1. Introduction:Melanoma is a highly aggressive form of skin cancer characterized by a propensity for early metastasis, resulting in the highest mortality rate among skin cancers (2.7 deaths per 100,000) [1, 2]. With its incidence reaching 22.0 per 100,000 in 2018 and an average increase of 1.2% per year since 2009, reducing mortality in patients with melanoma has become a top priority [2, 3]. The advent of immune checkpoint inhibitors has transformed adjuvant therapy for patients with metastatic melanoma. PD-1 inhibitor therapy with nivolumab or pembrolizumab has become the standard adjuvant treatment for patients with resected stage III and stage IV melanoma [4, 5].
However, the decision to initiate adjuvant care for patients with low-stage (I-II) melanoma is more complex. Despite lower staging, stage IIA-IIC melanomas still have a 12-25% 10-year mortality rate [6]. Standard of care for these patients consists of a wide local excision with margins according to lesion Breslow depth, with sentinel lymph node biopsy being offered to all medically suitable candidates with intermediate thickness melanomas or low thickness melanomas with ulceration and/or high mitotic figures [7]. Some patients are then considered candidates for adjuvant therapy to prevent recurrence. Recently the Keynote 716 trial demonstrated that in resected stage IIB or IIC melanoma, pembrolizumab treatment decreased rates of recurrence from 24% to 15% compared to placebo [8]. However, immune checkpoint inhibitors carry the risk of serious side effects including pneumonitis, pancreatitis, myelitis, colitis, thyroiditis, and severe skin reactions [8, 9]. In the same trial, 16% of patients receiving pembrolizumab had a Grade 3 or greater adverse reaction, compared to 4% in the placebo arm [8]. Additionally, most patients on placebo did not see a recurrence in their melanoma without treatment, indicating if the entire IIB-IIC population were to be treated in the adjuvant setting we would be overtreating roughly 70% of patients. Given the risk of serious adverse events and the relatively small reduction in recurrence risk, it remains unclear which stage II melanoma patients should receive adjuvant anti-PD1 therapy. Identifying a subpopulation of early stage melanoma patients at higher risk for progression could spur future trials testing immunotherapy or other interventions specifically within this group.
Several histopathological prognostic predictors for low-stage melanoma are currently utilized including lesion ulceration, thickness, mitotic rate, neutrophil count, microsatellites, and tumor-infiltrating lymphocyte (TIL) status [10-13]. Ulceration is an independent risk factor for decreased overall survival and is included in staging [10]. Non-histopathological prognostic factors may also be used to inform decisions to start adjuvant therapy. Molecular analyses, like the DecisionDx-Melanoma assay, have been increasingly utilized; however, their prognostic ability varies by stage and is not reliable in predicting recurrence for low-stage melanoma patients [14].This test additionally is limited by lack of ability to monitor for recurrence longitudinally and may incur significant costs for the patient, highlighting the need for alternative predictors to stratify low-stage patients. Circulating tumor-DNA is another tool being investigated to assess prognosis in metastatic melanoma, but its use in deciding initial treatment remains limited [15].
In this retrospective chart review, we analyzed patients with stage I-II melanoma at our institution between 2010-2022 to determine independent variables associated with progression-free survival within readily available pathology reports. We hypothesized that absent TIL status would be associated with worse progression-free survival since the adaptive immune response is critical for anti-tumor response in melanoma [9, 16]. Evidence already exists that TIL may be a useful tool for assessing risk in thicker tumors, but there are ambiguous results when thin and radial growth melanomas are included [17]. Herein, we evaluate the prognostic value of commonly reported histopathologic findings in biopsy and surgical pathology specimens for stage I-II melanoma patients to identify higher-risk patients that may benefit from closer follow-up or early intervention.