Case of carbon-ion radiation recall mucositis associated with anti-programmed cell death 1 treatment for paranasal sinuses melanoma.

Since the treatment for mucosal melanoma often accompanies surgical difficulty, carbon-ion radiotherapy in combination with immune check point inhibitors (ICI) against programmed cell death 1(PD-1) and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a favorable choice. Radiation recall henomenon (RRP) is represented by an inflammatory reaction within previously irradiated fields,such as mucositis, dermatitis, and pneumonitis, in association with theadministration of chemotherapeutic agents.1 Here, we report a case of carbon-ion radiation recall mucositis associated with nivolumab and pembrolizumab for melanoma located in the paranasal sinuses. A 71-year-old Japanese woman was referred to us because of cheek pain and bloody rhinorrhea. Computed tomography revealed a tumor in the left paranasal sinuses without metastasis.Histopathological examinations showed that atypical cells proliferated in the mucosa (Figure 1a). The tumor cells were positive for Melan-A and HMB-45 (Figure 1b), consistent with mucosal melanoma. As thetumor was unresectable, it was treated with carbon-ion radiotherapy(Figure 1c), and local resolution was achieved. However, bilateral adrenalmetastases were observed 1 year later without local recurrence,and then nivolumab as anti-PD-1 antibody was administrated. At 1 week after the first administration of nivolumab, the patient complained of left oral pain. Physical examination revealed erythema and swelling on the left upper lip (Figure 1d), and erosive ulcers on the left side of the palatal, buccal, and nasal mucosa (Figure 1e), although histopathological examination was not performed in accordance with the patient’s wishes. The symptoms were resolved by discontinuation of nivolumab. Despite the change from nivolumab to pembrolizumab as another anti-PD-1 antibody, mucositis recurred 1 week after the administration of pembrolizumab (Figure 1f). We diagnosed the patientas radiation recall mucositis associated with anti-PD-1 therapy, since:(i) the irradiated fields were exclusively affected; and (ii) the symptomsappeared only when anti-PD-1 antibodies were administrated,in disagreement with radiomucocitis (Figure 1g). Pembrolizumab was intermittently administrated on the occasion of the improvement of mucositis, and the volume of adrenal metastases decreased. Radiation recall phenomenon has been reported to occur in relation with antineoplastic drugs including anthracyclines, alkylating agents, antimetabolites, nucleoside analog, and taxanes.1 However,RRP induced by anti-PD-1 antibodies has rarely been reported,2as well as that induced by carbon-ionradiation. Although the mechanisms of radiation recall mucositis/dermatitis are still controversial,several mechanisms have been suggested including DNArepair impairment, radiation-impaired epithelial function of stem cells, and increasing sensitivity to antineoplastic drugs.3 Carbon-ion radiation elicits local immune responses through a greater cell-killing effect by high density of energy deposition per unit length than conventional radiation.4,5 ICI elicits intensive immune responses through PD-1 and/or CTLA-4 blockade. Therefore, the combination may lead to higher risk of RRP. To our knowledge, this is the first report of the carbon-ion radiation recall mucositis associated with anti-PD-1 therapy. Since mucositis potentiallyserves as a limiting factor for ICI therapy, careful attention to RRP is required after administration of ICI as well as cytotoxic antineoplastic agents in combination with carbon-ion radiotherapy