The widespread COVID-19 vaccination led to unexpected PET findings. Notably, axillary and interpectoral lymphadenopathies ipsilateral to the vaccine inoculation were observed.

We aimed to assess the hypermetabolic lymphadenopathy (HLN) detection rate on PET/CT. Secondly, we investigated factors that might help in HLN differential diagnosis.

A retrospective analysis on 1196 consecutive patients referred for a PET/CT was performed. All patients were asked about the date, type and site of vaccine injections. HLNs were recorded and categorized according to risk classes and SUVmax grades. A statistical analysis was performed to assess the correlation between HLN detection and different clinical/vaccine data.

HLN detection rate was 15% and 27% in the No Vac- and vac-groups (p < 0.001), respectively. In the Vac-group, age (p < 0.001) and time interval from vaccine-to-PET (p = 0.010) were inversely correlated with HLN detection. Furthermore, SUVmax significantly changed during time intervals, with lower values beyond 20 days (p < 0.001).

In the era of mass COVID-19 vaccination, a higher axillary and interpectoral lymphadenopathies detection ipsilateral to vaccine injection was observed. These PET findings can be wrongly interpreted, complicating cancer patients’ management. To minimize these pitfalls, a detailed vaccination anamnesis must be recorded and should take into account the appropriate PET schedule.

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