International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System

Abstract

Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic (p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57–0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25–1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

Sinonasal Cancer: Improving Classification, Stratification and Therapeutic Options

“…Genetic analysis also allows for the identification of molecular targets for modern targeted therapies. Several studies on tumor-infiltrating lymphocytes and aspects of the PD-L1/PD1 checkpoint have indicated a role for immunotherapy in several sinonasal tumor subtypes [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ], and we strongly encourage research into the clinical response to treatment with immune checkpoint inhibitors in sinonasal cancers such as recently reported on MMM [ 17 ]. Next-generation sequencing identified recurrent subtype-unique mutations including: APC , CTNNB1 , PIK3CA and KRAS in ITAC, EGFR and CDKN2A in SNSCC, NRAS and NF1 in MMM, IDH2 in SNUC, and ARID1A , SMARCB1 and SMARCA4 in SNEC, SNUC and TCS [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”

“…The high incidence of recurrences and distant failures in MMM is the main cause of death, with reported one-, three-, and five-year recurrence-free and overall survival of 61, 31, and 22%, and 78, 49, and 38%, respectively [ 17 ]. With the aim to tackle this, Freiberger et al presented a pioneer longitudinal study on MMM describing an observed ‘switch’ from KRAS , KIT or no mutation in primary tumors to solely genomic alterations in NRAS in recurrent tumor, after developing resistance to immunotherapy.…”

Diagnostik und Therapie von Schleimhautmelanomen der Nase/Nasennebenhöhlen

“…Ein isolierter Septumtumor scheint mit einer guten Prognose verbunden zu sein [5]. Faktoren, welche die Prognose der Erkrankung negativ beeinflussen, sind ein fortgeschrittenes Lebensalter zum Zeitpunkt der Diagnose sowie eine Tumorgröße von mehr als 3-4 cm [6,7].…”

“…Die adjuvante Strahlentherapie ist ein fester Bestandteil der Behandlung von SNSM, insbesondere in der R1-oder RX-Situation. Eine Strahlentherapie scheint die lokoregionäre Kontrolle [13] sowie das Überleben zu verbessern [7], wobei die Datenlage hierzu nicht eindeutig ist [14,15]. Der Literatur zufolge liegt das Risiko eines Lokalrezidivs beim SNSM nach chirurgischer Therapie mit adjuvanter Radiatio bei bis zu 50 % [15].…”

“…Zentrale Bedeutung in der palliativen Therapie spielen Immuncheckpoint-Inhibitoren (ICI). In einer großen multinationalen, multizentrischen retrospektiven Auswertung von insgesamt 505 SNSM-Patienten wurde gezeigt, dass eine ICI-Therapie in der Rezidivsituation mit oder ohne Fernmetastasen mit einem signifikant längeren Gesamtüberleben einhergeht [7]. Ebenso konnte in einer 1874 Patienten umfassenden, retrospektiven Datenbankanalyse von Ganti et al gezeigt werden, dass mit ICI behandelte Patienten mit metastasiertem SNSM einen Überlebensvorteil aufweisen [13].…”