Primary esophageal malignant melanoma without recurrence after surgery and adjuvant therapy with nivolumab

Abstract

Primary malignant melanoma of the esophagus is a rare disease with a severely poor prognosis. Here, we report a patient with primary malignant melanoma of the esophagus surviving without recurrence after surgery and adjuvant therapy with nivolumab. The patient was a 60-year-old female with dysphagia. Esophagogastroscopy showed an elevated dark brown tumor in the lower thoracic esophagus. A histological examination of the biopsy revealed human melanoma black 45 and melan-A positivity. The patient was diagnosed with primary malignant melanoma of the esophagus and was treated with radical esophagectomy. As postoperative treatment, the patient was given nivolumab (240 mg/body) every 2 weeks. Although bilateral pneumothorax occurred after 2 courses, she recovered after chest drainage. Nivolumab treatment is still ongoing over 1 year after the surgery, and the patient has survived without recurrence. We conclude that nivolumab is an optimal option as a postoperative adjuvant treatment for PMME.

Introduction

Primary malignant melanoma of the esophagus (PMME) is an extremely rare disease that accounts for 0.1–0.2% of all malignant esophageal tumors, and 0.5% of all noncutaneous melanomas [1, 2]. PMME behaves aggressively and has a poor prognosis and 5-year overall survival (OS) rate of < 5% [3]. No comprehensive treatment strategy has been established because the number of patients with PMME is very low, leading to a lack of clinical evidence.

In recent years, immune-checkpoint inhibitors, such as the anti-programmed cell death 1 (PD-1) antibody, nivolumab, have been reported as effective treatments for malignant melanoma [4–6]. Some reports demonstrated the efficacy of nivolumab to treat recurrent or unresectable PMME [7, 8]. However, there are few reports of nivolumab as an adjuvant therapy for PMME. Here, we report the first example of a patient with PMME who underwent surgery followed by adjuvant nivolumab monotherapy and survived without recurrence.

Case report

A 60-year-old woman visited our hospital with dysphagia as her chief complaint. The patient had a past medical history of dermatomyositis and breast cancer. Esophagogastroscopy showed an elevated dark brown tumor 60 mm in size with black pigmentations on its surface, located in the lower thoracic esophagus (Fig. 1a). An esophageal double contrast study revealed a mass with a smooth surface and clear margins (Fig. 1b). Computed tomography (CT) was used to determine the localized wall thickness (Fig. 1c). Fluorine-18 fluorodeoxyglucose positron emission tomography (PET)-CT indicated an abnormal accumulation in the same region (Fig. 1d).

Fig. 1.

Preoperative diagnostic imaging. (a) Esophagogastroscopy showed an elevated tumor in the lower thoracic esophagus. (b) An esophageal double contrast study revealed a huge mass with a smooth surface. (c) CT was used to determine the wall thickness of the esophagus. (d) PET-CT showed an abnormal accumulation in the tumor region

A histopathological examination of the biopsy specimen revealed atypical round cells with oval hyperchromatic nuclei, occasional distinct nucleoli, ill-bordered cytoplasm, and melanin pigments (Fig. 2a). Immunohistochemical staining demonstrated the positive expression of human melanoma black 45 (HMB-45) (Fig. 2b) and melan-A (Fig. 2c). There were no signs of cutaneous melanoma or pigmentation on the rest of the body. No lymph node metastasis or distant metastasis was observed, and the patient was diagnosed with clinical T3N0M0 Stage II PMME, according to the Japanese Classification of Esophageal Cancer, 11th Edition [9].

Fig. 2.

Microscopic findings of the biopsy specimen. (a) Histopathological examination (HE) with magnification × 20. (b) HMB-45 staining with magnification × 20. (c) Melan-A staining with magnification × 20

The patient underwent thoracoscopic esophagectomy with two-field lymphadenectomy reconstructed by a gastric tube through the posterior sternum route. The postoperative hospital stay was 15 days with no complications. The resected specimen showed a type 1 tumor measuring 70 × 45 mm with black pigmentation (Fig. 3). Microscopic examination demonstrated subserosal invasion of atypical cells (T3) and lymph node metastases in the No. 1, No. 11p, and No. 107 nodes (N4). The pathological diagnosis was T3N4M0 Stage IV a according to the Japanese Classification of Esophageal Cancer, 11th Edition. A molecular study indicated no V600E mutation in the V-raf murine sarcoma viral oncogene homolog B1 (BRAF).

Fig. 3.

Surgical specimen of the esophagus

As adjuvant treatment, intravenous nivolumab (240 mg/body) was administered every 2 weeks. After 2 courses, the patient complained of dyspnea and chest radiography showed a bilateral pneumothorax. Chest drainage with 8 Fr tubes was carried out and the patient recovered. Careful follow-up was continued every 3 months with chest and abdominal CT. The patient survived without recurrence over 1 year following the surgery.

Discussion

In this case report, we showed that nivolumab may be a beneficial option as a postoperative adjuvant treatment for resectable PMME, in the absence of evidence for a comprehensive treatment strategy.

Melanocytes are present in the gastrointestinal tract mucosa such as the oral cavity, esophagus, and anorectum. PMME mostly occurs in the lower and middle segment of the esophagus due to a greater concentration of melanocytes [10]. Dysphagia is one of the common presenting symptoms. As the PMME is commonly soft in nature, fewer symptoms are observed compared to esophageal carcinoma. Therefore, PMME is often diagnosed at advanced stages, with 30–40% of patients having lymph node involvement or distant metastases [11]. Because most esophagogastrointestinal melanomas are metastases from cutaneous melanoma, metastasis must be ruled out before making a diagnosis of PMME. In our case, the patient complained of dysphagia and a large tumor was located in the lower thoracic esophagus. No primary lesions of the skin, mucosa or any other organ were discovered, and the patient was, therefore, diagnosed with PMME.

Radical surgery is the preferred treatment for resectable PMME, with a postoperative 5-year survival rate of 37% [12]. On the other hand, X. Wang et al. analyzed 76 cases of patients with PMME and reported that postoperative recurrence occurred in 89.7% of patients who underwent complete excision, and the median recurrence-free survival (RFS) was only 4.5 months [13]. The risk of recurrence is extremely high after radical surgery, reflecting the important role of multimodal treatment including adjuvant therapy. However, because of the rarity of PMME, optimal adjuvant treatments have not yet been established. A previous trial reported that adjuvant chemotherapy with temozolomide could improve both RFS and OS in patients with mucosal melanoma [14]. Another report showed that the RFS of PMME patients who received adjuvant chemotherapy with temozolomide and dacarbazine was 6 months, whereas the RFS of patients who did not receive adjuvant therapy was 2 months [13]. These results demonstrate that RFS is still low despite the above adjuvant chemotherapies.

Nivolumab is one of the standard treatments for advanced malignant melanoma [4–6]. The CheckMate 238 clinical trial showed that, in patients with resected stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in a significantly longer RFS versus ipilimumab [15]. Some reports have noted the antitumor efficacy of nivolumab in recurrent or unresectable PMME [7, 8, 16]. M. Urabe et al. administered nivolumab as the adjuvant therapy in one patient, but the RFS was only 4 months [17]. Our patient was given nivolumab following radical surgery based on the above trials and reports, and she has now experienced over 1 year of RFS.

Nivolumab causes adverse effects, known as immune-related adverse events, through immune-mediated tissue damage. There are a few reports of pneumothorax during nivolumab administration [18, 19]. These reports indicate that immunotherapy may cause immune-related pneumothorax based on immune pneumonitis. Although there are several factors that can cause pneumothorax, such as past smoking, lean body shape, and thoracoscopic esophagectomy in our patient, the causal relationship between pneumothorax and nivolumab cannot be denied considering that it occurred in bilateral thoracic cavities. We carefully re-administered nivolumab after explaining the risk of pneumothorax recurrence, and pneumothorax has not recurred so far.

Some limitations exist in this report. First, the follow-up period was short. Second, the results were based on only one case. Further follow-up and cases are required to clarify these.

In conclusion, to our knowledge, this case demonstrates the longest RFS to date in a patient with PMME treated with nivolumab as adjuvant treatment following esophagectomy. We also showed that nivolumab may be an optimal option as a postoperative adjuvant treatment for PMME.

Abbreviations

PMME

Primary malignant melanoma of the esophagus

OS

Overall survival

PD-1

Programmed cell death 1

CT

Computed tomography

PET

Positron emission tomography

HMB-45

Human melanoma black 45

BRAF

V-raf murine sarcoma viral oncogene homolog B1

RFS

Recurrence-free survival

Author contributions

All authors attest that they meet the criteria for authorship. All authors read and approved the final manuscript.

Funding

This study was not funded.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Conflict of interest

No potential conflicts of interest were disclosed.

Ethics approval

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.