Many factors confound the interpretation of radiographic imaging for cancer patients receiving systemic therapy during the COVID-19 pandemic. Like other strongly immunogenic vaccines, COVID-19 vaccines can serve as strong antigenic stimuli resulting in unilateral adenopathy [
15]. While clinical context remains a key determinant in the evaluation and management of patients with lung cancer, evolving information regarding COVID-19 vaccination has shaped the approach and level of caution. While our patient appeared to have a durable response to immunotherapy, new adenopathy after prolonged immunotherapy maintenance needed to be evaluated by histological exam to distinguish vaccine-associated hypermetabolic lymphadenopathy from local tumor recurrence. COVID-19 vaccination can contribute to regional lymphadenopathy, making it difficult to discern reactive lymphadenopathy from malignancy [
16,
17]. In a SCOPUS review of 19 studies, 68 patients developed reactive lymphadenopathy within the first day and lasted 4–6 weeks following their first or second COVID-19 vaccination [
18]. As observed in our patient, the Pfizer–BioNTech vaccine resulted in the most cases of lymphadenopathy (44.1%) compared with Moderna (25%) and Oxford-AstraZeneca (1.5%) COVID-19 vaccines [
18]. Most common sites of lymphadenopathy involved ipsilateral axillary, supraclavicular, cervical, and subpectoral nodal regions. More than 80% of these patients had a prior or active cancer history with most cases presenting as breast cancer (
n = 40 cases). In this study, only four cases of lung cancer were found [
18]. In another study, hypermetabolic lymphadenopathy was detected by PET scan in 266 cases out of 728 cancer patients following their COVID-19 vaccination. From these cases, 17 cancer patients were found to have malignancy-associated hypermetabolic lymphadenopathy and 49 patients had equivocal results. Approximately 50% of patients had not developed hypermetabolic lymphadenopathy following their COVID-19 vaccination [
19]. These studies highlight the importance of vaccinating patients in the arm contralateral to the tumor’s expected nodal drainage when feasible. For example, in a patient with a localized tumor in the left lung, the COVID-19 vaccine should be administered in the right arm to minimize confusion and assist in the radiologic interpretation of PET scans. Our patient developed unilateral adenopathy, which is typical for vaccine associated lymphadenopathy, but the distribution of lymphadenopathy forewarned lung cancer progression and prompted a diagnostic biopsy. COVID-19-vaccine-associated hypermetabolic lymphadenopathy may last up to 10 weeks [
21]. For these reasons, biopsy of enlarging and hypermetabolic lymph nodes is warranted to rule out tumor progression. To conclude, physicians should consider delaying PET scan imaging for at least 10 weeks after vaccination in lung cancer patients to allow resolution of lymphadenopathy [
20,
21]. If a patient has cancer with laterality, the vaccine should be administered in the contralateral arm to avoid confounding radiologic interpretation [
22,
23]. Alternatively, injecting COVID-19 vaccine in thigh muscle instead of the deltoid muscle of lung cancer patients might be a reasonable option.
Much remains to be discovered regarding the interplay between immunity from COVID-19 infection, COVID-19 vaccination, and the PD-1/PD-L1 axis responsible for cancer immune escape. Cancer patients being treated with checkpoint blockade (or PD-L1 axis blockade) can develop decreased SARS-CoV-2 antibody titers after vaccination resulting in the CDC recommendation for a third booster in this population [
24]. Furthermore, studies have shown that several co-inhibitory molecules (PD-L1, CTLA-4, TIM-3, LAG3, VISTA, TIGIT) are upregulated on T cells in patient with COVID-19 infections, and this might negatively interfere with antitumor immune responses induced by checkpoint inhibitors [
25,
26]. One study has suggested that while PD-1 expressing CD8
+ T cells from COVID-19 patients are still functional, these T cells become exhausted [
27,
28]. There are currently several ongoing clinical trials examining the efficacy of PD-L1 axis blockade to combat deleterious effects of COVID-19-induced T-cell exhaustion [
29]. Whether the immune response generated by COVID-19 vaccination produces T-cell exhaustion in cancer patients (as seen with chronic infections) to sufficiently dampen immune checkpoint blockade in patients being treated for malignancy remains unknown. A multicenter study of 2084 Chinese patients treated with immune checkpoint inhibitors showed no difference in overall response rate between vaccinated and unvaccinated patients, although immune-related adverse events were more frequently observed in vaccinated patients [
30]. Ultimately, clinical context in light of our evolving understanding of COVID-19 remains the driving factor for evaluation and management of oncologic patients.