Glioblastoma and malignant melanoma: Serendipitous or anticipated association?

Dear editor, We read with great interest the article by Yang et al. in Neuropathology that described a case of concomitant malignant melanoma (MM) and primary glioblastoma (GB). This article underscores the rare association of these two entities, suggesting that the co-occurrence of GB and MM is likely not coincidental. In our center, we are currently following two patients suffering from both GB and MM, postulating the hypothesis that the co-occurrence of the two neoplasms may not happen by chance. A 46-year-old left-handed man (case 1) visited to an emergency department after a focal non-motor epileptic seizure. Gadolinium-contrasted magnetic resonance imaging (MRI) of the brain revealed a left temporal solid ring enhancing lesion (Fig. 1A, B). There was no family history of primitive central nervous system tumors. The patient underwent a total surgical removal of the lesion in June 2019. Histological investigation on hematoxylin and eosin (HE) staining made the diagnosis of WHO grade IV GB with the presence of the O-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation and the isocitrate dehydrogenase 1/2 gene (IDH1/IDH2) wild-type and the absence of 1p/19q codeletion at a 30% of the Ki67 labeling index (Fig. 1C). The Karnofsky performance status score (KPS) at discharge was 100. The patient was treated according to the protocol recommendation by Stupp et al., followed by adjuvant chemotherapy with temozolomide at 12 cycles until September 2019. There was no reoccurrence of the disease. In October 2020, he underwent a dermatological screening due to his family history of MM, because the patient’s father had been diagnosed as having MM in situ (Clark’s I level) in 2013. An atypical melanocytic lesion was detected on his forehead skin specimen by means of dermoscopy and confocal laser microscopy. A wide local excision was performed, and the histopathological examination revealed a primary MM, of nevoid subtype (Clark’s III level: Breslow 0.7 mm, non-ulcerated: stage IA according to the eighth edition of AJCC melanoma staging system) (Fig. 1D). Clinicoradiological follow-up was indicated. The last follow-up visit in 2021 did not reveal signs of disease recurrence. A 64-year-old right-handed woman (case 2) visited the emergency department after a focal non-motor seizure, with loss of consciousness. Brain MRI revealed the presence of a nodular contrast-enhancing right temporal lesion (Fig. 2A, B). The patient underwent a total surgical removal in September 2018. Histological investigation on HE staining made the diagnosis of WHO grade IV GB with the presence of MGMT promoter methylation and IDH1/IDH2 wild-type and the absence of 1p/19q codeletion at a 20% of the Ki-67 labeling index (Fig. 2C). The KPS after the surgery was 100. She was treated with the Stupp protocol and adjuvant chemotherapy with temozolomide at 12 cycles until January 2020. In October 2019, the patient developed a flat hyperpigmented lesion in her right forearm skin. Because confocal laser microscopy depicted epidermal and junctional cytologic atypia, the lesion was excised, and the histopathological evaluation revealed an MM in situ (Clark’s I level) (Fig. 2D). The last follow-up visit in 2021 did not reveal signs of disease recurrence. We agree with Yang et al. who suggested that the cooccurrence of GB and MM, which share a neuroectodermal origin, might not be coincidental. Different authors have described a familial predisposition syndrome that includes an increased risk for MM and nervous system tumors, mainly astrocytoma, recognized in the melanoma– astrocytoma syndrome. The genetic base stands on the deletion of the cyclin-dependent kinase inhibitor 4 (INK4) gene (INK4) locus, which contains the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene (CDKN2A) and the CDKN2B gene (CDKN2B), known as tumor suppressor genes. This syndrome is now appreciated to be autosomaldominant and caused by a germline mutation in CDKN2A (600160) on chromosome 9p21 (Online Mendelian Inheritance in Man, entry # 155755). However, a specific correlation between MM and GB has not yet been found. Some genetic studies have shown a high association of both the tumors with mutations in genes that are involved in Correspondence: Francesco Cavallieri, MD, Neurology Unit, Neuromotor and Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. Email: francesco.cavallieri@unimore.it