Breslow Tumor Thickness Research Articles

Incidence and risk factors for central nervous system (CNS) metastasis (met) in patients (pts) with stage III melanoma treated with adjuvant (ADJ) anti-PD1 immunotherapy (IMT).

9581 Background: The identification of risk factors for CNS met in stage III melanoma pts will facilitate the development of personalized surveillance strategies. Previously we characterized the incidence (3.6%, 9.6%, and 15.8% at 1, 2, and 5 yrs) and risk factors for CNS met in pts diagnosed with stage III melanoma from 1998 to 2014. It is unknown if the incidence of CNS met has changed in the ADJ IMT era. Methods: We performed an institutionally approved retrospective chart review of pts diagnosed with stage III melanoma treated with ADJ IMT between 1/1/2018 and 12/31/2020 at MD Anderson Cancer Center (MDA) or the Melanoma Institute of Australia (MIA). Exclusion criteria included mucosal or uveal melanoma or prior systemic therapy (other than ADJ interferon). Pts had to have CNS imaging within 1 month before or 4 months after stage III diagnosis. Pt and tumor features, treatments, and distant recurrence events (CNS met; non-CNS met) were captured. Time-to-CNS and time-to-non-CNS met were computed from start date of ADJ IMT to date of CNS/non-CNS met. Cumulative incidence of distant met events was determined using competing risks (death) and pts alive with no met at last follow-up were censored. Associations were determined using proportional sub-distribution hazards regression models; group differences were assessed using Gray’s test. Results: 361 pts were included in the analysis (MDA, 212; MIA, 149). With a median FU of 34.1 months (range 1.7-61.9), 128 (35.5%) of pts were diagnosed with distant mets. Among pts with distant mets, 56 had CNS met (15.5% of full cohort; 43.8% of pts with distant met); 24 (18.8% of pts with distant mets) pts had CNS met at initial diagnosis of stage IV disease. The 1-, 2-, and 5-yr rates of CNS met in the full cohort were 7%, 12%, and 17%. There was no difference in CNS met incidence between MDA and MIA. On univariate analysis, risk of CNS met was associated with AJCC stage IIID (Hazard Ratio [HR] 6.4; 95% Confidence Interval [CI] 2.2 – 18.8, p<0.001); increased primary tumor Breslow thickness (HR 1.1, CI 1.1 – 1.2, p<0.001), ulceration (HR 2.8; CI 1.5 – 5.1, p<0.001), and mitotic rate > 9/mm (HR 2.3; CI 1.1 – 4.6, p=0.025). There was a trend for decreased risk of CNS met in pts that stopped ADJ IMT due to toxicity (HR 0.4; CI 0.2 – 1.1, p=0.08). Multivariable (MV) model with these features did not identify any significant (p<0.05) associations with CNS met. Primary tumor ulceration and mitotic rate were significantly associated with non-CNS met on MV analysis. Conclusions: Despite the established impact of ADJ IMT on distant met free survival, the incidence of CNS met in stage III melanoma pts treated with ADJ IMT remains high. The results support the need for continued investigation of risk factors, prevention strategies and optimal surveillance for CNS met in stage III melanoma pts.

Invasive Cutaneous Melanoma: Evaluating the Prognostic Significance of Some Parameters Associated with Lymph Node Metastases.

Background and Objectives: This study aimed to assess the clinical-pathological profile of patients with invasive cutaneous melanomas and to identify the parameters with a prognostic role in the lymph nodal spread of this malignant tumor. Materials and Methods: We performed a retrospective study on patients with invasive cutaneous melanomas who underwent surgery in the "Pius Brînzeu" County Clinical Emergency Hospital from Timișoara, Romania, and were evaluated for the status of loco-regional lymph nodes. We selected and analyzed some parameters searching for their relationship with lymph node metastases. Results: We identified 79 patients with invasive cutaneous melanomas (29 men and 50 women, mean age 59.36 years). A percentage of 58.3% of melanomas had Breslow tumor thickness >2 mm; 69.6% of melanomas showed a Clark level IV-V. Tumor ulceration was present in 59.5% of melanomas. A mitotic rate of ≥5 mitoses/mm2 was observed in 48.1% of melanomas. Tumor-infiltrating lymphocytes (TILs), non-brisk, were present in 59.5% of cases and 22.8% of patients had satellite/in-transit metastasis (SINTM). Tumor regression was identified in 44.3% of cases. Lymph nodes metastases were found in 43.1% of patients. Statistical analysis showed that lymph node metastases were more frequent in melanomas with Breslow thickness >2 mm (p = 0.0002), high Clark level (p = 0.0026), mitotic rate >5 mitoses/mm2 (p = 0.0044), ulceration (p = 0.0107), lymphovascular invasion (p = 0.0182), SINTM (p = 0.0302), and non-brisk TILs (p = 0.0302). Conclusions: The Breslow thickness >2 mm, high Clark level, high mitotic rate and ulceration are the most important prognostic factors for lymph nodal spread in cutaneous melanomas. However, some melanomas without these clinical-pathological features can have an unexpected, aggressive evolution, which entails the necessity of close and prolonged clinical follow-up of patients, including those with lesions considered without risk.

Morphological and immunohistochemical analysis of tumor-infiltrating lymphocytes, M2 macrophages, BCL 6 and SOX10 in the tumor microenvironment of nodular cutaneous melanoma

Introduction. Cutaneous melanoma is one of the most aggressive malignant tumors, and its nodular form with vertical growth is characterized by unfavorable prognosis. However, in the recent years due to advances in basic oncology, a breakthrough in drug therapy of this pathology was made. To a great extent, it is linked to implementation of new therapy with checkpoint inhibitors. The best and longest response rates of cutaneous melanoma to this treatment were achieved compared to other oncological diseases. This fact can be explained by immunogenicity of cutaneous melanoma, high mutational load, as well as features of its tumor microenvironment, where in most cases high infiltration by immunocompetent cell is observed. However, immune cells vary by their composition and functions. Some of them can even promote tumor growth. Therefore, study of cell composition, degree and distribution of immune infiltration in the tumor can help identify potential factors of favorable and unfavorable prognosis for cutaneous melanoma which is important in clinical practice.Aim. To determine the frequency of CD3+-, CD4+-, CD8+-T-lymphocytes, CD163, BCL6 and SOX10 expression in patients with primary nodular cutaneous melanoma, as well as correlation of these markers with each other and standard morphological parameters for this non-epithelial malignant tumor.Materials and methods. In the study, the expression frequency of CD3+-, CD4+-, CD8+-T-lymphocytes, CD163, BCL6 and SOX10 in the postoperative material of 20 patients with true primary nodular cutaneous melanoma was measured using immunohistological analysis. The correlation of these markers with each other and standard morphological parameters was determined.Results. In most cases of nodular cutaneous melanoma, moderate and marked lymphocytic (immune) infiltration (grade II–III) was observed with no correlation with Breslow tumor thickness. Study of the ratio between CD4-positive T helpers and CD8-positive cytotoxic T lymphocytes in the tumor microenvironment showed that the number of the latter increased the higher was the degree of immune infiltrate. Markedness of macrophage infiltration directly correlated with markedness of lymphocytic infiltration. BCL6 expression in lymphocytes was observed in all cases of infiltration.Conclusion. Immune infiltrate in nodular cutaneous melanoma is a multicomponent, dynamic microenvironment containing both antitumor and tumor-promoting components with balance shifting to one or other side. Their qualitative, quantitative and, possibly, topographic ratios in the primary lesion of cutaneous melanoma affect the effectiveness of drugs and disease prognosis. Knowledge on the predominance of components negatively affecting tumor growth in the primary lesion can help an oncologist in selection of correct treatment tactics and disease observation.

The impact of the COVID-19 pandemic on the diagnosis of cutaneous melanomas: A retrospective cohort study from five European skin cancer reference centres.

The COVID-19 lockdown had a dramatic impact on primary care access and resulted in postponed skin cancer screenings. This raises concerns for a diagnostic delay on primary cutaneous melanomas, which can subsequently increase morbidity and mortality. The aim of the study was to investigate the impact of the COVID-19-related restrictions on the melanoma diagnosis in five European skin cancer reference centres in Switzerland, Germany, Austria and Italy. A total of 7865 cutaneous melanoma cases were collected between 01 September 2018 and 31 August 2021. The time period was stratified into pre-COVID (pre-lockdown) and post-COVID (lockdown and post-lockdown) according to the established restrictions in each country. The data collection included demographic, clinical and histopathological data from histologically confirmed cutaneous melanomas. Personal and family history of melanoma, and presence of immunosuppression were used to assess the diagnosis delay in high-risk individuals. There was an overall increase of the Breslow tumour thickness (mean 1.25 mm vs. 1.02 mm) during the post-COVID period, as well as an increase in the proportion of T3-T4 melanomas, rates of ulceration and the number of mitotic rates ≥2 (all, p < 0.001). Patients with immunosuppression and personal history of melanoma showed a decrease in the mean log10-transformed Breslow during lockdown and post-COVID. In the multivariate analysis, age at melanoma diagnosis (p < 0.01) and personal history of melanoma (p < 0.01) showed significant differences in the mean Breslow thickness. The study confirms the diagnostic delay in cutaneous melanomas due to the COVID-19 lockdown. High-risk individuals, such as patients with personal history of melanoma and elderly individuals, were more hesitant to restart their regular skin cancer screenings post-COVID. Further studies with longer follow-up are required to evaluate the consequences of this diagnostic delay in long-term outcomes.

Long-Term Sequential Digital Dermoscopy of Low-Risk Patients May Not Improve Early Diagnosis of Melanoma Compared to Periodical Handheld Dermoscopy

Sequential digital dermoscopy (SDD) enables the diagnosis of a subgroup of slow-growing melanomas that lack suspicious features at baseline examination but exhibit detectable change on follow-up. The combined use of total-body photography and SDD is recommended in high-risk subjects by current guidelines. To establish the usefulness of SDD for low-risk individuals, we conducted a retrospective study using electronic medical records of low-risk patients with a histopathological diagnosis of cutaneous melanoma between 1 January 2016 and 31 December 2019, who had been referred and monitored for long-term follow-up of clinically suspicious melanocytic nevi. We sought to compare the distribution of "early" cutaneous melanoma, defined as melanoma in situ and pT1a melanoma, between SDD and periodical handheld dermoscopy in low-risk patients. A total of 621 melanomas were diagnosed in a four-year timespan; 471 melanomas were diagnosed by handheld dermoscopy and 150 by digital dermoscopy. Breslow tumor thickness was significantly higher for melanomas diagnosed by handheld compared to digital dermoscopy (0.56 ± 1.53 vs. 0.26 ± 0.84, p = 0.030, with a significantly different distribution of pT stages between the two dermoscopic techniques. However, no significant difference was found with respect to the distribution of pT stages, mean Breslow tumor thickness, ulceration, and prevalence of associated melanocytic nevus in tumors diagnosed on periodical handheld dermoscopy compared to SDD. Our results confirm that periodical dermoscopic examination enables the diagnosis of cutaneous melanoma at an earlier stage compared to first-time examination as this was associated in our patients with better prognostic features. However, in our long-term monitoring of low-risk subjects, Breslow tumor thickness and pT stage distribution did not differ between handheld periodical dermoscopy and SDD.

PD-L1, CD4+, and CD8+ Tumor-Infiltrating Lymphocytes (TILs) Expression Profiles in Melanoma Tumor Microenvironment Cells.

(1) Background: Because melanoma is an aggressive tumor with an unfavorable prognosis, we aimed to characterize the PD-L1 expression in melanomas in association with T cell infiltrates because PD-1/PD-L1 blockade represents the target in treating melanoma strategy. (2) Methods: The immunohistochemical manual quantitative methods of PD-L1, CD4, and CD8 TILs were performed in melanoma tumor microenvironment cells. (3) Results: Most of the PD-L1 positive, expressing tumors, have a moderate score of CD4+ TILs and CD8+TILs (5-50% of tumor area) in tumoral melanoma environment cells. The PD-L1 expression in TILs was correlated with different degrees of lymphocytic infiltration described by the Clark system (X2 = 8.383, p = 0.020). PD-L1 expression was observed often in melanoma cases, with more than 2-4 mm of Breslow tumor thickness being the associated parameters (X2 = 9.933, p = 0.014). (4) Conclusions: PD-L1 expression represents a predictive biomarker with very good accuracy for discriminating the presence or absence of malign tumoral melanoma cells. PD-L1 expression was an independent predictor of good prognosis in patients with melanomas.

Changes in outcomes and factors associated with survival in melanoma patients with brain metastases.

Treatment options for patients with melanoma brain metastasis (MBM) have changed significantly in the last decade. Few studies have evaluated changes in outcomes and factors associated with survival in MBM patients over time. The aim of this study is to evaluate changes in clinical features and overall survival (OS) for MBM patients. Patients diagnosed with MBMs from 1/1/2009 to 12/31/2013 (Prior Era; PE) and 1/1/2014 to 12/31/2018 (Current Era; CE) at The University of Texas MD Anderson Cancer Center were included in this retrospective analysis. The primary outcome measure was OS. Log-rank test assessed differences between groups; multivariable analyses were performed with Cox proportional hazards models and recursive partitioning analysis (RPA). A total of 791 MBM patients (PE, n=332; CE, n=459) were included in analysis. Median OS from MBM diagnosis was 10.3months (95% CI, 8.9-12.4) and improved in the CE vs PE (14.4 vs 10.3months, P<.001). Elevated serum lactate dehydrogenase (LDH) was the only factor associated with worse OS in both PE and CE patients. Factors associated with survival in CE MBM patients included patient age, primary tumor Breslow thickness, prior immunotherapy, leptomeningeal disease, symptomatic MBMs, and whole brain radiation therapy. Several factors associated with OS in the PE were not significant in the CE. RPA demonstrated that elevated serum LDH and prior immunotherapy treatment are the most important determinants of survival in CE MBM patients. OS and factors associated with OS have changed for MBM patients. This information can inform contemporary patient management and clinical investigations.

456 Multispectral imaging algorithm predicts Breslow tumor depth of malignant melanoma

Breslow tumor thickness is a major prognostic factor for melanoma. As it is based on histopathological evaluation, it is not available to aid clinical decision making at the time of the melanoma diagnosis. In this work, we assessed the efficacy of multispectral imaging (MSI) to predict Breslow tumor thickness and developed a melanoma classification algorithm to determine the optimal surgical safety margins. First, we excluded nevi from the analysis with the use of a novel quantitative parameter.

Prediction of early-stage melanoma recurrence using clinical and histopathologic features

Prognostic analysis for early-stage (stage I/II) melanomas is of paramount importance for customized surveillance and treatment plans. Since immune checkpoint inhibitors have recently been approved for stage IIB and IIC melanomas, prognostic tools to identify patients at high risk of recurrence have become even more critical. This study aims to assess the effectiveness of machine-learning algorithms in predicting melanoma recurrence using clinical and histopathologic features from Electronic Health Records (EHRs). We collected 1720 early-stage melanomas: 1172 from the Mass General Brigham healthcare system (MGB) and 548 from the Dana-Farber Cancer Institute (DFCI). We extracted 36 clinicopathologic features and used them to predict the recurrence risk with supervised machine-learning algorithms. Models were evaluated internally and externally: (1) five-fold cross-validation of the MGB cohort; (2) the MGB cohort for training and the DFCI cohort for testing independently. In the internal and external validations, respectively, we achieved a recurrence classification performance of AUC: 0.845 and 0.812, and a time-to-event prediction performance of time-dependent AUC: 0.853 and 0.820. Breslow tumor thickness and mitotic rate were identified as the most predictive features. Our results suggest that machine-learning algorithms can extract predictive signals from clinicopathologic features for early-stage melanoma recurrence prediction, which will enable the identification of patients that may benefit from adjuvant immunotherapy.

Hypoxia and Ezrin Expression in Primary Melanoma Have High Prognostic Relevance.

Hypoxia affects tumor aggressiveness and activates pathways associated with epithelial mesenchymal transition (EMT) which are crucial for tumor progress. In this study, the correlation of hypoxia and EMT with sentinel lymph node status and tumor-specific survival was investigated in primary melanomas. CD34 for capillary count and Hypoxia inducible factor-1α (HIF-1α) as hypoxia indicators as well as Ezrin and L1-Cell Adhesion Molecule (L1CAM), both critical proteins contributing to EMT, were analyzed using immunohistochemistry in 49 melanoma patients with long follow-up (F/U, mean 110 months; range 12–263 months). We found a significant correlation between Breslow tumor thickness and Ezrin expression (p = 0.018). L1CAM expression in primary melanoma was significantly associated with HIF-1α expression (p < 0.0001) and sentinel lymph node metastasis (p = 0.011). Furthermore, low capillary count, reflecting hypoxic condition, was significantly associated with Ezrin expression (p = 0.047) and decreased tumor-specific survival (p = 0.035). In addition, patients with high Ezrin expression in their primary melanoma had a dramatic loss of life early in their F/U period (mean survival time 29 months; range 15–44 month). Our results highlight the relevance of Ezrin, L1CAM and HIF-1α as prognostic markers in melanoma patients. Additionally, we demonstrate that hypoxia in primary melanoma affects EMT and is at least partly responsible for early metastatic dissemination.

Resilience of melanoma diagnostics at a tertiary-care hospital during the SARS-CoV-2 pandemic

To the Editor: On March 11, 2020, the World Health Organization elevated the coronavirus disease 2019 (COVID-19) to global pandemic status. Systems-level changes in governance, health care resource allocation, and social-behavioral norms developed worldwide in efforts to reduce viral spread. An unintended consequence of these changes was a disruption of routine preventative health care practice, leading to delay or deferral of diagnostic evaluation and therapy across multiple disciplines.1Bhatt A.S. Moscone A. McElrath E.E. et al.Fewer hospitalizations for acute cardiovascular conditions during the COVID-19 pandemic.J Am Coll Cardiol. 2020; 76: 280-288Crossref PubMed Scopus (157) Google Scholar,2Elmas Ö.F. Demirbaş A. Düzayak S. Atasoy M. Türsen Ü. Lotti T. Melanoma and COVID-19: a narrative review focused on treatment.Dermatol Ther. 2020; 33e14101Google Scholar In the field of melanoma, screening, biopsy, and histopathologic diagnosis form the foundation of secondary prevention. Importantly, early detection via timely screening has been shown to reduce melanoma-specific mortality.3Watts C.G. McLoughlin K. Goumas C. et al.Association between melanoma detected during routine skin checks and mortality.JAMA Dermatol. 2021; 157: 1425-1436Crossref PubMed Scopus (9) Google Scholar To evaluate the longitudinal effects of care interruptions during the COVID-19 pandemic on melanoma diagnoses, we performed a retrospective cohort analysis of patients evaluated in a tertiary care setting. The timeframe of greatest preventive care interruption was selected as March 2020 to May 2020 based on the population-level SARS-CoV-2 case count and mortality statistics for Suffolk County, Massachusetts (Fig 1).4Mullen J.L. Tsueng G. Latif A.A. et al.Center for Viral Systems Biology.https://outbreak.info/Date: 2020Date accessed: April 5, 2022Google Scholar Unbiased structured data were extracted from standardized synoptic surgical pathology reports for 3160 melanoma cases between January 2016 and January 2022, comprising 1113 dermatopathology cases from MGH clinics and 2047 dermatopathology consultations reviewed for patients referred to the MGH Melanoma Center. Patient demographics, case dates, and tumor Breslow thickness were recorded; cases with Breslow thickness ≤0.1 mm and >20 mm were manually reviewed. Statistical analyses were performed using GraphPad Prism 9.3.1. Data were binned at 1-month resolution and the number of melanoma diagnoses visualized depicting seasonal and pandemic-related variation (Fig 1). Monthly melanoma diagnoses fell sharply between March and May 2020 from an overall mean of 44 to a low of 17, corresponding with peak county-wide SARS-CoV-2 mortality (Fig 1). Breslow thickness is considered the most important prognostic factor for primary cutaneous melanoma.5Gershenwald J.E. Scolyer R.A. Hess H.R. et al.Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 472-492Crossref PubMed Scopus (1164) Google Scholar To evaluate if patients presented with more advanced lesions during periods of reduced screening and biopsy, mean Breslow thickness was compared. Nonparametric Kruskal-Wallis analysis of variance showed a significant increase in Breslow thickness of melanomas diagnosed in April 2020 when compared to April of 2016, 2017, 2018, and 2019 (Fig 1) as well as compared to aggregate prepandemic April data (Fig 2, left; 95% confidence interval [CI]: 2.9-5.3 mm vs 1.4-2.8 mm, P < .0005). The difference was driven by loss of thin melanomas (<1 mm), suggesting that patients with more clinically advanced lesions were triaged for evaluation and biopsy during the pandemic shutdowns. There were only 2 diagnoses of primary cutaneous melanoma made on dermatopathology specimens from MGH clinics in April 2020, with Breslow thickness of 3.2 mm and 5.3 mm (range, April 2016-2019: 95% CI: 0.8-2.9 mm). The mean Breslow thickness for consultation cases was also increased in April 2020 compared to prior years (95% CI: 1.5-5.6 mm vs 1.4-2.3 mm; P < .01). While the long-term effects of transiently delayed evaluation may not become apparent for several years, overall prepandemic (January 2016-March 2020) and pandemic era (April 2020-January 2022) Breslow thickness was unchanged in our cohort (Fig 2, right). This encouraging finding suggests resilience of our health care system during the COVID-19 pandemic. Soma Jobbagy, Kristine Chaudet, Matthew Gayhart, Veronica Klepeis, and Lyn Duncan have no interests to report. Genevieve Boland reports a relationship with Olink Proteomics, InterVenn Biosciences, Merck & Co, Iovance Biotherapeutics Inc, Palleon Pharmaceuticals Inc, and Ankyra Therapeutics. Hensin Tsao reports a relationship with Epiphany Dermatology, LazarusAI, Wolters Kluwer UpToDate, and JAAD.

Clinical history analysis of Japanese melanoma cases and characteristics of melanoma with childhood onset.

It remains debatable whether melanoma with a clinical history of early childhood onset truly arises from a nevus. To clarify the clinical and genetic characteristics of melanoma detected at birth or several years afterwards, 249 melanoma cases seen at Shinshu University Hospital between 2006 and 2015 were retrospectively analyzed. Ten (4.0%) cases (median age 39.5 years, range 19-70 years; male/female 2/8; lesion site, 6 extremities, 2 trunk, 1 head, 1 face; cumulative sun damage [CSD] skin, 9 low-CSD, 1 high-CSD; detection at birth 3) had recorded early childhood onset. Median Breslow's tumor thickness in those cases was 6.0 mm (range: 0.4-17.5 mm). The frequency of lesions detected at <20 years of age was significantly higher for low-CSD melanoma (17.5%) than for high-CSD (3.3%) and acral (0.8%) melanoma. Although melanoma with a history of early childhood onset is rare, the characteristics of such cases should be established since most have progressed to an advanced stage at the initial visit.

The prognostic significance of the clinical and histological parameters in primary cutaneous melanoma patients

Cutaneous melanoma is the most aggressive form of skin cancer and its incidence is unfortunately increasing. In the last decades, a progressive increase of new cases of diagnosed thin melanoma has been noted. This may be due to earlier detection, better surveillance, improved diagnostic criteria or increased exposure to sunlight. Despite the fact that Breslow tumor thickness has the strongest proven prognostic significance, there are still thin melanomas that metastasize and thick melanomas with favorable evolution. Therefore, the identification of strong predictive factors for survival is mandatory, particularly for patients with thin melanoma.

Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study.

SummaryBackgroundUlceration is regarded as an adverse prognostic factor and is used together with tumour thickness to subcategorize patients with cutaneous melanoma. However, the prognostic impact of ulceration in acral melanoma (AM) is controversial.ObjectivesTo assess the prognostic impact of ulceration in AM and the variability across different Breslow thicknesses and clinical stages.MethodsA multicentre retrospective study of patients diagnosed with AM between January 2000 and December 2017. Differences in melanoma‐specific survival (MSS) between patients with and without ulceration were assessed using the multivariable Cox proportional hazards model and log‐rank test.ResultsAmong 1053 enrolled patients, 62.6% had ulceration. After a median follow‐up of 61 months, patients with ulceration had a lower median MSS than those without: 66.1 months, 95% confidence interval (CI) 60.0–86.0 vs. not reached; hazard ratio 1.41, 95% CI 1.09–1.82; P = 0.012. Among patients with thin (≤ 1 mm) melanoma, the survival curves of patients with vs. without ulceration clearly separated over time (P < 0.001). No association between ulceration and MSS was observed for melanomas of thickness > 1 mm (subgroups of T2, T3 and T4; all P‐values > 0.05) or patients with stage III disease (hazard ratio 1.09, 95% CI 0.71–1.68, P = 0.39).ConclusionsUlceration is an independent negative prognostic factor for patients with AM, but the impact varies across Breslow thicknesses and clinical stages. Ulceration has a significant effect on prognosis for patients with thin (≤ 1 mm) melanoma, but there was no association between ulceration and survival in intermediate/thick AM or stage III AM. What is already known about this topic? Ulceration status is used together with Breslow tumour thickness to subcategorize patients into different stages according to the America Joint Committee on Cancer melanoma staging system.As one distinctive subtype of cutaneous melanoma, acral melanoma (AM) is characterized by poor survival outcomes due to delayed diagnosis and a high prevalence of negative prognostic and genetic features.The prognostic impact of ulceration in AM is still controversial. What does this study add? This was the first large‐scale study to assess the prognostic and staging values of ulceration in patients with AM.Ulceration has a significant effect on prognosis for patients with thin (≤1 mm) melanoma, but no association between ulceration and survival was found in intermediate/thick or stage III AM.These findings should be considered when using ulceration‐based staging systems.

Melanoma survival with classification and regression trees analysis: a complement for the communication of prognosis to patients.

Background Prognostic factors in cutaneous melanoma are commonly evaluated by the Cox proportional hazard model. However, the interpretation of the effect of multiple variables is not straightforward. Classification and Regression Trees Analysis (CART), which allows a more friendly data evaluation, could be a valid integration of the message from Cox model. Methods The CART algorithm splits up data, creating a tree of groups of patients with different profiles for risk of death. Results are easy to interpret in clinical practice. A total of 2,692 patients with invasive cutaneous melanoma registered in Romagna (northern Italy) between 1993-2012 and followed-up until the end of 2013 were included. The Cox model and CART analysis were applied to sex, patient age, histological subtype, Breslow's tumour thickness, ulceration, site of disease, and Clark level. Results The CART analysis identified 15 categories which were collapsed into five classes with statistically different survival. The best prognostic group (10-year observed survival, 99.1%) included subjects with Breslow's thickness ≤ 0.78 mm and age 16-81 years. The worst prognostic group (10-year observed survival, 35.8%) comprised subjects with thickness ≥ 3.75 mm and age 16-96 years. According to the Cox model, patient age, histological subtype, Breslow thickness, ulceration, and site of disease had a significant independent prognostic value. Conclusions CART and Cox models provided consistent results. CART seemed friendlier in its interpretation and it could facilitate the communication of risk.

Trend Shifts in Age-Specific Incidence for In Situ and Invasive Cutaneous Melanoma in Sweden.

Simple SummaryThe incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age- and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM by analysing data obtained from the Swedish Melanoma Register and the Swedish Cancer registry for 35,350 in situ tumours and 59,932 CM. Trend shifts in age-specific incidence for in situ and invasive CM reflect a rise among both sexes since the 2000s and could be a result of more effective secondary prevention efforts and a higher awareness of CM.Background: The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age- and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM. Methods: Joinpoint regression models were used to analyse data from the Swedish Cancer Register and the Swedish Melanoma Registry 1997–2018 (N = 35,350 in situ CM; 59,932 CM). Results: The AAPC of CM for women was 4.5 (4.1–5.0; p < 0.001) for the period 1997–2018. For men, the APCC was 4.2 (3.0–5.4; p < 0.001), with a significantly higher annual percentage change (APC) for the period 2000–2018 (5.0; 4.6–5.4; p < 0.001) compared to 1997–1999. An increasing annual incidence of CM ≤ 0.6 mm and 0.7 mm Breslow tumour thickness was found for men with a significant incidence shift for the period 2006–2015, respectively. Similarly for women, with a significantly higher APC for CM ≤ 0.6 mm from 2005. The incidence of intermediate thick CM (2.1–4.0 mm) has not increased since 2011. The incidence of CM > 4.0 mm has been increasing among both sexes, with a significantly lower APC among women from 2005. Conclusions: The incidence of in situ and low-risk CM ≤ 1.0 mm in tumour thickness has been rising among both sexes since the 2000s.

PARP1 as a Marker of an Aggressive Clinical Phenotype in Cutaneous Melanoma-A Clinical and an In Vitro Study.

(1) Background: Poly(ADP-ribose) polymerase 1) (PARP1) is a pleiotropic enzyme involved in several cellular processes, e.g., DNA damage repair, regulation of mitosis, and immune response. Little is known about the role of PARP1 in melanoma development and progression. We aimed to investigate the prognostic significance of PARP1 expression in cutaneous melanoma through evaluation of mRNA and protein levels of PARP1 in normal melanocytes and melanoma cell lines, as well as in patients’ tissue material from surgical resections. (2) Methods: An in vitro model was based on two types of normal human melanocytes (HEMn-DP and HEMn-LP) and four melanoma cell lines (A375, WM1341D, Hs294T, and WM9). PARP1 mRNA gene expression was estimated using real-time polymerase chain reaction (RT-PCR), whereas the protein level of PARP1 was evaluated by fluorescence confocal microscopy and then confirmed by Western Blotting analysis. The expression of PARP1 was also assessed by immunohistochemistry in formalin-fixed paraffin-embedded tissues of 128 primary cutaneous melanoma patients and correlated with follow-up and clinicopathologic features. (3) Results: The in vitro study showed that melanoma cells exhibited significantly higher PARP1 expression at mRNA and protein levels than normal melanocytes. High PARP1 expression was also associated with the invasiveness of tumor cells. Elevated nuclear PARP1 expression in patients without nodal metastases strongly correlated with significantly shorter disease-free survival (p = 0.0015) and revealed a trend with shorter cancer-specific overall survival (p = 0.05). High PARP1 immunoreactivity in the lymph node-negative group of patients was significantly associated with higher Breslow tumor thickness, presence of ulceration, and a higher mitotic index (p = 0.0016, p = 0.023, and p < 0.001, respectively). In patients with nodal metastases, high PARP1 expression significantly correlated with the presence of microsatellitosis (p = 0.034), but we did not confirm the prognostic significance of PARP1 expression in these patients. In the entire analyzed group of patients (with and without nodal metastases at the time of diagnosis), PARP1 expression was associated with a high mitotic index (p = 0.001) and the presence of ulceration (p = 0.036). Moreover, in patients with elevated PARP1 expression, melanoma was more frequently located in the skin of the head and neck region (p = 0.015). In multivariate analysis, high PARP1 expression was an independent unfavorable prognosticator in lymph node-negative cutaneous melanoma patients. (4) Conclusions: In vitro molecular biology approaches demonstrated enhanced PARP1 expression in cutaneous melanoma. These results were confirmed by the immunohistochemical study with clinical parameter analysis, which showed that a high level of PARP1 correlated with unfavorable clinical outcome. These observations raise the potential role of PARP1 inhibitor-based therapy in cutaneous melanoma.

Clinicopathological Features and Prognostic Factors of Primary Acral Melanomas in Caucasians.

Background: Cutaneous melanomas located on the acral part of extremities (hand and foot melanoma; HFM) comprise a rare group within all melanomas in Caucasians. HFM is associated with a poor prognosis. We aimed to evaluate clinicopathological features, long-term outcomes, and prognostic factors in primary HFM in Caucasians. Methods: Medical records of all consecutive patients treated between 1997 and 2014 were revised. Patients were diagnosed with primary cutaneous melanoma at I-II clinical stage, and sentinel lymph node biopsy was conducted. The analysis was performed to define the clinicopathological factors influencing outcomes in the HFM and subungual cohort. Among 2537 consecutive patients diagnosed with primary cutaneous melanoma, 247 cases of HFM (9.7%) were found, with a median follow-up time of 7.8 years. Results: Median primary tumor Breslow thickness in subungual melanomas and HFMs was 4.0 mm and 3.3 mm, respectively, significantly higher than in the entire population (median 2.2 mm; p < 0.01). In the HFM group, 37.6% of tumors were ulcerated. Metastases to sentinel lymph node (SLN) were found in 28.3% of HFMs. The 10-year overall survival rate in the HFM group and subungual melanomas was 48.1% and 49.3%, respectively, compared to 63.0% in non-HFM melanomas. Conclusions: Our results confirm that patients with HFMs display worse overall survival compared to the entire melanoma population, with male gender and positive SLN biopsy status acting as independent negative prognostic factors.

Features associated with melanoma metastasis in Latvia.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, exhibits an increasing incidence worldwide and has a high potential to develop metastasis. The current study aimed to identify a set of parameters that may aid in predicting the probability and timing of the onset of CM metastasis. A retrospective analysis was performed using the archive data of 2,026 patients with CM that were treated at the Riga East University Hospital Latvian Oncology Centre, which is the largest oncological hospital in the country, between 1998 and 2015. A case-control study design was employed, where patients with metastasis (n=278) were used as the cases and patients without metastasis were used as the controls. The present study examined the associations between metastasis and potential risk factors and constructed multivariate models of features that predicted metastasis using stepwise regression. Time until metastasis was analyzed using negative binomial regression models. The results of the present study indicated an increase in the number of melanomas that developed metastases during 1998–2015. Tumor Breslow thickness was demonstrated to be significantly larger in patients with metastasis compared with those without (P=0.012). The presence of ulceration significantly increased the risk of metastases [odds ratio (OR), 1.66; 95% CI, 1.07-2.59; P=0.033]. The absence of pigment in melanoma tissues was indicated to lead to a greater likelihood of metastasis (OR, 2.14; 95% CI, 1.10-4.19; P=0.035). Shorter times from diagnosis until the onset of metastases were observed in older patients (incident rate ratio (IRR), 6.85; 95% CI, 2.43-19.30; P=2.78×10−4), and a borderline significant association was observed in those with ulcerated tumors (IRR, 1.33; 95% CI, 0.98-1.80; P=0.064). Therefore, the main features associated with the development of melanoma metastasis in Latvia were indicated to be tumor ulceration, absence of pigment and Breslow thickness.

Impact of Biopsy Technique on Clinically Important Outcomes for Cutaneous Melanoma: A Systematic Review and Meta-analysis.

We performed a systematic review and meta-analysis to examine the relationship between the type of biopsy technique employed in the diagnosis of cutaneous melanoma and 4 clinically important outcomes: melanoma-specific mortality, all-cause mortality, Breslow tumor depth, or melanoma recurrence. Our database was obtained by searching PubMed, Ovid MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Library from inception until December 6, 2019. Studies were identified that compared biopsy techniques used to diagnose cutaneous melanoma with any of our study outcomes. We included 7 observational studies for our meta-analysis after screening 3231 titles and abstracts. Pooled data identified a significantly higher all-cause mortality in the punch biopsy group (risk ratio [RR], 1.520; P=.02). A higher, but nonsignificant, rate of melanoma-specific mortality (RR, 1.96; P=.22) and melanoma recurrence (RR, 1.20; P=.186) was also found for the punch biopsy group. Breslow tumor thickness was not significantly lower for punch incision (standardized mean difference, −0.42; P=.27). We found limited evidence for differences in clinically important outcomes across the spectrum of the most common methods employed in clinical practice for the initial diagnosis of cutaneous melanoma. A small, but significant, increase (P=.02) in all-cause mortality with punch biopsies was not seen for the other outcomes and was most likely due to small sample sizes and demographic differences in the included studies and unlikely represents a clinically important outcome. Our findings support the use of existing clinical practice guidelines for evaluating pigmented lesions suspicious for cutaneous melanoma.