A 51-year-old woman presented in August 2022 with a hard, non-mobile 2-cm preauricular subcutaneous nodule. The patient had been diagnosed with xeroderma pigmentosum (XP) variant XPV at the age of 34 years and carried a compound heterozygous mutation in the POLH gene, resulting from the combination of two different genetic alterations: c.764+1G>A (intron 6) and c.1445C>A (p.Ser482, exon 11).1 She had been followed in Dermatology from 2007 through 2016, when she stopped attending follow-up visits, during which period she developed 11 melanomas, most of them in situ and superficial. Family history was notable for a maternal cousin with XP. Since childhood, the patient had progressive photosensitivity and showed, on photoexposed body surfaces including the lips, pigmented macules of different shades ranging from light brown to black, without lesions on the skin of covered areas (axillae, buttocks).

The lesion was excised, and histological examination confirmed the diagnosis of dermal and subcutaneous metastasis of melanoma with a BRAF wild-type genotype. Staging studies did not reveal other distant lesions, and the disease was classified as stage IV in the absence of a known primary tumor. Nivolumab (6mg/kg) was administered, with a total of 12 cycles between November 2022 and December 2023. Ten months into therapy (8 cycles), the patient developed a grade 1 immune-mediated exanthem on the upper and lower limbs that improved with oral dexamethasone 1mg daily for 7 days and subsequently every 48h until completing 2 weeks. Coinciding with this phenomenon, a significant and generalized lightening of her skin was observed, with progressive disappearance of ephelides and lentigines in photoexposed areas, particularly those on the face and trunk (Fig. 1). This effect persisted even 7 months after discontinuation of nivolumab, and at the 11-month follow-up no new tumor lesions have been reported.

Fig. 1.

(A–D) Generalized hyperpigmentation with ephelides, lentigines, and atypical nevi prior to the initiation of nivolumab (A and B), and subsequent facial (C) and truncal (D) lightening with resolution of lesions 7 months after treatment discontinuation. Irregular whitish macules are present on the trunk due to surgical procedures.

XP is an autosomal recessive genodermatosis2–4 with complete penetrance3 in which genes regulating DNA repair are affected. This condition leads to marked cutaneous sensitivity to ultraviolet radiation, resulting in early, intense, and diffuse skin damage with an increased risk of non-melanoma skin cancer and melanoma.2–4

In these patients, melanoma and squamous cell carcinoma are the main causes of death.5 Currently, new drugs have proven effective in advanced tumors and particularly in metastatic melanoma.5 Immunotherapy stands out, appearing to be more effective in tumors with a high mutational burden, such as those located in photoexposed areas of patients with XP. Available agents include anti-programmed cell death protein 1 antibodies (cemiplimab, pembrolizumab, nivolumab) and anti-cytotoxic T-lymphocyte antigen 4 antibodies (ipilimumab), among others.

Fernandez et al.6 conducted a retrospective review of 22 cases of XP with different neoplasms (19 of them melanomas and/or squamous cell carcinomas), observing an initial complete remission rate of 100% and immune-mediated adverse effects in 50% of patients, with 9% being grades 3–5. This toxicity was not significantly higher vs the population without XP. The appearance of new tumor lesions concomitant with or subsequent to treatment was notable in 36.3% of cases.

Regarding the cutaneous lightening observed in our patient, its description in the literature is scarce. Salomon et al.4 described a man with metastatic melanoma who, after 4 doses of pembrolizumab, showed regression of cutaneous carcinomas and actinic keratoses, in addition to vitiligo-like depigmentation in photoexposed areas.

Scheer et al.5 and Hauschild et al.7 described a woman and a man with stage IV melanoma treated with nivolumab and pembrolizumab, respectively. Both patients developed a diffuse inflammatory reaction in body areas with greater solar damage and with precursor lesions. This phenomenon improved their cutaneous characteristics and was interpreted in both cases as an antitumoral response against precursor lesions. One of the patients subsequently showed gradual repigmentation.

Furthermore, Itoyama et al.8 described facial cutaneous improvement in a man with metastatic squamous cell carcinoma after administration of 20 doses of nivolumab.

This effect has also been observed following topical treatment with imiquimod, which has been proposed as a possible field therapy for patients with XP.9,10

In conclusion, immunotherapy may produce improvement of the cutaneous lesions in patients with XP. The possibility that this effect is due to the disappearance of subclinical premalignant lesions, potentially leading to a better prognosis, raises the question of whether systemic immunotherapy could be used in early stages of the disease to reduce the development of aggressive tumors. Furthermore, the cutaneous lightening observed due to improvement of pigmented lesions could provide psychosocial benefits for these patients.