ECOG performance status of 1 or more (RR = 1.49), or metastatic disease in the gastrointestinal (GI) tract (RR = 1.49), liver (RR = 1.44), pleura (RR = 1.35), or lung (RR = 1.19). Prior immunotherapy (RR = 0.84) and female sex (RR = 0. 87) were associated with prolonged survival. Although only 12% of patients responded to protocol treatment, landmark analysis showed this to be a significant prognostic factor (RR = 0.57). A model based on three recent studies in which baseline values for alkaline phosphatase, lactate dehydrogenase (LDH), and platelets were available identified an increased number of sites of metastasis (RR = 1.30), abnormal LDH (RR = 1.89), abnormal alkaline phosphatase (RR = 1.76), abnormal platelets (RR = 1.63), and GI metastases (RR = 1. 66) as prognostic for poorer survival. Response to treatment, when examined by landmark analysis of studies with laboratory parameters, was associated with decreased risk of death (RR = 0.47).
This study demonstrates the importance and utility of laboratory parameters as prognostic factors for survival and confirmed the deleterious effects of multiple metastatic sites. Prior immunotherapy and female sex were associated with improved prognosis. Prognostic factors identified in this analysis are consistent with the findings of prior published studies and argue for the adoption of laboratory findings in the staging systems that are used for entry and stratification of clinical trials in the future.
To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC).
The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system.
Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.
This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.
The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal.
There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients.
This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients.
The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.
Elective lymph node dissection (ELND) may contribute to a survival benefit in certain stratified subsets of melanoma patients. We hypothesized that lymphatic mapping and sentinel lymph node (SLN) biopsy (with complete node dissection if metastases are present) may improve both staging and survival of patients with clinically negative nodes, without subjecting all patients to the morbidity associated with complete ELND.
We reviewed the data for all 14,914 N0 patients of the AJCC Melanoma Staging Database to determine the effect of SLN biopsy and ELND on staging and survival.
Retrospective analysis revealed that there was an apparent statistically significant survival advantage to SLN biopsy in patients with melanomas > 1 mm (n = 9024; 68.5% and 26.2% reduction in mortality compared with patients staged to be N0 by clinical exam and ELND, respectively; P < .0001). Five-year survivals were 90.5%, 77.7%, and 69.8%, respectfully, for patients staged by SLN biopsy (n = 2552), ELND (n = 2014), and clinical examination alone (n = 5192). The survival advantage of SLN biopsy was statistically significant for each T-stage category (T2, T3, and T4) and ulceration status. There was no advantage to SLN biopsy in patients with melanomas <1 mm (n = 5890).
SLN biopsy provides more accurate staging and may contribute to a survival benefit in populations of patients with melanoma.
To correlate the presence of extracapsular spread (ECS) of regional nodal metastases, and micrometastasis near the primary tumor, with disease outcome in the intergroup study E1690 in relation to the impact of recombinant interferon-alfa (rIFN alpha)-2b.
E1690 included 642 patients with American Joint Committee on Cancer stage IIB or III cutaneous melanoma. Patients were randomized into high- and low-dose rIFN alpha-2b treatment arms and an observation arm. Pathologic slides were reviewed for selected parameters from at least half of the subjects in all three arms. Evaluation of the primary tumor included notations regarding ulceration, mitotic activity, thickness, microscopic satellites (MS), and nodal ECS on a standardized pathology form. These data were collated in relation to relapse-free survival (RFS) and overall survival (OS) at 50 months' follow-up and studied using Cox regression analysis.
Ulceration, mitotic activity, thickness, and size of tumor-bearing lymph nodes did not show a statistically significant correlation with either OS or RFS across all treatment arms. The presence of MS was correlated with RFS (P =.0008) and OS (P =.05). ECS correlated with RFS (hazard ratio = 1.44, P =.032) but not OS (P =.11).
The presence of MS (in 6% [18 of 308 patients]) had a significant adverse impact on both RFS (P =.0008) and OS (P =.053). Ulceration, mitotic activity, thickness, and number of positive lymph nodes had no significant effect on OS in this subset study (univariate or multivariate Cox analysis). The presence of ECS in lymph nodes had a significant adverse effect on RFS (P =.032) but not on OS.
The aim of this study was to define prognostic factors for survival, and especially for long-term survival in a mature data-set of patients with stage IV melanoma treated within a randomised trial of cytokine-based protocols. Long-term follow-up data on patients enrolled into a European Organization for Research and Treatment of Cancer (EORTC) trial comparing interferon-alpha (IFNalpha) plus interleukin-2 (IL-2) with or without cisplatin were collected. Univariate and multivariate Cox regression analyses were performed to define prognostic factors for survival. The characteristics of patients alive at 2 and 5 years after randomisation were compared with the entire cohort using the chi(2) test. The minimum potential follow-up of the 131 evaluable patients was 5 years. 18 patients (14%) were alive 2 years after randomisation, and 11 (8%) 5 years after randomisation. Pretreatment performance status (PS), serum lactate dehydrogenase (LDH) and tumour mass were significant predictors for survival, whereas site of metastases and number of sites were non-significant. PS and LDH were the only independent prognostic factors. All except 1 patient alive at 2 and 5 years had a pretreatment PS of 100%, and only three long-term survivors had elevated pretreatment LDH. There was no association between the site of metastases and long-term survival. Response to treatment was a major predictor for long-term survival, whereas addition of cisplatin did not impact upon overall survival probability or on long-term survival. The probability of long-term survival in stage IV melanoma patients after IL-2-based treatments is governed by pretreatment PS, serum LDH and response to treatment. Site of metastases, the basis for the M-subcategories of the new AJCC staging system, was not informative in this study.
The overall prognosis of patients with thick cutaneous melanoma (TCM) is generally thought to be poor. Surgically staging these patients with sentinel lymph node (SLN) biopsy remains controversial. This study was performed to determine whether SLN status improved our ability to predict outcome over other known prognostic factors and to develop a model incorporating independent prognostic factors to estimate the risk of recurrence for an individual patient.
A prospective database identified patients with TCM (>4.0 mm or Clark level V) and clinically negative nodes who underwent SLN biopsy. Univariate and multivariate analyses were performed.
From 1991 to 2001, 126 patients were identified; 75 (60%) were male. The median age was 60 years. The median tumor thickness was 5.5 mm, and 43% were ulcerated. Thirty percent of patients had a positive SLN. Recurrence was seen in 50 patients (40%). Median follow-up, relapse-free survival, and overall survival were 25, 50, and 68 months, respectively. Factors independently predictive of recurrence were age >/=60 years, depth >5.5 mm, ulceration, and SLN positivity. SLN status was the most significant prognostic factor (P <.001). The relative risk of recurrence for an individual patient ranged from 1 in patients for whom no adverse factors were present to 29.4 when all factors were present.
SLN status was the strongest independent predictor of outcome in patients with TCM. However, patients with TCM are prognostically heterogeneous, and all independently predictive factors should be considered when an individual patient's risk of recurrence is assessed.
Thick (>or=4-mm) primary melanomas are believed to be associated with a high incidence of occult distant metastases. The use of sentinel lymph node (SLN) mapping and biopsy in the treatment lesions has been questioned.
A retrospective review of a computerized database identified 114 patients who underwent successful SLN mapping and biopsy from January 1, 1994, to December 31, 1999. Records were reviewed for clinicopathologic features of the patients and their tumors. Survival curves were constructed from Kaplan-Meier estimates and analyzed with log-rank tests and Cox proportional hazards modeling.
There were 75 men and 39 women with a mean age of 57 years (range, 24-85 years). The primary tumor sites were head and neck (n = 29; 25.4%), trunk (n = 44; 38.6%), and extremities (n = 41; 36%). Tumor thickness ranged from 4 to 17 mm (median, 5.2 mm; mean, 6.3 mm). Ulceration was present in 40 (35.1%) tumors. Thirty-seven patients (32.5%) had a positive SLN biopsy, and 18 of these patients (48.6%) had a single tumor-positive lymph node after dissection. The mean follow-up was 37.8 months. The overall 3-year survival for SLN-negative patients was 82%, versus 57% for SLN-positive patients (P =.006). Lymph node status and tumor ulceration were independent predictors of overall survival in multivariate Cox regression analysis.
The pathologic status of the SLN in patients with thick melanomas is a strong independent prognostic factor for survival, and SLN mapping should be routinely performed.
The late Dr. Vincent McGovern (1915 to 1983) was an international authority on melanoma pathology and one of the first to suggest that assessment of tumor mitotic rate (TMR) might provide useful prognostic information. Data for a large cohort of patients, now with extended follow-up, whose tumors had been assessed by Dr. McGovern were analyzed to reassess the independent prognostic value of TMR in primary localized, cutaneous melanoma.
Information was extracted from the Sydney Melanoma Unit database for 1317 patients treated between 1957 and 1982 for whom there was complete clinical information and whose primary lesion pathology, which included tumor thickness, ulcerative state, and TMR, had been assessed by Dr. McGovern. All these assessments were made according to the recommendations of the Eighth International Pigment Cell Conference, held in Sydney in 1972 under the auspices of the International Union Against Cancer. Factors predicting melanoma-specific survival were analyzed with the Cox proportional hazards regression model.
Stage, according to the recently revised American Joint Committee on Cancer Staging System (which is based on tumor thickness and ulceration) was the most predictive factor for survival (P<.0001). This was followed by primary lesion site (P<.0001), patient age (P=.0005), and TMR (P=.008).
TMR was confirmed to be an important independent predictor of survival of patients with primary cutaneous melanoma. However, its predictive value was less than it was when assessed according to the 1982 revisions of the 1972 TMR recommendations.
Lymphatic mapping and sentinel lymph node (SLN) biopsy are widely used as a staging technique for patients with cutaneous malignant melanoma who are at risk for metastases. SLN status has been shown to be a strong predictor of prognosis, and a variety of techniques have been used to identify minimal metastatic disease in SLNs. However, there is no validated consensus method for the optimal histologic analysis of SLNs harvested from melanoma patients. This study was conducted: 1) to assess the yield of metastatic melanoma detected in SLNs deemed negative by initial routine pathologic analysis (RPA) by subjecting them (after review of the original slides) to enhanced pathologic analysis (EPA) that included complete step-sectioning and immunohistochemistry (IHC); 2) to characterize the distribution of metastatic melanoma deposits within the SLNs; 3) to determine a preferred method of pathologic analysis applicable to daily practice; and 4) to attempt to assess the clinical significance of disease detected by EPA. A total of 105 SLNs were harvested from 49 patients who underwent successful SLN biopsy procedures during the period of study. Ten SLNs from 10 patients were positive on initial RPA and were not analyzed further. Ninety-five SLNs from the remaining 39 patients were reviewed and processed with additional hematoxylin and eosin, S-100 protein, and HMB-45 stains at 50-microm intervals for 20 levels or until the SLN tissue was exhausted. A single pathologist reviewed all sections without knowledge of the results of the other stains. Overall, metastatic melanoma was discovered in SLNs from 20 of the 39 patients: SLNs from 6 patients were found to have melanoma on review of the original hematoxylin and eosin slides, and SLNs from 14 patients were positive only after EPA. Twenty-one individual positive SLNs from these 14 patients were detected by EPA; of these, 10 positive SLNs were identified solely by IHC, representing 12% of the patient cohort and 10% of all SLNs studied by EPA. Detection rates were significantly associated with the staining method and the number of levels performed (P < 0.01). S-100 protein staining resulted in the highest yield of SLN positivity (86%), followed by HMB-45 (81%) and hematoxylin and eosin (52%). No single method detected all of the micrometastases. A detailed topographic mapping of metastatic deposits in SLNs was carried out. When using all three staining techniques, all 20 levels were required to identify 100% of the micrometastases; 95% of positive SLNs were identified with 17 levels, 90% with 15 levels, 75% with 10 levels, and 42% with 3 levels. Projected rates of detection for various different sectioning strategies were determined, with alteration of either the number of levels examined, the interval between the levels, or both. Detection of SLN positivity can be increased to 71% by performing three levels at 250-mum intervals, each level being composed of a set of three sections stained with hematoxylin and eosin, S-100 protein, and HMB-45, respectively. Therefore, this is the methodology we propose for the study of SLNs in melanoma patients. After a median follow-up of 87 months (range, 9-134 months), patients with EPA-detected disease and those with negative SLNs by EPA demonstrated improved recurrence-free and disease-specific survival compared with patients with RPA-detected disease in SLNs. Sampling error introduced by variations in pathologic processing should be addressed by standardization of pathologic methods, and the clinical significance of minimal SLN disease should be addressed in prospective studies of homogeneously staged patients.
Lymphatic mapping and sentinel lymphadenectomy (LM/SL) provide important prognostic information for patients with early-stage melanoma. Although the use of this technique in patients with thin melanomas (< or =1.00 mm) is not routine, risk factors that may predict sentinel lymph node (SLN) positivity in this patient population are under investigation. We sought to determine whether mitotic rate (MR) is associated with SLN positivity in thin-melanoma patients and, therefore, whether it may be used to risk-stratify and select patients for LM/SL.
Clinical and histopathologic variables were reviewed for 181 patients with thin melanomas who underwent LM/SL from January 1996 through January 2004. Univariate and multivariate logistic regression analyses were performed to identify factors associated with SLN positivity. Risk groups were defined on the basis of the development of a classification tree.
The overall SLN positivity rate was 5%. All patients with positive SLNs had an MR of >0. By univariate analysis, MR and thickness were significant predictors of SLN positivity. The association between MR and SLN positivity remained significant controlling for each of the other variables evaluated. On the basis of a classification tree, patients with an MR >0 and tumor thickness > or =.76 mm were identified as a higher-risk group, with an SLN positivity rate of 12.3%.
In patients with thin melanomas, MR >0 seems to be a significant predictor of SLN positivity that may be used to risk-stratify and select patients for LM/SL. To confirm these results, the predictive value of MR for SLN positivity needs to be validated in other populations of thin-melanoma patients.
To determine the impact of microsatellites as a prognostic factor in primary cutaneous melanoma.
Retrospective cohort study.
Tertiary referral center. Patients A total of 504 patients with a history of primary melanoma observed for 2 years or having experienced a first relapse.
Overall survival (OS) and relapse-free survival (RFS).
Forty-five patients had evidence of microsatellites in their primary melanoma. Presence of microsatellites significantly correlated with the presence of several other histologic high-risk factors such as tumor thickness, ulceration, Clark level, vascular factors, and mitotic rate. Univariate analysis demonstrated decreased RFS and OS in patients with microsatellites. Presence of microsatellites was associated with increased locoregional metastasis but not distant metastasis. In multivariate analysis, with the inclusion of 6 other clinical and histologic factors, presence of microsatellites was a significant predictor of RFS but not OS. Patients with clinical macrosatellites had a trend toward worsening OS compared with those with microsatellites.
The presence of microsatellites is intimately tied to other markers of melanoma aggressiveness. Microsatellites appear to predict locoregional relapse and RFS but neither distant metastasis nor OS. These results may have implications for patient care as well as the inclusion of microsatellites in stage III of the current classification.
The natural history of metastatic melanoma in lymph nodes in the absence of a known primary site (MUP) has been defined poorly; thus, treatment guidelines for patients with MUP are not clear-cut.
The authors conducted a retrospective analysis of consecutive patients with melanoma (from 1990 to 2001) who underwent surgical resection for melanoma metastatic to regional lymph nodes. Among those patients, 71 patients with MUP and 466 control patients who had regional lymph node metastases of similar stage with a known primary site were identified. Associations between clinicopathologic factors and survival were estimated by using the Cox proportional hazards model.
After they underwent lymph node dissection, patients with MUP were classified with N1b disease (47%), N2b disease (14%), or N3 disease (39%). With a median follow-up of 7.7 years, the 5-year and 10-year overall survival rates were 55% and 44%, respectively, for patients with MUP, compared with 42% and 32%, respectively, for the control group (P = .04). In multivariate analyses, age 50 years or older, male gender, and N2b or N3 disease status were identified as adverse prognostic factors, and MUP was identified as a favorable prognostic factor (hazard ratio, 0.61; 95% confidence interval, 0.42-0.86; P = .006) for overall survival.
The relatively favorable long-term survival of patients with MUP in the current study suggested that patients with MUP have a natural history that is similar to (if not better than) the survival of many patients with Stage III disease. Therefore, patients with MUP should be treated with an aggressive surgical approach with curative intent and should be considered for Stage III adjuvant therapy protocols. Cancer 2006. (c) 2006 American Cancer Society.
"The pathology of melanoma is discussed in relation to surgical diagnosis and management. Pitfalls that may result in problems of clinicopathologic communication are emphasized. A compelling vision for the future is that all tumors will be characterized by their driving oncogenes, suppressor genes, and other genomic factors. The success of targeted therapy directed against individual oncogenes, despite its limitations, suggests that a repertoire of targeted agents will be developed that can be used against a variety of different tumors, depending on the results of genetic testing. Nevertheless, histopathologic diagnosis and surgical therapy will remain mainstays of management for melanoma."
Copyright © 2015 Elsevier Inc. All rights reserved.
The American Joint Committee on Cancer (AJCC) has recently modified staging criteria for primary melanoma patients and recommends sentinel lymph node (SLN) biopsy in many because microscopic nodal metastasis represents the most important factor predicting survival. The purpose of this study was to correlate the incidence of SLN metastasis with revised AJCC staging.
The records of 1375 melanoma patients undergoing SLN biopsy were reviewed. Univariate and multivariate analyses were performed to identify predictors of a positive SLN. Patients were stratified by using revised AJCC criteria to determine whether such groups also predicted positive SLNs.
A positive SLN was found in 16.9% of patients. By multivariate analysis, tumor thickness (relative risk [RR], 3.4) and ulceration (RR, 2.2) were dominant independent predictors of SLN metastases; age < or =50 years (RR, 1.8) and axial tumor location (RR, 1.5) were also significant. When patients were stratified by AJCC staging criteria, a significant increase in SLN metastases between successive stages was demonstrated.
Stratification of patients by using AJCC classification reveals an increasing risk of SLN metastases with successive stage groups. Given the significant association of SLN status and survival, the ability of the revised AJCC staging system to predict survival is likely due to its ability to predict the risk of occult nodal disease.
No primary lesion is identified in 10% to 20% of patients presenting with palpable evidence of regional metastatic melanoma. Because the prognostic significance of unknown primary melanoma (MUP) is unclear, we compared clinical outcomes of patients with MUP and known primary melanoma (MKP) with regional nodal metastases.
We reviewed our 13,000-patient prospective melanoma database (1971 through 2005) to identify patients managed with regional lymphadenectomy for palpable nodal metastases from MUP or MKP. Multivariate analysis identified prognostic factors significant for survival. MUP and MKP were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis.
Multivariate analysis of data from 1,571 study patients identified four significant covariates associated with worse prognosis: age >or= 60 years (hazard ratio [HR] = 1.294; P = .0017), male sex (HR = 1.335; P = .0004), nodal tumor burden >or= one (HR = 1.256; P < .0001), and known primary (HR = 1.507; 95% CI, 1.220 to 1.862; P = .0001). Five-year OS was significantly higher for 262 patients with MUP than for 1,309 patients with MKP (55% +/- 6% v 44% +/- 3%; P = .0021). Computerized matching of MUP and MKP by four significant covariates (age, sex, nodal tumor burden, and decade of diagnosis) yielded 221 matched pairs. Median and 5-year OS rates were 165 months and 58% +/- 7%, respectively, for MUP as compared with 34 months and 40% +/- 7%, respectively, for MKP (P = .0006).
Lymphadenectomy is effective for nodal metastasis from MUP. The significantly better postoperative survival for MUP versus MKP suggests a strong endogenous immune response against the primary melanoma. Immunologic studies to identify cell-mediated and antibody components of this response may lead to new approaches for determining melanoma prognosis and treatment.
Melanoma has a wide spectrum of histologic features which mimic epithelial, hematologic, mesenchymal, and neural tumors. Immunohistochemistry has been the primary tool to distinguish melanomas from these other tumors; it has also been studied for use as an adjunct to distinguish benign and malignant melanocytic tumors and to elucidate prognosis. Furthermore, there has been extensive effort to find a suitable marker to differentiate spindle cell and desmoplastic melanoma from other tumors. We have reviewed the literature investigating melanocytic differentiation markers, proliferation markers, immunomodulatory markers, signaling molecules, and nerve growth factors and receptors. Despite the proliferation of immunohistochemical markers, S-100 remains the most sensitive marker for melanocytic lesions, while markers such as HMB-45, MART-1/Melan-A, tyrosinase, and MITF demonstrate relatively good specificity but not as good sensitivity as S-100. No marker has proven useful in distinguishing spindle cell and desmoplastic melanomas from other tumors. Ki67 remains the most useful adjunct in distinguishing benign from malignant melanocytic tumors. None of the markers reviewed has been shown conclusively to have prognostic value for melanocytic neoplasms.
Survival of patients with stage IV melanoma is poor. In the current American Joint Committee on Cancer (AJCC) staging system, site of distant disease and lactate dehydrogenase (LDH) are the only prognostic factors included for stage IV disease. We sought to validate the current AJCC staging system in a contemporary, prospectively collected cohort of patients and explore additional factors that may influence prognosis.
Our prospective database was searched to identify patients with stage IV melanoma; only patients seen at our institution before developing stage IV disease were included (n = 589). Demographic, clinical, and tumor characteristics were abstracted. Univariate and multivariate assessment of prognostic factors associated with survival were performed by Cox regression.
Overall median survival was 9 months. Differential survival by AJCC substage was observed (P < .001). For each site of disease described within the AJCC staging system, an abnormal LDH level was associated with a poorer prognosis. By multivariate analysis, older age at diagnosis (as a continuous variable, hazard ratio [HR] 1.02, 95% confidence interval [95% CI]) 1.01-1.02), an abnormal LDH (HR 1.42, 95% CI 1.11-1.82), site of disease (lung HR 1.22, 95% CI .89-1.66; other viscera 1.61, 95% CI 1.18-2.21), more than one organ involvement (HR 1.27, 95% CI 1.01-1.60), and more than one metastasis (HR 2.27, 95% CI 1.65-3.14) were independently associated with poorer survival. Sex, antecedent stage, and disease-free interval were not statistically significant.
In our patient cohort, the AJCC staging system was valid. The strongest predictor of survival-the number of metastases present at the diagnosis of stage IV disease-represents a variable to consider in future staging systems.
This retrospective analysis aimed to identify the prognostic factors that influenced long-term survival of patients with metastatic melanoma. The medical records for 616 chemo-naive patients who were treated with systemic therapy on eight phase II/III clinical trials were reviewed. Clinical characteristics, disease stage, metastatic sites, baseline serum albumin, LDH, and response to treatment were compared between the treatment groups and significant prognostic factors were identified. Cox proportional-hazards regression analysis identified treatment with biochemotherapy, younger age, normal baseline serum albumin and LDH levels, ECOG P.S. < 2 and absence of visceral metastasis as favorable prognostic factors for long-term survival.
The role of microsatellites as a prognostic factor in primary malignant melanoma AJCC Melanoma Staging www.jco.org © 2009 by American Society of Clinical Oncology 6205 27. Neuman HB, Patel A, Ishill N, et al: A singleinstitution validation of the AJCC staging system for stage IV melanoma
- L Shaikh
- Rw Sagebiel
- Ferreira
- Cm
Shaikh L, Sagebiel RW, Ferreira CM, et al: The role of microsatellites as a prognostic factor in primary malignant melanoma. Arch Dermatol 141: 739-742, 2005 AJCC Melanoma Staging www.jco.org © 2009 by American Society of Clinical Oncology 6205 27. Neuman HB, Patel A, Ishill N, et al: A singleinstitution validation of the AJCC staging system for stage IV melanoma. Ann Surg Oncol 15:2034-2041, 2008
Sondak Collection and assembly of data: Charles M
- John F Gershenwald
- Michael B Thompson
- Daniel G Atkins
- Alexander M Coit
- Keith T Eggermont
- John M Flaherty
- Kelly M Kirkwood
- Merrick I Mcmasters
- Ross
- Vernon
Gershenwald, John F. Thompson, Michael B. Atkins, Daniel G. Coit, Alexander M. Eggermont, Keith T. Flaherty, John M. Kirkwood, Kelly M. McMasters, Merrick I. Ross, Vernon K. Sondak Collection and assembly of data: Charles M. Balch, Jeffrey E.
Sondak Data analysis and interpretation: Charles M
- John F Gershenwald
- Michael B Thompson
- Daniel G Atkins
- Shouluan Coit
- Alexander M Ding
- Phyllis A Eggermont
- John M Gimotty
- Kelly M Kirkwood
- Donald L Mcmasters
- Morton
- Vernon
Gershenwald, John F. Thompson, Michael B. Atkins, Daniel G. Coit, Shouluan Ding, Alexander M. Eggermont, Phyllis A. Gimotty, John M. Kirkwood, Kelly M. McMasters, Donald L. Morton, Vernon K. Sondak Data analysis and interpretation: Charles M. Balch, Jeffrey E.
Schering-Plough Expert Testimony: None Other Remuneration
- John M Kirkwood
- M Kelly
- M Mcmasters Charles
- Jeffrey E Balch
- Gershenwald
- John F Soong
- Michael B Thompson
- Atkins
- J Alistair
- Daniel G Cochran
- Alexander M Coit
- Keith T Eggermont
- Phyllis A Flaherty
- John M Gimotty
- Kelly M Kirkwood
- Martin C Mcmasters
- Mihm
- Donald L Jr
- M Morton Charles
- Balch
- Jeffrey
John M. Kirkwood, Schering-Plough; Kelly M. McMasters, Schering-Plough Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Charles M. Balch, Jeffrey E. Gershenwald, Seng-jaw Soong, John F. Thompson, Michael B. Atkins, Alistair J. Cochran, Daniel G. Coit, Alexander M. Eggermont, Keith T. Flaherty, Phyllis A. Gimotty, John M. Kirkwood, Kelly M. McMasters, Martin C. Mihm Jr, Donald L. Morton, Arthur J. Sober, Vernon K. Sondak Provision of study materials or patients: Charles M. Balch, Jeffrey E.
Sondak Manuscript writing Sondak Final approval of manuscript: Charles M
- John F Gershenwald
- Michael B Thompson
- Antonio C Atkins
- Buzaid
- J Alistair
- Daniel G Cochran
- Shouluan Coit
- Alexander M Ding
- Keith T Eggermont
- Phyllis A Flaherty
- John M Gimotty
- Kelly M Kirkwood
- Martin C Mcmasters
- Mihm
- Merrick I Jr
- Arthur J Ross
- Sober
- Charles M Vernon
- Jeffrey E Balch
- Gershenwald
- John F Soong
- Michael B Thompson
- Antonio C Atkins
- Buzaid
- J Alistair
- Daniel G Cochran
- Keith T Coit
- Phyllis A Flaherty
- John M Gimotty
- Kelly M Kirkwood
- Martin C Mcmasters
- Mihm
- Jr
- J Arthur
- Sober
- Vernon
- M Kelly
- Martin C Mcmasters
- Mihm
- Donald L Jr
- Morton
- Merrick
Gershenwald, John F. Thompson, Michael B. Atkins, Antonio C. Buzaid, Alistair J. Cochran, Daniel G. Coit, Shouluan Ding, Alexander M. Eggermont, Keith T. Flaherty, Phyllis A. Gimotty, John M. Kirkwood, Kelly M. McMasters, Martin C. Mihm Jr, Merrick I. Ross, Arthur J. Sober, Vernon K. Sondak Manuscript writing: Charles M. Balch, Jeffrey E. Gershenwald, Seng-jaw Soong, John F. Thompson, Michael B. Atkins, Antonio C. Buzaid, Alistair J. Cochran, Daniel G. Coit, Keith T. Flaherty, Phyllis A. Gimotty, John M. Kirkwood, Kelly M. McMasters, Martin C. Mihm Jr, Arthur J. Sober, Vernon K. Sondak Final approval of manuscript: Charles M. Balch, Jeffrey E. Gershenwald, Seng-jaw Soong, John F. Thompson, Michael B. Atkins, David R. Byrd, Antonio C. Buzaid, Alistair J. Cochran, Daniel G. Coit, Alexander M. Eggermont, Keith T. Flaherty, Phyllis A. Gimotty, John M. Kirkwood, Kelly M. McMasters, Martin C. Mihm Jr, Donald L. Morton, Merrick I.
Schering-Plough (C) Stock Ownership: None Honoraria: Charles M
- Vernon K Sondak
Vernon K. Sondak, Schering-Plough (C) Stock Ownership: None Honoraria: Charles M. Balch, Schering-Plough;
Sondak Provision of study materials or patients Sondak Collection and assembly of data Sondak Data analysis and interpretation al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma
- Daniel G Cochran
- Alexander M Coit
- Keith T Eggermont
- Phyllis A Flaherty
- John M Gimotty
- Kelly M Kirkwood
- Martin C Mcmasters
- Mihm
- Donald L Jr
- Arthur J Morton
- Sober
- K Vernon
- M Charles
- Jeffrey E Balch
- John F Gershenwald
- Michael B Thompson
- Daniel G Atkins
- Alexander M Coit
- Keith T Eggermont
- John M Flaherty
- Kelly M Kirkwood
- Merrick I Mcmasters
- Ross
- K Vernon
- M Charles
- Jeffrey E Balch
- John F Gershenwald
- Michael B Thompson
- Daniel G Atkins
- Shouluan Coit
- Alexander M Ding
- Phyllis A Eggermont
- John M Gimotty
- Kelly M Kirkwood
- Donald L Mcmasters
- Morton
- K Vernon
- M Charles
- Jeffrey E Balch
- John F Gershenwald
- Michael B Thompson
- Antonio C Atkins
- Alistair J Buzaid
- Daniel G Cochran
- Shouluan Coit
- Alexander M Ding
- Keith T Eggermont
- Phyllis A Flaherty
- John M Gimotty
- Kelly M Kirkwood
- Martin C Mcmasters
- Mihm
- Merrick I Jr
- Arthur J Ross
- Sober
- K Vernon
- M Charles
- Jeffrey E Balch
- Seng-Jaw Gershenwald
- John F Soong
- Michael B Thompson
- David R Atkins
- Antonio C Byrd
- Alistair J Buzaid
- Daniel G Cochran
- Alexander M Coit
- Cm Balch
- Sj Soong
- Je Gershenwald
Cochran, Daniel G. Coit, Alexander M. Eggermont, Keith T. Flaherty,
Phyllis A. Gimotty, John M. Kirkwood, Kelly M. McMasters, Martin C.
Mihm Jr, Donald L. Morton, Arthur J. Sober, Vernon K. Sondak
Provision of study materials or patients: Charles M. Balch, Jeffrey E.
Gershenwald, John F. Thompson, Michael B. Atkins, Daniel G. Coit,
Alexander M. Eggermont, Keith T. Flaherty, John M. Kirkwood, Kelly M.
McMasters, Merrick I. Ross, Vernon K. Sondak
Collection and assembly of data: Charles M. Balch, Jeffrey E.
Gershenwald, John F. Thompson, Michael B. Atkins, Daniel G. Coit,
Shouluan Ding, Alexander M. Eggermont, Phyllis A. Gimotty,
John M. Kirkwood, Kelly M. McMasters, Donald L. Morton,
Vernon K. Sondak
Data analysis and interpretation: Charles M. Balch, Jeffrey E.
Gershenwald, John F. Thompson, Michael B. Atkins, Antonio C. Buzaid,
Alistair J. Cochran, Daniel G. Coit, Shouluan Ding, Alexander M.
Eggermont, Keith T. Flaherty, Phyllis A. Gimotty, John M. Kirkwood,
Kelly M. McMasters, Martin C. Mihm Jr, Merrick I. Ross, Arthur J.
Sober, Vernon K. Sondak
Manuscript writing: Charles M. Balch, Jeffrey E. Gershenwald, Seng-jaw
Soong, John F. Thompson, Michael B. Atkins, Antonio C. Buzaid,
Alistair J. Cochran, Daniel G. Coit, Keith T. Flaherty, Phyllis A. Gimotty,
John M. Kirkwood, Kelly M. McMasters, Martin C. Mihm Jr, Arthur J.
Sober, Vernon K. Sondak
Final approval of manuscript: Charles M. Balch, Jeffrey E. Gershenwald,
Seng-jaw Soong, John F. Thompson, Michael B. Atkins, David R. Byrd,
Antonio C. Buzaid, Alistair J. Cochran, Daniel G. Coit, Alexander M.
Eggermont, Keith T. Flaherty, Phyllis A. Gimotty, John M. Kirkwood,
Kelly M. McMasters, Martin C. Mihm Jr, Donald L. Morton, Merrick I.
Ross, Arthur J. Sober, Vernon K. Sondak
REFERENCES
1. Balch CM, Buzaid AC, Soong SJ, et al: Final
version of the American Joint Committee on Cancer
staging system for cutaneous melanoma. J Clin
Oncol 19:3635-3648, 2001
2. Balch CM, Soong SJ, Gershenwald JE, et al:
Prognostic factors analysis of 17,600 melanoma
patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin
Oncol 19:3622-3634, 2001
American Joint Committee on Cancer Schering-Plough; Kelly M. McMasters, Schering-Plough Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Charles M
- Jeffrey E Gershenwald Alexander
- M Eggermont
- M Schering-Plough ; John
- Kirkwood
Jeffrey E. Gershenwald, American Joint Committee on Cancer; Alexander
M. Eggermont, Schering-Plough; John M. Kirkwood, Schering-Plough; Kelly
M. McMasters, Schering-Plough Expert Testimony: None Other
Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Charles M. Balch, Jeffrey E. Gershenwald,
Seng-jaw Soong, John F. Thompson, Michael B. Atkins, Alistair J.
Schering-Plough; Alexander M. Eggermont, Schering-Plough Schering-Plough; Kelly M. McMasters, Schering-Plough
- Jeffrey E Gershenwald John
- M Kirkwood
Jeffrey E. Gershenwald, Schering-Plough; Alexander M. Eggermont,
Schering-Plough; John M. Kirkwood, Schering-Plough; Kelly M. McMasters,
Schering-Plough; Merrick I. Ross, Schering-Plough, Genentech,
PharmAdura; Vernon K. Sondak, Schering-Plough Research Funding:
PharmAdura (C); Vernon K. Sondak, Schering-Plough (C) Stock Ownership: None Honoraria: Charles M
- Merrick I Ross
Merrick I. Ross, PharmAdura (C); Vernon K. Sondak, Schering-Plough (C)
Stock Ownership: None Honoraria: Charles M. Balch, Schering-Plough;