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.