When a CT or MRI scan finds a suspicious mass in the kidney, the standard approach is to remove it surgically and examine it under a microscope to see whether it is malignant or benign. Yet in about two out of ten people who have the operation, histology shows the mass to be benign. «This margin of error is to be expected even in the most advanced hospitals», says Dr Alessandro Larcher. A urologist at IRCCS San Raffaele Hospital and an alumnus of Vita-Salute San Raffaele University (UniSR), he is the principal investigator (PI) of the CAT-VHL study.
Together with Dr Fabrizia Gelardi, co-PI of the trial, Dr Larcher is adapting carbonic anhydrase IX PET (CAIX-PET), first developed to study sporadic kidney cancer, to von Hippel-Lindau (VHL) disease. This rare genetic condition predisposes people to tumours of the kidney as well as of the central nervous system, pancreas, adrenal glands and other parts of the body.
«Our clinical trial grew out of a collaboration, started in 2023, between the Urological Research Institute (URI), directed by Prof. Andrea Salonia, and the nuclear medicine team of Prof. Arturo Chiti, Full Professor of Imaging and Radiotherapy at UniSR. The project took shape as an academic study thanks to one million euros in funding, which we won through a competitive call issued by the Ministry of Health under the PNRR [Italy's National Recovery and Resilience Plan], funded by the European Union», Larcher recalls.
Von Hippel-Lindau disease is a rare genetic condition that affects about 1 in 36,000 people. People with the condition develop their first clinical signs early, between the ages of 20 and 40, and over their lifetime they undergo several operations. «These people have yearly surveillance MRI scans. In the most complex cases, the scans become hard to read even for an experienced radiologist: a doctor may identify 10 lesions when in fact there are 15 or even more», Larcher notes.
The disease involves several organs, and kidney tumours are among the main causes of death linked to it. The most common and aggressive form of kidney cancer is clear cell renal cell carcinoma, which accounts for about 70–80% of all kidney tumours.
The ZIRCON study, a phase 3 trial run at 36 centres in 9 countries, was published in The Lancet Oncology in 2024. It showed that CAIX-PET identifies clear cell renal cell carcinoma with a sensitivity and specificity above 85%.
«These results inspired us to assess this diagnostic technique in von Hippel-Lindau disease. We are now running a phase 2 study at IRCCS San Raffaele Hospital, the only centre in Italy recognised by the VHL Alliance, the world's leading patient association for this disease», Larcher explains.
PET (positron emission tomography) is a safe and effective diagnostic scan, used above all in oncology to detect tumours. It relies on a radioactive tracer that “lights up” suspicious areas of the body. In CAIX-PET, the tracer is the monoclonal antibody girentuximab. This antibody binds to the biomarker carbonic anhydrase IX, an enzyme expressed specifically by tumour cells in clear cell renal cell carcinoma. The enzyme is present both in sporadic tumours and in those linked to von Hippel-Lindau disease. The antibody is labelled with zirconium-89, a radioactive isotope that makes the tumours visible on the scan. The test is extremely safe: so far, no significant side effects have been reported.
In current clinical practice, the pathologist looks for carbonic anhydrase IX in tissue removed during surgery to diagnose a malignant tumour, after a CT or MRI scan has found a suspicious mass in the kidney. «The advantage of using PET with a tracer that is specific to carbonic anhydrase IX is that we can avoid surgery, where possible. In other words, CAIX-PET can reveal a malignant tumour non-invasively, before a kidney biopsy», says Larcher. In 2026, Theranostics published the team's preliminary results from three people enrolled in the CAT-VHL study.
CAIX-PET was positive in the two cases of clear cell carcinoma and negative in the third, a chromophobe carcinoma. In one person, the scan also found a hidden metastasis in a rib. CT and histology then confirmed the suspected metastasis, so the lesion that conventional imaging had missed could be treated early.
Larcher has also helped develop an artificial intelligence model, built with the S-RACE platform, that assesses a kidney cancer patient's risk before surgery.
For now, CAIX-PET remains an experimental technique. Dr Larcher's team is completing enrolment for the phase 2 clinical trial, which will test the technique's efficacy and safety in a larger group of patients. «The preliminary results tell us that the technology is extremely accurate in detecting kidney tumours, while its results for the other organs affected by the disease are more variable. Our team has already gained more experience in this field than any other in Europe, and we have launched further clinical studies based on this method», Larcher adds. «For all patients with kidney cancer and for people living with von Hippel-Lindau disease, CAIX-PET will become a key tool for better care», he concludes.
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