Germline VHL Mutation Discovered in Association with EGFR-Positive Lung Cancer and Metachronous Hepatocellular Carcinoma: A Case Report

Abstract

VHL is a tumor suppressor gene located on chromosome 3 that is classically associated with tumors of the eye and CNS, renal cell carcinoma, and pheochromocytoma. We describe what appears to be the first report of an association between a germline VHL mutation and non-small cell lung cancer and metachronous hepatocellular carcinoma (HCC). Our case involves a 63-year-old nonsmoking male who was initially diagnosed with EGFR mutation-positive metastatic nonsquamous, non-small cell lung adenocarcinoma, who subsequently developed HCC and squamous cell carcinoma of the femur despite first-line treatment with EGFR-blocking osimertinib. Caris molecular profiling unexpectedly identified a shared underlying VHL mutation in all 3 lesions. Genetic mapping through a machine learning-based tool called Genomic Prevalence Score (GPSai<sup>™</sup>) helped determine that the femur tumor was a metastatic lesion as opposed to a separate primary and that the HCC was a distinct primary malignancy. We not only highlight the association between these tumors and a VHL mutation but also emphasize the value of next-generation sequencing and a molecular disease classifier in a patient with multiple primaries, how it helps guide therapy, and its value in guiding future studies.

Retinal Capillary Hemangioma Leading to a Diagnosis of von Hippel-Lindau Disease in a Patient with Retinopathy of Prematurity

“…In particular, it is important for the clinician to be aware of diseases such as VHL that have risk for additional tumors not only in the individual but also in family members as in this case where the patient's diagnosis led to examination and diagnosis of VHL in the patient's mother and aunt. This is similar to work by Kuhlman et al [ 7 ] who found an incidental diagnosis of VHL in a patient who presented with both lung cancer and hepatocellular carcinoma. RCH is often the first presenting sign of a diagnosis of VHL, and one must be aware of the systemic implications [ 8 ].…”