Clinical and Imaging Follow-Up for High-Risk Cutaneous Melanoma: Current Evidence and Guidelines.

The most recent (eighth) edition of the American Joint Committee on Cancer (AJCC) staging system divides invasive cutaneous melanoma into two broad groups: "low-risk" (stage IA-IIA) and "high-risk" (stage IIB-IV). While surveillance imaging for high-risk melanoma patients makes intuitive sense, supporting data are limited in that they are mostly respective and used varying methods, schedules, and endpoints. As a result, there is a lack of uniformity across different dermatologic and oncologic organizations regarding recommendations for follow-up, especially regarding imaging. That said, the bulk of retrospective and prospective data support imaging follow-up for high-risk patients. Currently, it seems that either positron emission tomography (PET) or whole-body computerized tomography (CT) are reasonable options for follow-up, with brain magnetic resonance imaging (MRI) preferred for the detection of brain metastases in patients who can undergo it. The current era of effective systemic therapies (ESTs), which can improve disease-free survival (DFS) and overall survival (OS) beyond lead-time bias, has emphasized the role of imaging in detecting various patterns of EST response and treatment relapse, as well as the importance of radiologic tumor burden.

Long-term outcomes after amputation and sentinel node biopsy for subungual melanoma: A single-institution series.

BACKGROUND: Subungual melanoma (SUM) is a rare tumor with historically poor outcomes. Thus, the benefit of proximal versus distal amputation in SUM remains unclear. METHODS: We performed a retrospective review of our prospectively-maintained institutional melanoma database, including SUM and non-subungual acral melanoma (AM) patients who underwent sentinel lymph node biopsy (SLNB) between 1999 and 2022. All SUMs had distal joint or proximal amputations. Primary endpoints were overall survival (OS) and recurrence free survival (RFS). Kaplan-Meier estimates, and Cox univariate and multivariate analyses were performed. Tests were repeated on propensity score matched (PSM) populations in a 2:1 ratio. RESULTS: 123 patients underwent resection with SLNB for SUM (n â€‹= â€‹27) and AM (n â€‹= â€‹96). Median follow-up was 9.2 years. Unadjusted median OS was 149.1 months for AM and 198.1 months for SUM. In the PSM comparison, median OS and RFS remained comparable between SUM and AM (149.5 months versus 198.1 months; p â€‹= â€‹0.612). Sentinel node positivity was associated with significantly worse overall survival outcome (Hazard Ratio 5.49; CI (1.59-18.97), p â€‹= â€‹0.007). In the PSM population, male sex was also associated with a significant hazard of death (HR 3.00, CI (1.03-8.71), p â€‹= â€‹0.043). Proximal amputations were associated with significantly worse OS (p â€‹< â€‹0.002) and RFS (p â€‹< â€‹0.01) compared to distal amputations in SUM. CONCLUSION: SUM was well-treated with distal amputations, and had better OS and RFS compared to SUM treated with proximal amputations. Sentinel lymph node status is an important prognostic factor for SUMs and AMs. SUMs can be treated similarly to AMs with comparably good long-term outcomes.

Metastasectomy for metastatic melanoma in the era of effective systemic therapy.

INTRODUCTION: Effective systemic therapy (EST) in patients with metachronous metastatic melanoma (MMM) improves survival and alters surgical decision-making. Surgical metastasectomy is another treatment option, however, it is unclear if metastasectomy confers survival benefit. This study seeks to identify any survival benefit associated with surgical management of MMM. METHODS: Patients with MMM from 2009 to 2021 were grouped by receipt of metastasectomy and treatment era (pre-versus post-EST). Overall survival (OS) was calculated from date of metastasis and evaluated with Kaplan-Meier analysis. RESULTS: Our dataset identified 226 patients with MMM; 32% were diagnosed pre-EST. On Kaplan-Meier analysis, OS was improved for patients undergoing treatment post-versus pre-EST (p < 0.001). In the post-EST era, metastasectomy was associated with an increase in OS compared to no resection (p = 0.022). CONCLUSIONS: In the post-EST group, EST paired with metastasectomy was associated with improved OS compared to the pre-EST group, suggesting persistent evidence of a survival benefit from metastasectomy.

Routine imaging guided by a 31-gene expression profile assay results in earlier detection of melanoma with decreased metastatic tumor burden compared to patients without surveillance imaging studies.

Patients with early-stage disease typically have a good prognosis, but still have a risk of recurrence, even with negative sentinel lymph node biopsy (SLNB). This study explores the utility of routine imaging to detect metastases in patients with negative SLNB but high-risk 31 gene expression profile (31-GEP) scores. We retrospectively identified melanoma patients with negative SLNBs. Patients with high-risk GEP results were placed in the experimental group and patients without GEP testing were placed in the control group. Among both cohorts, recurrent melanoma groups were identified. The tumor burden at the time of recurrence and the time to recurrence were compared between experimental group patients with routine imaging and control group patients without imaging schedules. We identified 327 control patients and 307 experimental patients, of which 14.1% versus 20.5% had melanoma recurrence, respectively. Of the patients with recurrent melanoma, those in the experimental group were older (65.75 versus 59.20), had higher Breslow depths (3.72 mm versus 3.31 mm), and had advanced tumor staging (89.5% versus 71.4% of patients presenting clinical stage ≥ II) compared to the control group at primary diagnosis. However, melanoma recurrence was detected earlier (25.50 months versus 35.35 months) in the experimental group at a lower overall tumor burden (73.10 mm versus 27.60 mm). A higher percentage of experimental patients started immunotherapy when offered (76.3% and 67.9%). Patients who received routine imaging after high-risk GEP test scores had an earlier recurrence diagnosis with lower tumor burden, leading to better clinical outcomes.

A Clinical Decision Tool to Calculate Pretest Probability of Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma.

BACKGROUND: Although sentinel lymph node biopsy (SLNB) status is a strong prognostic indicator for cutaneous melanoma, unnecessary SLNBs have substantial cost and morbidity burden. OBJECTIVE: This study was designed to develop, validate, and present a personalized, clinical, decision-making tool using nationally representative data with clinically actionable probability thresholds (Expected Lymphatic Metastasis Outcome [ELMO]). METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) Registry from 2000 to 2017 and the National Cancer Database (NCDB) from 2004 to 2015 were used to develop and internally validate a logistic ridge regression predictive model for SLNB positivity. External validation was done with 1568 patients at a large tertiary referral center. RESULTS: The development cohort included 134,809 patients, and the internal validation cohort included 38,518 patients. ELMO (AUC 0.85) resulted in a 29.54% SLNB reduction rate and greater sensitivity in predicting SLNB status for T1b, T2a, and T2b tumors than previous models. In external validation, ELMO had an accuracy of 0.7586 and AUC of 0.7218. Limitations of this study are potential miscoding, unaccounted confounders, and effect modification. CONCLUSIONS: ELMO ( https://melanoma-sentinel.herokuapp.com/ ) has been developed and validated (internally and externally) by using the largest publicly available dataset of melanoma patients and was found to have high accuracy compared with other published models and gene expression tests. Individualized risk estimates for SLNB positivity are critical in facilitating thorough decision-making for healthcare providers and patients with melanoma.

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

Sentinel lymph node biopsy in patients with T1a cutaneous malignant melanoma: A multicenter cohort study.

BACKGROUND: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN+) in this population are poorly characterized. OBJECTIVE: To determine factors associated with SLN+ in patients with T1a melanoma. METHODS: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN+ were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into ≤42 (25% quartile cutoff) and >42 years. RESULTS: Of the 965 patients identified, the overall SLN+ was 4.4% (N = 43). Factors associated with SLN+ were age ≤42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and ≥2 mitoses/mm2 (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with ≥2 mitoses/mm2 (N = 38) had a SLN+ rate of 18.4%. LIMITATIONS: Retrospective study. CONCLUSION: SLN+ is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN+.

Clinical Utility of Dermoscopy and 31-Gene Expression Profiling by Dermatology Providers in Melanoma Management Care.

OBJECTIVE: A 31-gene expression profile (31-GEP) test that predicts metastatic risk in patients with cutaneous malignant melanoma (CMM) has previously been validated and is available for clinical use. The test dichotomizes patients into lower risk and higher risk groups based on differences that correspond to unique genetic expression patterns. Although the impact of such a test on dermatology providers' clinical decision-making has been studied, little is known about whether there exists an association between certain clinical features, such as dermoscopy, and 31-GEP results. METHODS: In this retrospective analysis of 31-GEP test results ordered by dermatologists, we evaluated the frequency of dermoscopic features, using a modified dermoscopy three-point checklist, in 17 cases (n=17) and compared these findings to other key clinicopathologic features including tumor thickness, ulceration, and mitotic rate to 31-GEP results. Additionally, we evaluated the dermatologist's perspective and incorporation of GEP testing as part of patient discussion on melanoma management. RESULTS: 31-GEP stratified patients into 4 groups; groups 1A and 1B are considered low risk of metastasis or recurrence, while 2A and 2B are considered high risk. Of the 17 cases, we had fifteen group 1A (88.23%), one 1B (5.88%), and one 2B (5.88%) result. Overall frequency of dermoscopic features is as follows; 100% of lesions presented with asymmetry, 47% with round structures, and 70.6% with blue-white color. The average time providers spent explaining and ordering the test was 15 minutes, with a range of 10 to 20 minutes. CONCLUSIONS: This study represents our experience and understanding of the dermatologist’s role ordering 31-GEP in the care pathway of melanoma patients and we recommend that dermatology providers consider ordering the test for newly diagnosed CMM patients. J Drugs Dermatol. 2022;21(12): doi:10.36849/JDD.6889.

Efficacy of Abemaciclib in the Management of Refractory Metastatic Extramammary Paget's Disease.

Published systemic therapy options for metastatic extramammary Paget's disease have largely been anecdotal due to the rarity of this disease, which has precluded the ability to conduct clinical trials. We describe the favorable response of a 72-year-old man with extramammary Paget's disease, whose disease has been controlled with the CDK4/6 inhibitor, abemaciclib. The rationale behind the selection of this therapy is discussed.

Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

The efficacy of immune checkpoint blockade for melanoma in-transit with or without nodal metastases - A multicenter cohort study.

PURPOSE: Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. METHODS: A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. RESULTS: A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. CONCLUSION: Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

Is the presence of tumor-infiltrating lymphocytes predictive of outcomes in patients with melanoma?

BACKGROUND: The significance of tumor-infiltrating lymphocytes (TILs) in melanoma is debated. This article presents a multicenter, retrospective study assessing the predictive and prognostic value of TILs. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with known TIL data. TILs were categorized as absent or present, which included nonbrisk (NB), brisk (B), and present but unspecified TIL levels. Clinicopathologic factors were correlated with TILs, sentinel lymph node (SLN) status, and melanoma-specific survival (MSS). RESULTS: Overall, 3203 patients were included. The median thickness was 1.5 mm, and 469 cases had SLN metastases. TILs were present in 2458 cases (76.7%), with NB, B, and unspecified TILs seen in 1691 (68.8%), 691 (28.1%), and 76 (3.1%), respectively. Multivariable analysis showed that the presence of TILs significantly predicted a negative SLN biopsy (P < .05). The median follow-up was 25.2 months. MSS was significantly better for cases with TILs than cases without TILs (P < .001). According to multivariable analysis, age, gender, thickness, mitotic rate, ulceration, lymphovascular invasion, and SLN status were significantly prognostic of MSS (all P values < .05). Although TILs were not prognostic of MSS, when multiple imputation was used and the SLN status was excluded, the presence of TILs was significantly prognostic of improved MSS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.95; P = .0154). CONCLUSIONS: TILs are a favorable marker because their presence significantly predicts a negative SLN, and the absence of TILs may be a prognostic marker of worse survival in patients with a positive SLN but not a negative SLN. TILs may also serve as a prognostic marker of survival when the SLN status is not considered.

Expanded evidence that the 31-gene expression profile test provides clinical utility for melanoma management in a multicenter study.

OBJECTIVE: National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma (CM) recommend physicians consider increased surveillance for patients who typically have lower melanoma survival rates (stages IIB-IV as determined by the American Joint Committee on Cancer (AJCC), 8th edition). However, up to 15% of patients identified as having a low recurrence risk (stages I-IIA) experience disease recurrence, and some patients identified as having a high recurrence risk will not experience any recurrence. The 31-gene expression profile test (31-GEP) stratifies patient recurrence risk into low (Class 1) and high (Class 2) and has demonstrated risk-appropriate impact on disease management and clinical decisions. METHODS: Five-year plans for lab work, frequency of clinical visits, and imaging pre- and post-31-GEP test results were assessed for a cohort of 509 stage I-III patients following an interim subset analysis of 247 patients. RESULTS: After receiving 31-GEP results, 50.6% of patients had a change in management plans in at least one of the following categories-clinical visits, lab work, or surveillance imaging. The changes aligned with the risk predicted by the 31-GEP for 76.1% of patients with a Class 1 result and 78.7% of patients with a Class 2 result. A Class 1 31-GEP result was associated with changes toward low-intensity management recommendations, while a Class 2 result was associated with changes toward high-intensity management recommendations. CONCLUSION: The 31-GEP can stratify patient recurrence risk in patients with CM, and clinicians understand and apply the prognostic ability of the 31-GEP test to alter patient management in risk-appropriate directions.

When caught early, cancer of the skin can usually be removed, and patients have excellent chances of survival. However, some patients will have their cancer come back or spread to a new location in their body.The 31-gene expression profile (GEP) test measures the expression levels of 31 genes from an individual patient's tumor. A proprietary formula uses this information to identify the risk of recurrence or spread as low risk (Class 1) or high risk (Class 2). Cancers with low-risk 31-GEP scores have a lower chance of cancer recurrence or spread than patients with a high-risk score.In this study, we wanted to determine if doctors treated patients with low-risk scores differently from patients with high-risk scores. We found that doctors changed approximately half of patient treatment plans (doctor visits, lab work, or imaging to see if the cancer has come back) after learning the 31-GEP test results. Doctors usually planned less frequent follow-up visits for Class 1 results and more frequent follow up for Class 2 results.This study found doctors understand and make changes to their treatment plans based on the patient's 31-GEP test result.

Is There a Relationship Between TILs and Regression in Melanoma?

BACKGROUND: The relationship between tumor-infiltrating lymphocytes (TILs) and regression in melanoma is unknown. This report describes a large multicenter study assessing the association between TILs and regression. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with TILs and regression data. Clinicopathologic factors were correlated with regression and TIL status, sentinel lymph node (SLN) status, and overall survival (OS). RESULTS: The study enrolled 2450 patients. In 1811 cases, TILs (73.9%) were present, with regression present in 328 of these 1811 (18.1%) cases and in 49 (7.7%) of 639 cases without TILs. The presence of TILs was significantly associated with regression (p < 0.0001) as well as a negative SLN (p < 0.05). However, when TILs were stratified by regression status, only absence or presence of both TILs and regression were significantly associated with SLN metastases (p = 0.038). Although the presence of TILs was associated with OS (p < 0.05), regression status by itself was not (p = 0.2058 and 0.252, respectively). Furthermore, when TILs were stratified by regression status, only the presence of TILs with or without regression was significantly associated with improved OS (p = 0.0081 and 0.0137, respectively) versus the absence of both TILs and regression, with regression status not significantly affecting OS for patients with or without TILs (p = 0.2314 and 0.65, respectively). CONCLUSIONS: Regression is highly correlated with TILs, but only TILs are significantly associated with SLN metastasis and OS in melanoma patients, whereas regression is not. The impact of regression on outcomes ultimately appears dependent upon the absence or presence of TILs.