Editor's note: Primary esophageal melanoma is a malignant tumor of melanoblasts that occurs in the basal layer of the esophageal mucosal epithelium, which is extremely rare in clinical practice, accounting for 0.1%-0.3% of esophageal malignant tumors. The prognosis of patients is very poor, and only a few patients survive long-term after surgery or radiotherapy.
Professor Li Gaofeng of Yunnan Cancer Hospital is the executive editor-in-chief of this issue of "Expert Group Draft", who will discuss the progress of the diagnosis and treatment of esophageal melanoma with Professor Li Ruilei in the second issue, aiming to provide a deeper understanding and reference for the medical community and patients.
About the Speaker
Li Gaofeng
Vice President of Yunnan Hospital, Peking University Cancer Hospital (Yunnan Provincial Cancer Hospital, Third Affiliated Hospital of Kunming Medical University).
Doctoral supervisor, postdoctoral cooperative supervisor, second-level professor, chief physician
Yunnan Health Guard, Provincial Association for Science and Technology Outstanding Society Worker
President of Yunnan Translational Medicine Society
Vice Chairman of Yunnan Anti-Cancer Association
Chairman of the Thoracic and Cardiovascular Surgery Branch of Yunnan Medical Association
Chairman of the Minimally Invasive Treatment Committee of Thoracic Tumors of Yunnan Anti-Cancer Association
Executive Director of Yunnan Preventive Medicine Association and Chairman of Lung Cancer Professional Committee
Member of the International Association for the Study of Lung Cancer
He is a member of the Standing Committee of the Mediastinal Tumor Professional Committee of the Chinese Anti-Cancer Association
Member of the Thoracoscopic Surgery Group of the Thoracic and Cardiovascular Surgery Branch of the Chinese Medical Association
Member of the Working Committee of the Medical Consortium of the Chinese Hospital Association
Member of the National Lung Cancer MDT Expert Committee
National outstanding scientific and technological worker, expert enjoying special allowance of the State Council
Winner of the National May Day Labor Medal, Yunnan Provincial Medical Leading Talent, Yunling Famous Doctor
Yunnan Province has outstanding professional and technical personnel with outstanding contributions and experts contacted by the provincial party committee
Li Ruilei
Attending physician of the Tumor Biotherapy Center of Yunnan Hospital, Peking University Cancer Hospital (Yunnan Provincial Cancer Hospital, Third Affiliated Hospital of Kunming Medical University), Doctor of Oncology
Member of the Patient Education Committee of the Chinese Society of Clinical Oncology (CSCO).
Member of the Melanoma Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
He is a member of the Head and Neck Malignant Melanoma Professional Committee of the Beijing Cancer Prevention and Control Society
He is a member of the Clinical Application Committee of Pharmaceutical Biotechnology of China Pharmaceutical Biotechnology Association
Member of the Melanoma Professional Committee of Beijing Science and Technology Innovation Medical Development Foundation
Member of the Cell and Gene Therapy Branch of Yunnan Translational Medicine Society
Phase II: Progress in the diagnosis and treatment of esophageal melanoma, a rare malignant tumor of the esophagus
◾ Li Gaofeng, Li Ruilei, Yunnan Provincial Cancer Hospital
Executive Editor-in-Chief: Professor Li Gaofeng
Primary malignant melanoma of the esophagus (PMME) is an extremely rare cancer, first described by Bauer in 1906[1], accounting for 0.1% to 0.2% of all malignant esophageal tumors and all melanoma subtypes< 0.05 percent [2,3], with an estimated incidence of 0.0036 cases per million per year [4]. From the first case report to 2021, the majority of cases reported globally were case-by-case reports, with more than 300 PMME cases reported. PMME is a highly aggressive tumor with a poor prognosis, with a 5-year overall survival (OS) of <5%[5].
1. Epidemiology and origin
PMME accounts for 5.6% of all gastrointestinal melanoma (GI), and the median age at diagnosis of PPME patients is 60.4 years, which is younger than esophageal squamous cell carcinoma (71 years). The incidence of PMME is significantly higher in males than in females, with a male-to-female ratio of approximately 2:1 [6,7]. In approximately 90 percent of cases, PMME originates from the lower to mid-esophagus [8]. The origin of PPME has been controversial since it was first reported [4,9,10], and it was not until direct endoscopic visualization that melanoma may also originate in the esophagus [11]. The esophagus does not normally contain melanoblasts, so abnormal migration of esophageal melanocytes may explain the occurrence of PMME [12].
2. Clinical manifestations and diagnostic difficulties
PMME presents with gastrointestinal symptoms such as dysphagia, nonspecific retrosternal pain, and acid reflux, which are similar to esophageal squamous cell carcinoma [6,8]. Approximately 25 to 30 percent of PMMEs are associated with "melanocytosis", which is characterized by an increased number of pigment-rich melanocytes in the basal layer of the esophageal squamous epithelium, and an increase in the amount of melanin in the esophageal mucosa [13]. PMME tumors are partially covered by normal mucosa and are rarely ulcerated. Approximately 10-25% of PMME shows different colors depending on the amount of melanin, including purple, brown, and white, and there is no melanin in "melanoma-free" cases. Despite biopsy, 20 to 50 percent of patients are misdiagnosed as poorly differentiated carcinoma due to the lack of melanin granules [12-14].
3. Molecular typing
Genetic testing has revealed that NRAS and BRAF mutations are frequently observed in cutaneous melanoma [15,16]. However, PMME is a mucosal melanoma with a genetic change that is different from cutaneous melanoma. There are only a few BRAF mutations in PMME [17]. Conversely, the incidence of NRAS and KIT mutations is higher in PMME than in cutaneous melanoma [18]. NGS analysis based on DNA and RNA hybridization captures of 13 PMME samples revealed that NF1 was the most common mutated gene (30%). Other mutations detected in PMME include SF3B1 (20 percent), KRAS (10 percent), BRCA2 (10 percent), KIT (10 percent), and TP53 (10 percent) [19].
Genome sequencing analysis by mainland researchers [20] showed that genomic aberrations in PMME were dominant among the classic cancer driver genes, and BRAF, N/KRAS, and NF1 mutations were present in about half of PMME cases. In contrast, the majority of non-esophageal mucosal melanoma (NEMM) cases are triple-wild-type. Transcriptome analysis showed that compared with NEMM, PMME showed more significant proliferative and inflammatory characteristics, higher expression of antigen presentation and differentiation-related genes, lower immunosuppressive characteristics, and lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. Multiplex immunohistochemistry analysis also showed that CD8+ T cell infiltration was higher in PMME than in NEMM. PMME (n=28) was also found to have a better response to anti-PD-1 therapy than NEMM (n=64), with objective response rates [33.3% (95% CI 14.3% to 52.3%) and 6.6% (95% CI 0.2% to 12.9%)] and disease control rates (74.1% (95% CI 56.4% to 91.7%)) and 37.7% (95% CI 25.2% to 50.2%).
Fourth, treatment progress
Staging of disease There was no standard TNM staging system in the past. Although the initial TNM staging of PMME for AJCC staging of esophageal cancer was found to be significantly correlated with both RFS and OS, suggesting that this staging system can accurately distinguish the prognosis of patients with PMME, further larger-scale studies are needed to determine the standard staging system for PMME. Therefore, it is urgent to establish a standardized staging system for mucosal melanoma at different primary sites. Recently, mainland researchers [21] based on the evidence of 1814 cases of mucosal melanoma staging system, suggest that the staging system of mucosal melanoma is: (1) stage I: T1N0M0, (2) stage II: T2-4N0M0; (3) Stage IIIA: T1-4N1M0, Stage IIIB: T1-4N2M0; (4) Stage IV: TanyNanyM1. This staging system is the world's first staging system for mucosal melanoma at different primary sites, which will help standardize the staging of mucosal melanoma in the future and provide a basis for clinical diagnosis and treatment and translational research.
Surgery Traditionally, surgery has been the only option to prolong survival in patients with PMME, and total or subtotal esophagectomy has provided a more favorable survival outcome. Researchers from mainland China [6] reported single-center data from Beijing Cancer Hospital: 59 patients (77.6%) underwent subtotal esophageal resection or esophagogastrostomy plus systemic mediastinal or abdominal lymph node dissection. The reasons for not performing surgery were as follows: 2 patients were in very poor condition, 1 patient had unresectable T4 tumors, and 14 patients had distant metastases. In addition, national multicenter data [22] showed that a total of 70 patients with PMME who underwent surgery were included, of whom 41 (58.6%) underwent Sweet surgery, 17 (24.3%) underwent McKeown surgery, and 9 (12.9%) underwent Ivor With the Lewis procedure, 3 patients (4.3%) underwent abdominal esophagectomy, with a median follow-up of 22.3 months and a median overall survival (OS) of 13.5 months, with 1-year and 3-year OS of 53.1% and 19.0%, respectively. Multivariate Cox regression analysis showed that gender, lymph node metastasis, lymph node dissection extent and postoperative treatment were independent factors for prognosis. Several studies have found that patients can develop lymph node metastases even in the early stages of tumors, and lymph nodes are the most common sites of postoperative recurrence and metastasis. Therefore, lymph node dissection should be emphasized in the surgical treatment of PMME.
Adjuvant therapy The five-year survival rate for patients with PMME ranges from 4 to 37 percent [7,18,23]. The increasing number of cases detected early has contributed to improved prognosis [24]. Both the CheckMate-238 and CheckMate-915 studies included a small number of patients with mucosal melanoma (84-86). In CheckMate-238, immune checkpoint inhibitors were associated with significantly longer recurrence-free survival than placebo when used as adjuvant therapy for stage IIIB-D or IV melanoma [25,26]. CheckMate-915 compared nivolumab in combination with ipilimumab with nivolumab alone as adjuvant therapy for stage IIIB-D or IV melanoma, but failed to show any advantage of the combination [27].
Researchers from mainland China [6] found that 37 patients (62.7%) received adjuvant therapy after surgery, 22 patients in the observation group had a shorter RFS of only 2 months (P = 0.001), and the RFS time of adjuvant chemotherapy patients was 6 months, and the risk of recurrence was significantly lower than that of the control group (HR 0.56; P = 0.006). In another adjuvant study[28], 12 cases of esophageal melanoma were included, including 2 cases with Ki67 <30% and 10 cases with Ki67≥30%, and the results showed that there was no effect on low expression of Ki67 ( There was no significant difference in the effect of adjuvant temozolomide (TMZ) chemotherapy with high-dose interferon a2b (HDI) on RFS <30%) (33.9 versus 22.7 months, P = 0.329). However, in patients with high Ki67 expression (≥30%), adjuvant chemotherapy compared with HDI resulted in good RFS (18.0 versus 6.7 months) and MSS tended to improve (41.4 versus 25.1 months, P = 0.067). However, as the standard treatment and efficacy of ICIs for PMME are unclear, a larger randomized controlled trial of a cohort of PMME patients is needed.
Late-stage treatment Data from clinical trials related to immunotherapy include limited data on mucosal melanoma. A pooled analysis of data from 35 patients with mucosal melanoma treated with nivolumab plus ipilimumab from the CheckMate-067 and CheckMate-069 trials showed that combination therapy was clinically superior to nivolumab alone, although statistically significant findings were not reported [29,30]. The study found that in mucosal melanoma, the addition of PD-1 inhibitor monotherapy did not confer additional efficacy benefit.
PD-1 checkpoint inhibitors have shown activity against PMME in previous studies. Preliminary results showed a response rate of 75% and a median duration of response of 11.4 months. In addition, multivariate survival analyses showed that systemic therapy was associated with significant OS benefit. Previous studies have concluded that PD-1 checkpoint inhibitor monotherapy has achieved unsatisfactory clinical outcomes in patients with mucosal melanoma, particularly those with visceral metastases (ORR 17.6%). However, the PMME subtype of mucosal melanoma has a significantly high response rate.
The mainland investigators proposed[31] the international guideline for axitinib in combination with toripalimab in the treatment of mucosal melanoma was rewritten, with an ORR of 24.5% (95% CI, 17.3-31.6) for 143 patients, including 2 cases of CR and 33 cases of PR, with a DCR of 72.7% (95% CI, 65.3-80.1), a median DOR of 9.2 months (95% C1, 7.2-11.2), and a median of 0S of 11.1 months (95% CI, 7.2-15.0). A total of 18 patients with esophageal melanoma were included in the study, 11 were treated in the first line and 7 were treated in the second line, with an overall efficacy: CR 0%, PR 33.3%; SD 55.5%； PD 11.2%。 In another clinical study of atezolizumab combined with bevacizumab in 40 patients with unresectable or advanced melanoma [32], the ORR was 45.0% (95% CI, 29.3% to 61.5%; 1 CR, 17 PR), the median PFS was 8.2 months (95% CI, 2.7-9.6), the median PFS was 8.2 months (95% CI, 2.7-9.6)), and the PFS rates at 6 and 12 months were 53.4% (95% CI, 36.6%–67.6%) and 28.1% (95% CI, 14.2%–43.9%). Median OS was not achieved (NR; 95% CI, 14.4-NR). The study showed that atezolizumab combined with bevacizumab has good efficacy and a manageable safety profile in the treatment of advanced mucosal melanoma.
Compared with chemotherapy alone, bevacizumab combined with carboplatin and paclitaxel significantly prolonged PFS and reduced the risk of disease progression by 54% (4.8 vs 3.0 months; HR 0.461, 95%CI: 0.306~0.695; P<0.001), significantly prolonged OS, and reduced the risk of death by 59% (13.6 vs 9.0 months; HR). 0.611，95%CI，0.407~0.917；P=0.017）。 More basic research, including whole-genome sequencing, is needed in the future to determine the mechanisms and biomarkers of immunotherapy for mucosal melanoma.
Conclusion PMME has a poor prognosis due to the potential distant involvement in the early stages. Surgery has been the only way to prolong the survival of patients with early-stage PMME, and for localized PMME, accurately obtain a diagnosis of depth of infiltration and lymph node metastasis before initiating treatment, and perform radical surgery with a focus on lymph node dissection. In some case reports, the advent of immunotherapy has significantly prolonged the OS phase in patients with metastatic PPME. As the occurrence of PMME is extremely rare, it is expected that diagnostic guidelines or more effective treatment strategies will be validated in the near future.
Editor-in-Chief's comments
PMME is potentially distant in the early stages, so the prognosis is poor. Surgery has been the only way to prolong survival in patients with early-stage PMME, and for localized PMME, an accurate diagnosis of depth of invasion and lymph node metastases is obtained prior to initiation of treatment, and radical surgery is performed with a focus on lymph node dissection. The basic study stage found that PMME had a low immune microenvironment suppression signature, which was consistent with a significantly high response rate. In some case reports, the advent of immunotherapy has significantly prolonged OS in patients with metastatic PPME. In addition, new immunotherapy combined with antivascular therapy and antivascular combined chemotherapy regimens significantly prolonged the PFS of the beneficiaries in patients. As the occurrence of PMME is extremely rare, it is expected that diagnostic guidelines or more effective treatment strategies will be validated in the near future.
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