Early Cutaneous Melanoma Research Articles

Adjuvant PD-1 Checkpoint Inhibition in Early Cutaneous Melanoma: Immunological Mode of Action and the Role of Ultraviolet Radiation.

Melanoma ranks as the fifth most common solid cancer in adults worldwide and is responsible for a significant proportion of skin-tumor-related deaths. The advent of immune checkpoint inhibition with anti-programmed death protein-1 (PD-1) antibodies has revolutionized the adjuvant treatment of high-risk, completely resected stage III/IV melanoma. However, not all patients benefit equally. Current strategies for improving outcomes involve adjuvant treatment in earlier disease stages (IIB/C) as well as perioperative treatment approaches. Interfering with T-cell exhaustion to counteract cancer immune evasion and the immunogenic nature of melanoma is key for anti-PD-1 effectiveness. Yet, the biological rationale for the efficacy of adjuvant treatment in clinically tumor-free patients remains to be fully elucidated. High-dose intermittent sun exposure (sunburn) is a well-known primary risk factor for melanomagenesis. Also, ultraviolet radiation (UVR)-induced immunosuppression may impair anti-cancer immune surveillance. In this review, we summarize the current knowledge about adjuvant anti-PD-1 blockade, including a characterization of the main cell types most likely responsible for its efficacy. In conclusion, we propose that local and systemic immunosuppression, to some extent UVR-mediated, can be restored by adjuvant anti-PD-1 therapy, consequently boosting anti-melanoma immune surveillance and the elimination of residual melanoma cell clones.

Ganglio centinela positivo en melanoma: factores predictivos y resultados del vaciamiento ganglionar

Background: Sentinel lymph node (SLN) biopsy is the technique accepted to determine the prognosis of early cutaneous melanomas. The advantage of lymph node dissection (LND) when SLN biopsy is positive has recently been questioned. Objective: The aim of this study is to describe the percentages and factors associated with SLN and non-sentinel node (NSN) metastases in LNDs of SLN-positive patients. Material and methods: The clinical records and pathology reports of 139 patients undergoing surgery for cutaneous melanoma between January 2012 and December 2019 were retrospectively reviewed. Results: Ninety-six (69%) patients underwent SLN biopsy. Mean age was 61.7 ± 17.5 years (19-93) and 53 (55.2%) were men. The primary lesion was located in the extremities in 47 (49%) cases, in the trunk in 39 (40.6%), and in the head and neck in 10 (10.4%). Mean Breslow thickness was 5.01 mm (1.05-50 mm) and ulceration was found in 35 cases (36.4%). The SLN was identified in all the cases and was positive in 39 (40.6%). There was an association with thickness ≥ 3 mm (p = 0.000017) and ulceration (p = 0.0011). Those patients with positive SLN biopsy underwent LND of the territory involved: axillary in 23, inguinal in 10 and cervical in 6. Twenty-three (59%) presented NSLN metastases and were associated with thickness (p = 0.022) and ulceration (p = 0.019). Conclusion: There was a high percentage of positive NSLN in the population studied which was associated with thickness and ulceration. These characteristics and the difficulty to achieve strict follow-up are the reasons for completion LND in SLN-positive patients.

Adjuvant immunotherapy for melanoma

Surgical resection is the treatment for early cutaneous melanoma and is often curative. Some patients, however, will subsequently relapse. High-risk features in the primary tumor and regional lymph node metastasis highlight patient subsets that are at increased risk for recurrent disease. Immunotherapy in the form of checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have been shown to improve recurrence-free survival for node-positive melanoma in the adjuvant setting and will be the focus of this review.

Noninvasive Analysis of High-Risk Driver Mutations and Gene Expression Profiles in Primary Cutaneous Melanoma

Tools that help reduce the number of surgical biopsies performed on benign lesions have the potential to improve patient care. The pigmented lesion assay (PLA) is a noninvasive tool validated against histopathology that helps rule out melanoma and the need for surgical biopsies of atypical pigmented skin lesions. Genetic information is collected using adhesive patches and the expression of two genes, LINC and PRAME, is measured. By using genetic material collected noninvasively and to further validate the PLA, somatic hotspot mutations in genes known to be drivers of early melanoma development (BRAF other than V600E, NRAS, and the TERT promoter) can also be identified. The frequency of these hotspot mutations in samples of early melanoma was 77%, which is higher than the 14% found in nonmelanoma samples (P < 0.0001). TERT promoter mutations were the most prevalent mutation type in PLA-positive melanomas; 82% of PLA-negative lesions had no mutations, and 97% of histopathologically confirmed melanomas were PLA and/or mutation positive (cohort 1, n= 103). Mutation frequencies were similar in prospectively collected real-world PLA samples (cohort 2, n= 519), in which 88% of PLA-negative samples had no mutations. Combining gene expression and mutation analyses enhances the ability to noninvasively detect early cutaneous melanoma.

Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: a 5-year survival analysis.

The presence of ulceration has been considered as one of the most important primary tumor characteristics of cutaneous malignant melanoma (CMM) for predicting patient outcome. Yet recently, scientific attention has been drawn towards another microscopic feature of primary tumors, the mitotic rate (MR). The present study aimed to examine the relationship between the presence of ulceration and the mitotic rate and clinicopathological characteristics and melanoma patient survival, and to discuss the results in the context of AJCC melanoma staging recommendations. Tissue samples were obtained from 104 patients treated for CMM. In classical H&E staining, the mitotic rate and the presence of ulceration were evaluated. Non-mitogenic tumors were defined as having 0 mitoses/mm2, low mitogenic potential, 1-2 mitoses/mm2 and highly mitogenic tumors, ≥3 mitoses/mm2. In the entire group of 104 patients, a high mitotic rate (hMR) and ulceration were highly negative prognostic factors, and indicated considerably shorter overall survival, cancer-specific overall survival and disease-free survival. Notably, hMR appeared to have a statistically significant negative impact on survival in early melanomas in both the pT1 (P=0.001) and pT2 subgroups (P=0.006). Kaplan‑Meier analysis of the remaining subsets (pT3 and pT4) did not reveal any important differences in the 5-year survival with regard to MR values. The presence of ulceration also had a prognostic significance for early melanomas, but only for pT1 tumors (P=0.05). Multivariate analysis confirmed that hMR was strongly associated with an unfavorable prognosis. Ulceration had no prognostic significance in the Cox proportional hazards model. Considering the biology of melanoma, hMR seems to be a more reliable parameter than the presence of ulceration. The value of MR categorizes melanomas into tumors with low or high proliferative potential, thus giving direct information concerning their capacity to infiltrate deeper layers of the dermis and, potentially, to generate regional lymph node and distant metastases.

Modern non-invasive diagnostic techniques in the detection of early cutaneous melanoma.

Over the past few years melanoma has grown into a disease of socio-economic importance due to the increasing incidence and persistently high mortality rates. Melanoma is a malignant tumor with a high tendency to metastasize. Therefore, an extremely important part of the therapeutic process is to identify the disease at an early stage: in situ or stage I. Many tools for early diagnosis of melanoma are available today, including dermoscopy, videodermoscopy and in vivo reflectance confocal microscopy. Other methods such as high frequency ultrasound, optical coherence tomography and electrical impedance spectroscopy may serve as additional diagnostic aids. Modern imaging techniques also allow the monitoring of melanocytic skin lesions over months or years to detect the moment of malignant transformation. This review summarizes the current knowledge about modern diagnostic techniques, which may aid early diagnosis of melanoma.

A 10‐year analysis of primary cutaneous malignant melanoma with sentinel lymph node biopsy and long‐term follow‐up

Sentinel lymph node biopsy (SLNB) is an important tool for accurate staging of patients with melanoma. There is an ongoing debate whether the procedure provides therapeutic benefits or not. We wanted to analyze 10-year data from an academic teaching hospital. During 1999-2009, 977 patients with early cutaneous melanoma have been treated. Of these, 419 patients had tumors ≥ 1 mm thickness. Patients with head and neck tumors were excluded, leaving 364 patients (202 men and 162 women). SLNB was not performed in 163 patients but was performed in 201 patients. For correction of bias, tumors >4 mm thickness were excluded from further statistical analysis. The detection rate of SLN was 94.4%. False negative SLN were observed in 8.9%. Adverse effects occurred in 5.5%. The rate of positive SLNB was 16.4% and lymph node involvement 20%. Patients undergoing SLNB had a lower relapse rate (10.6% vs. 33.3%; P < 0.001). The most important finding is an almost 50% lower total death rate and melanoma-related death rate in the SLNB subgroup (P < 0.001 for both). Sentinel lymph node biopsy is an accurate instrument for melanoma staging to detect occult regional lymph node involvement. Data suggest a positive effect on relapse-free survival. The observation of improved long-term survival needs validation in prospective multicenter trials. The limitations of this study were that it was a single center retrospective analysis.

The value of cyclooxygenase-2 expression in differentiating between early melanomas and histopathologically difficult types of benign human skin lesions

Early cutaneous melanomas may present a substantial diagnostic challenge. We have already reported that expression of cyclooxygenase-2 (COX-2) may be useful for differentiating between cutaneous melanomas and naevi. The purpose of this study was to examine the value of COX-2 in a challenging task of differential diagnosis of early melanomas and melanocytic naevi considered by histopathologists as morphologically difficult to unequivocally diagnose as benign lesions. The material for the study comprised formalin-fixed paraffin-embedded samples of 46 naevi (including 27 cases of dysplastic, Spitz and Reed naevi) and 30 early human cutaneous melanomas. The expression of COX-2 was detected immunohistochemically. Melanomas expressed COX-2 significantly more strongly compared with naevi. The test, on the basis of determination of the percentage fractions of COX-2-positive cells, allows for differentiation of early skin melanomas and naevi with high sensitivity and specificity. Receiver operating characteristic analysis of the test results yielded areas under receiver operating characteristics curves (AUC)=0.946±0.030 for central regions and AUC=0.941±0.031 for the peripheries of the lesions. The performance of the test in differentiating between melanomas and the naevi group comprising dysplastic, Spitz and Reed naevi was also good, with AUC=0.933±0.034 and 0.923±0.037 for the central and the border regions of the lesions, respectively. Using a more complex diagnostic algorithm also accounting for the staining intensity did not result in an improvement in the resolving power of the assay. A diagnostic algorithm using differences in the percentage fractions of cells expressing COX-2 may serve as a useful tool in aiding the differential diagnosis of 'histopathologically difficult' benign melanocytic skin lesions and early melanomas.

Geometric Cutaneous Melanoma

BACKGROUND Malignant melanomas change shape in a random pattern, with ovoid, crescentic, or nodular shapes seen most frequently. We have observed a number of malignant melanomas that have presented with a geometric, angular shape and have noted that pigmented lesions with this configuration are often found to be malignant. We present 20 patients with malignant melanoma whose lesion displayed a geometric, angular shape. METHODS Before excision for formal histopathology, all lesions were scored using the seven-point checklist and ABCDE systems and were divided into low-risk or significant risk of melanoma. RESULTS Five different geometric shapes were observed. Depending on the scoring system employed, 20% to 40% of the geometric melanomas were considered to be of low risk of malignancy. CONCLUSION The development of geometrical angular patterns in a malignant melanoma may represent a morphologic growth pattern that can be used as a clinical risk sign. Even apparently benign low-risk lesions with a geometric shape may pose a significant risk of malignant melanoma. By definition, the majority of lesions that are morphologically geometric are symmetrical in shape, which is more in favor of a benign diagnosis. This may increase the likelihood that early cutaneous melanomas with a geometric shape may be missed. Any pigmented lesion with a geometric configuration should raise the clinician's suspicion of malignancy even if considered otherwise to be of low risk by the standard melanoma checklists.

Geometric cutaneous melanoma: a helpful clinical sign of malignancy?

Malignant melanomas change shape in a random pattern, with ovoid, crescentic, or nodular shapes seen most frequently. We have observed a number of malignant melanomas that have presented with a geometric, angular shape and have noted that pigmented lesions with this configuration are often found to be malignant. We present 20 patients with malignant melanoma whose lesion displayed a geometric, angular shape. Before excision for formal histopathology, all lesions were scored using the seven-point checklist and ABCDE systems and were divided into low-risk or significant risk of melanoma. Five different geometric shapes were observed. Depending on the scoring system employed, 20% to 40% of the geometric melanomas were considered to be of low risk of malignancy. The development of geometrical angular patterns in a malignant melanoma may represent a morphologic growth pattern that can be used as a clinical risk sign. Even apparently benign low-risk lesions with a geometric shape may pose a significant risk of malignant melanoma. By definition, the majority of lesions that are morphologically geometric are symmetrical in shape, which is more in favor of a benign diagnosis. This may increase the likelihood that early cutaneous melanomas with a geometric shape may be missed. Any pigmented lesion with a geometric configuration should raise the clinician's suspicion of malignancy even if considered otherwise to be of low risk by the standard melanoma checklists.

The “Missing Link” in the Chain of Discovery of Early Melanoma of the Skin

A34-year-old male internist working at a large teaching hospital died of metastatic melanoma 3 years after a silent primary tumor was discovered by his wife. The patient’s wife, a pediatric resident, noted the lesion on his back after attending a lecture on melanoma and premelanoma. The patient had been seen annually by his primary care physician, and during these encounters the primary melanoma was present on his back but was overlooked. In addition, he had 4 of the 6 MMRISK factors: 1) inability to tan, 2) severe sunburns in youth, 3) family history of cutaneous melanoma, and 4) the presence of 6 dysplastic nevi (Table). The primary care physician was not alert to the fact that the patient had a high risk of melanoma. If the primary tumor had been identified early and excised, the patient’s probability of 5-year survival would have been >90%. Table MMRISK: a mnemonic for melanoma The “missing link” is the failure of the primary physician to discover melanoma early in a curable stage by inspecting the skin during the initial encounter. Inspection and assessment of all moles and pigmented lesions is an essential part of every physical examination. The detection of early melanoma is in the hands and eyes of the primary care physicians (generalists, gynecologists, internists). Early melanoma is missed because most physicians do not examine the skin adequately. Inspection of the skin in white patients at the time of the first visit is a necessary part of good patient care, just as is taking the blood pressure. Even if the physician cannot make the diagnosis, he or she should look for large (>1.0 cm) dark-brown lesions with the 2 cardinal signs of atypicality: irregular borders and variegation of color. The patient can then be referred to a dermatologist for dermatoscopy (epiluminescence microscopy) and/or surgical excision of the lesion for biopsy. Having each white patient complete a simple, user-friendly checklist of the MMRISK factors of cutaneous melanoma on the initial information form is enormously helpful in judging who is at high risk for acquiring melanoma and how frequently they should have a skin scan by their physician or a dermatologist. Having this at hand and seeing melanoma risk factors alerts the primary physician or nurse to inspect the total skin surface for suspicious pigmented lesions. When individuals with black skin acquire primary cutaneous melanoma, the palms, soles, mucous membranes, and nailfolds are sites of predilection. Too many people are dying of melanoma principally because most physicians are not “on the alert” for pigmented lesions in the physical examination and overlook early cutaneous melanomas, especially on the backs of men and women or on the legs of women. This failure to examine the total skin in persons at high risk for melanoma constitutes a serious deviation of the standard of care.

Cathepsin D expression in early cutaneous malignant melanoma.

The aspartic proteinase cathepsin D is believed to be associated with proteolytic processes leading to the invasion and seeding of tumor cells. An association between cathepsin D tissue concentration and aggressiveness of tumors has been detected in different cancer types, as well as in metastatic melanoma. The concentration of cathepsin D was measured immunoradiometrically (ELSA-CATH-D kit, CIS Bio International) in the cytosols of 51 primary cutaneous melanomas (with Breslow index < 4 mm) to estimate the tissue concentrations of cathepsin D in early cutaneous melanoma. A significantly elevated concentration of cathepsin D was measured in the tumor cytosols as compared to adjacent normal tissue (44.2 vs. 14.7 pmol/mg of total protein, P < 0.001). Our results indicate that cathepsin D is expressed at high levels by melanoma cells. The extremely high expression of cathepsin D in two of our patients, with later progression of the disease over a 42-month follow-up period, suggests a possible correlation between the cathepsin D tissue concentration and the prognosis of primary cutaneous malignant melanoma.

Small melanomas

The ABCD (asymmetry, border, colour, dimension) criteria represent a commonly used clinical guide for the diagnosis of early cutaneous melanoma (CM). This guide stipulates that CMs usually are more than 6 mm in diameter. The purpose of this retrospective study was to establish the frequency of occurrence of small (< or =6 mm) melanomas in a clinical context. Our series consisted of 270 consecutive CMs (39 in situ and 231 invasive) in 267 patients. Of these 270 lesions, 47 (17%) were small lesions, ranging from 2 to 6 mm in maximum linear extent, with a median value of 5 mm. Of these small lesions, 14 were in situ and 33 Invasive CMs. The median thickness of the 33 small invasive lesions was 0.31 mm. The clinical features of CMs were sufficiently distinctive to suggest a diagnosis of CM in half of the cases, irrespective of the invasiveness or not of the lesions. Dermatoscopy was performed on 36 of the small lesions and achieved a correct diagnosis in 72% of the cases. The combination of simple visual examination with dermatoscopy allowed a higher rate of recognition (86%) than when the two methods were considered separately. Results of our study show that small CMs represent a considerable clinical subset of all CMs. Clinicians must be aware of this fact in their diagnostic activity.

CLINICAL RECOGNITION OF MELANOMA AND ITS PRECURSORS

This article reviews the essential clinical features of cutaneous melanoma, as well as those of the more common benign pigmented lesions that need to be distinguished on clinical examination.

Clinical characteristics of early cutaneous melanoma

Clinical characteristics of the primary tumor in 786 patients with superficial spreading melanoma were studied in a prospective sequential series of patients from the Melanoma Clinical Cooperative Group. The most useful features for early diagnosis were change in size and change in color, present in 71% and 55% respectively of patients with level II lesions. Increase in height of lesion correlated with more advanced disease. Ulceration and bleeding were predominantly found in advanced primary lesions and are consequently of limited use in early recognition. Awareness of the historical and clinical features of the primary tumor should result in early recognition and cure of most primary superficial spreading melanomas.