A Rare Case of Xeroderma Pigmentosum: Nivolumab Treatment for Three Cutaneous Malignancies with Clinical and Metabolic Imaging Correlation

The patient, after 6 months of follow-up, is still in complete remission, under immunotherapy treatment, with no signs or symptoms of immunotherapy-related toxicity. Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by extreme sensitivity to UV light [1]. The underlying defect involves germline biallelic loss-of-function mutations in genes of the nucleotide excision repair (NER) pathway, leading to an accumulation of unrepaired DNA damage [2,3,4,5]. Consequently, XP patients are highly predisposed to developing multiple cutaneous malignancies of different histological types [6,7]. Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on lymphocytes, and its ligands, PD-L1 and PD-L2, inhibit immune activation, promoting self-tolerance [8,9]. Tumor-infiltrating lymphocytes often exhibit high levels of PD-1, while cancer cells and elements of the tumor microenvironment frequently express PD-L1. This mechanism enables tumors to evade immune surveillance by suppressing T-cell activity. Given this, immune checkpoint inhibitors targeting PD-1/PD-L1 have emerged as an effective therapeutic strategy, restoring T-cell activation and triggering an anti-tumor immune response. Moreover, studies have demonstrated a correlation between response to checkpoint blockade therapy and tumor mutational burden (TMB) [10,11]. Since XP patients exhibit a severe DNA repair deficiency, it is hypothesized that their tumors harbor an elevated mutational load, potentially making them more responsive to immune checkpoint blockade. In this case, we administered nivolumab to a patient with metastatic localizations under the assumption that immune checkpoint inhibitors could enhance endogenous immune responses and that the high mutational burden associated with XP might be a predictive factor for response. Consistently, the patient demonstrated a remarkable therapeutic outcome, suggesting that the intrinsic DNA repair defect in XP may contribute to increased immunogenicity of the tumor, favoring sensitivity to PD-1 blockade. Notably, [¹⁸F]FDG PET/CT imaging has been rarely utilized in XP patients, although its application in metastatic melanoma is increasing [12,13,14,15]. In our case, [¹⁸F]FDG PET/CT played a crucial role in both staging and treatment monitoring. The decision to perform [¹⁸F]FDG PET/CT, although not standard in XP management, was justified by indeterminate thoracic findings on CT. Pre-treatment PET/CT facilitated a more precise staging by identifying a previously unrecognized hypermetabolic lesion in the parotid gland, refining the assessment of disease burden. Additionally, PET/CT proved instrumental in evaluating the patient’s response to immunotherapy, demonstrating complete metabolic resolution of both the parotid and pulmonary lesions. This highlights the potential utility of [¹⁸F]FDG PET/CT in XP patients with ambiguous radiological findings, particularly in guiding therapeutic decisions and monitoring treatment efficacy. In conclusion, this XP patient showed a remarkable response to nivolumab, reinforcing the potential impact of checkpoint inhibitors in this unique genetic context. We propose that the DNA repair deficiency in XP may lead to a heightened mutational load, enhancing tumor immunogenicity and responsiveness to PD-1 blockade. To validate this hypothesis, further studies should evaluate the immune landscape and mutational burden of XP-associated tumors. Additionally, identifying recurrent mutational patterns in different XP-related skin malignancies may provide insights into factors influencing sensitivity or resistance to nivolumab. Our experience underscores the need for further investigation into the optimal therapeutic strategies for XP-associated malignancies. While immune checkpoint inhibition appears promising, integrating advanced imaging modalities such as FDG PET/CT into routine clinical practice may enhance disease assessment, ultimately improving patient management and outcomes.