A 55-year-old woman recently underwent a PET/CT scan that showed highfludeoxyglucose (¹⁸F-FDG) uptake in the right lung, suggesting possible malignancy. However, her blood-based liquid biopsy revealed no circulating tumor DNA (ctDNA) mutations associated with lung cancer. The oncologist is considering next-generation sequencing (NGS) for further analysis. Which of the following best explains this discordant finding and justifies the oncologist’s next step?

Question

A 55-year-old woman recently underwent a PET/CT scan that showed highfludeoxyglucose (¹⁸F-FDG) uptake in the right lung, suggesting possible malignancy. However, her blood-based liquid biopsy revealed no circulating tumor DNA (ctDNA) mutations associated with lung cancer. The oncologist is considering next-generation sequencing (NGS) for further analysis. Which of the following best explains this discordant finding and justifies the oncologist’s next step?

BlackTom AI · Accepted Answer

The question presents a scenario where imaging (PET/CT) suggests possible malignancy due to high 18F-FDG uptake, yet a blood-based liquid biopsy shows no ctDNA mutations associated with lung cancer. The task is to evaluate each option and explain why the correct choice explains the discordance and justifies next steps, while the other choices are flawed.
Option a: The absence of ctDNA mutations confirms there is no tumor, so no further testing is needed. This is incorrect because ctDNA can be undetectable even in the presence of cancer, especially if the tumor burden is low, the tumor is not shedding DNA into the bloodstream, or the cancer is localized. Therefore, a negative ctDNA result does not rule out malignancy, and additional testing remains warranted.
Option b: PET scans directly detect gene mutations through radioactive tracers, so NGS would be redundant. This is false. PET imaging measures metabolic activity by glucose uptake, not genetic mutations. It cannot identify tumor-specific mutations, so relying on PET alone does not obviate the need for genomic analysis like NGS.
Option c: PET scans measure glucose metabolism, so high uptake may reflect inflammation or infection rather than malignancy; NGS can confirm if tumor-specific mutations exist. This is correct. FDG-PET shows metabolic activity, which is increased in cancer but also in inflammatory or infectious processes. The negative ctDNA does not eliminate cancer risk; performing NGS can help detect tumor-specific mutations if a malignancy is present, guide targeted therapy, and reconcile the discordant findings by providing a genomic perspective that imaging alone cannot.
Option d: Liquid biopsies are always more accurate than imaging; repeating the PET scan would provide genetic confirmation. This is incorrect. Liquid biopsies have advantages but are not universally more accurate than imaging, and they do not provide direct information about tumor location or metabolic activity. Repeating PET would again assess metabolism but still would not genetically confirm mutations; also imaging reliability is not presumed absolute. The best next step remains genomic analysis to look for mutations if a tumor is suspected, rather than assuming superiority of one modality over another.

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