Here, we report a case of recurrent PMME with lymph node and bone metastases successfully treated with nivolumab. After the treatment, the lymph node and bone metastases showed a dramatic decrease, and no irAE were observed during the treatment. The patient received nivolumab for 16 months and showed no further signs of clinical disease progression. The incidence of malignant melanoma has increased over the past few decades, and approximately 132,000 people develop malignant melanoma each year worldwide [
5]. Almost all malignant melanoma cases arise from the skin, and it is reported that only 1% of melanomas arise from the mucosa (head and neck, eyes, and genitourinary and alimentary tracts) [
4]. Although mucosal melanomas generally carry a worse prognosis than those arising from cutaneous sites, no intrinsic risk factors and specific treatment options have been established. Furthermore, there is no evidence of a difference in sensitivity between skin and mucosal melanomas to nivolumab therapy. Xuan Wang
et al. [
6] reported that, in 76 PMME patients, PMME occurred more commonly in men, with a male-to-female ratio of 2.17:1. The majority of PMME patients are symptomatic on diagnosis, dysphagia being the most common major symptom of PMME, as was observed in the current case. Concerning the locations of PMME tumors, 92.1% were in the middle and lower portions of the esophagus, while half of the tumors invaded the muscularis propria or further. Consistent with the results of previous studies, the incidence of periesophageal lymph node metastasis did not correlate with the depth of tumor invasion. Surgical resection is the most common treatment, with 77.6% patients undergoing subtotal esophagectomy or esophagogastrostomy with lymph node dissection. Despite complete excision, recurrence occurred in 89.7% of the patients. In addition, the interval between primary surgery and recurrence was only 4.5 months. The risk of recurrence is extremely high after an initial staging operation, which likely reflects the aggressive characteristics of PMME and the important role of adjuvant therapy. Indeed, adjuvant therapy has been shown to increase recurrence-free survival (RFS) and to have varying effects on OS in patients with cutaneous melanoma [
7]. A previous trial suggested that temozolomide (TMZ)-based adjuvant chemotherapy can improve both RFS and OS in patients with mucosal melanoma [
8]. However, because of its rarity, optimal adjuvant therapies for PMME have not yet been established. Postoperative adjuvant chemotherapy may be considered for patients with PMME because it significantly improves RFS. However, even with adjuvant chemotherapy, the RFS is still much lower than in other subtypes of mucosal melanoma [
8]. A phase 3 randomized trial suggested that adjuvant therapy with ipilimumab was a treatment for stage III melanoma based on a significantly prolonged RFS [
9]. In addition, CheckMate 238 clinical trials showed that, among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in a significantly longer RFS and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab [
10]. Moreover, nivolumab may be effective for patients undergoing resection of stage III or IV PMME as adjuvant therapy.
The role of systematic therapy for metastatic or unresectable PMME remains unclear. The first-line systemic therapy for melanoma is immunotherapy such as nivolumab, ipilimumab, and pembrolizumab according to the NCCN guidelines. In previous studies, traditional cytotoxic chemotherapies have displayed very little efficacy against advanced-stage PMME. The overall response rate of chemotherapy in a previous cohort study was only 10.9%, with short progression-free survival (PFS) of just 3 months [
10]. Other studies have also shown unsatisfactory results of chemotherapy. Indeed, Weiner
et al. [
11] reported an OS of patients undergoing chemotherapy of only 7.7 months, and a 3-year OS of 0 in eight patients. The treatment options for patients with metastatic melanoma have improved dramatically in the past 5 years with the development of targeted therapies and immunotherapies. The immune checkpoint inhibitors nivolumab and ipilimumab represent novel treatment strategies for malignant melanoma. These drugs have been reported to demonstrate a substantial clinical benefit for patients with metastatic melanoma, with objective response rates of 31.0–40.0% [
12]. A number of previous case reports suggested that the usefulness of immunotherapy with nivolumab for PMME may be comparable to melanoma of other organs [
5,
13]. Patients with metastases at the time of diagnosis had a median survival rate of 15.8 months, whereas those who developed metastases later or had unresected stage III disease had an average survival rate of 22.8 months from the date of first diagnosis, and the median OS from the first diagnosis was 18.5 months.