The Role and Potential of 18F-FDG PET/CT in Malignant Melanoma: Prognostication, Monitoring Response to Targeted and Immunotherapy, and Radiomics

Abstract

Novel therapeutic approaches, consisting of immune check-point inhibitors (ICIs) and molecularly targeted therapy, have thoroughly changed the clinical management of malignant melanoma (MM), the most frequent and deadly skin cancer. Since only 30-40% of MM patients respond to ICIs, imaging biomarkers suitable for the pre-therapeutic stratification and response assessment are warmly welcome. In this scenario, positron emission computed tomography (PET/CT) with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) has been successfully utilized for advanced MM staging and therapy response evaluation. Furthermore, several PET-derived parameters (SUVmax, MTV, TLG) were particularly impactful for the prognostic evaluation of patients submitted to targeted and immunotherapy. In this review, we performed a web-based and desktop research on the clinical applications of ¹⁸F-FDG PET/CT in MM, with a particular emphasis on the various metabolic criteria developed for interpreting PET/CT scan in patients undergoing immunotherapy or targeted therapy or a combination of both. Furthermore, the emerging role of radiomics, a quantitative approach to medical imaging applying analysis methodology derived by the field of artificial intelligence, was examined in the peculiar context, putting a particular emphasis on the potential of this discipline to support clinicians in the delicate process of building patient-tailored pathways of care.

Keywords: 18F-FDG; BRAF mutation; PET/CT; artificial intelligence; malignant melanoma; precision medicine; radiomics.

Figure 1

A 62-year-old male, previously submitted to excision of nodular cutaneous melanoma (Breslow thickness of 8 mm, Clark level IV, stage pT4a), performed ¹⁸F-FDG PET/CT for staging before therapy. (A) MIP image showed areas of increased tracer incorporation in the left lung (black arrow) and adrenal gland (black bordered arrow). Molecular analysis was positive for BRAF V600e mutation and he started combination of BRAF and MEK inhibitors (dabrafenib plus trametinib). PET/CT MIP (B) performed after 3 months showed metabolic response to therapy. Fused corresponding PET/CT axial of the abdominal region (C) demonstrated almost complete regression of the non-homogenously hypermetabolic lesion in the left adrenal gland when baseline (upper row, arrow) is compared with follow-up PET/CT scan (lower row, arrow). Fused PET/CT axial of the lung (D) demonstrated regression of the hyperactive nodule in the left lung when baseline (upper row, arrow) is compared with follow-up scan (lower row, arrow).

Figure 2

A 74-year-old male, previously submitted to excision of nodular cutaneous melanoma of the right foot (Breslow thickness of 8 mm, Clark level IV, stage pT4a), performed ¹⁸F-FDG PET/CT before the start adjuvant immunotherapy. (A) MIP image showed physiological tracer biodistribution, with no evidence of pathological accumulation. PET/CT MIP (B) performed after 3 months of PD-1 blocker (nivolumab) depicted the appearance of an area of increased tracer accumulation in the left iliac fossa (black arrow). (C) Fused corresponding PET/CT axial (upper row) and coronal (lower row) of the abdominal region demonstrated the onset of a hypermetabolic nodule next to the abdominal wall, suspected to be peritoneal localization (white arrow). The pattern was interpreted according to PERCIMT criteria (i.e., pseudo-progression) and the patient continued immune check-point inhibitor. A further PET/CT MIP (D) after 6 weeks demonstrated complete spontaneous regression of the area of increased ¹⁸F-FDG accumulation in the left iliac fossa (black arrow), thus confirming the diagnosis of pseudo-progression.

Figure 3

A case of hyper-progression during immunotherapy. A 41-year-old male, affected by non-melanoma skin cancer (locally advanced cutaneous squamous cell carcinoma) of the left thigh, submitted to anti PD-1 immunotherapy (cemiplimab). ¹⁸F-FDG PET/CT before the start of therapy: (A) MIP image showed pathological tracer accumulation within a left inguinal node (black arrow). PET/CT MIP (B) performed after 2 months of PD-1 blocker depicted an impressive disease progression at nodal and cutaneous level (black arrow). (C) Fused corresponding PET/CT axial (upper row) acquired before therapy well demonstrated a hypermetabolic inguinal node (white arrow), fused PET/CT after 2 months of PD-1 blocker showed meaningful enlargement of the metastatic node (white arrow). Immunotherapy was discontinued, the patient was switched to chemotherapy but deceased after 3 months.

Figure 4

A case of irAEs. A 41-year-old female, previously submitted to excision of a nodular, high-risk MM, started adjuvant immunotherapy with nivolumab. After 4 cycles, she presented mild fatigue and grade 1 hyponatremia and orthostatic hypotension, with reduced level of morning cortisol. ¹⁸F-FDG PET/CT performed after symptoms’ onset (A) demonstrated bilateral increased tracer accumulation within adrenal glands (white arrows), compatible with the suspicion of immune-related adrenalitis, she discontinued immunotherapy and started on steroid therapy with excellent clinical response. PET/CT, acquired after steroid therapy and symptoms’ regression (B), revealed complete regression of the adrenal glands’ hypermetabolism. After multidisciplinary consensus meeting, immunotherapy was restarted, and no further complications were registered.