The author reports herein two cases of amelanotic malignant melanoma of the esophagus. Case 1 is an 87-year-old woman who was admitted to our hospital because of nausea and vomiting. Endoscopic examination revealed an ulcerated tumor of the distal esophagus, and a biopsy was taken. The biopsy showed malignant polygonal and spindle cells. No melanin pigment was recognized. Immunohistochemically, the tumor cells were positive for melanosome (HMB45), S100 protein, KIT and Platelet derived growth factor receptor-α (PDGFRA). The patient was treated by chemotherapy and radiation, but died of systemic metastasis 12 mo after the presentation. Case 2 is a 56-year-old man presenting with dysphagia. Endoscopic examination revealed a polypoid tumor in the middle esophagus, and a biopsy was obtained. The biopsy showed malignant spindle cells without melanin pigment. Immunohistochemically, the tumor cells were positively labeled for melanosome, S100 protein, KIT and PDGFRA. The patient refused operation, and was treated by palliative chemotherapy and radiation. He died of metastasis 7 mo after the admission. In both cases, molecular genetic analyses of KIT gene (exons 9, 11, 13 and 17) and PDGFRA gene (exons 12 and 18) were performed by the PCR direct sequencing method, which showed no mutations of KIT and PDGFRA genes. This is the first report of esophageal malignant melanoma with an examination of the expression of KIT and PDGFRA and the mutational status of KIT and PDGFRA genes.

Primary malignant melanoma of the esophagus is very rare; only case reports and studies of small series have been reported[1–7]. Primary amelanotic malignant melanoma of the esophagus is extremely rare; only a few case reports have been published in the literature[8–13].

Melanoma is a highly aggressive tumor, and NRAS and BRAF mutations are mainly involved in the pathogenesis of melanoma[1415]. KIT gene, mapped to 4q12, encodes an oncogenic transmembranous receptor tyrosine kinase, KIT, whose ligand is stem cell factor[6–21]. The platelet derived growth factor receptor-α (PDGFRA) gene, also mapped to 4q12, additionally encodes an oncogenic transmembranous receptor tyrosine kinase, PDGFRA[6–21]. The KIT gene plays an important role in melanocyte migration, development, differentiation and tumorigenesis[22]. A few previous studies have shown that activating mutations of the KIT gene may lead to tumorigenesis of cutaneous melanoma[1423]. Since both KIT and PDGFRA genes are mapped to 4q12, it is anticipated that PDGFRA gene mutations are also involved in the tumorigenesis of melanoma, as in the case of gastrointestinal stromal tumors[16–21]. However, the incidence of PDGFRA gene mutations in melanoma has rarely been estimated[24].

The author herein reports two cases of esophageal amelanotic malignant melanoma with immunohistochemical and molecular genetic study of KIT and PDGFRA.

Amelanotic melanoma of the esophagus is extremely rare, and the pathological diagnosis is very difficult because melanin pigment is absent. In fact, it has been frequently misdiagnosed as other sarcomas[1–13]. Immunohistochemistry of melanoma antigens such as melanosome (HMB45), Malan-A, and S100 protein are mandatory for the diagnosis of amelanotic melanoma. Ultrastructural demonstration of melanosome is also diagnostic. In the present study, both cases were positive for immunoreactive melanosome (HMB45) and S100 protein, confirming the diagnosis. In addition, positive KIT strongly suggests that the tumors are melanomas. Amelanotic melanoma can be diagnosed in biopsy specimens.

Malignant melanoma is a very aggressive tumor irrespective of its location. Malignant melanoma of the esophagus is therefore a very aggressive tumor, and its prognosis is very poor[1–13]. In the present study, the prognosis was indeed very poor in both patients. Operation followed by adjuvant chemotherapy and radiation is the best choice of treatment[1–13]. In the present cases, operation was impossible in one case and was not performed in another case because of the patient’s decision not to proceed.

The previously reported cases of esophageal melanoma were only case reports or clinical studies of very small series. There have been no reports of KIT and PDGFRA expression and mutations in esophageal melanomas. The present study is the first report of esophageal melanoma with an examination of KIT and PDGFRA protein expression and gene status of KIT and PDGFRA in esophageal melanoma. The tumors in the present cases expressed KIT and PDGFRA, but identified no mutations of KIT and PDGFRA. The positive expressions of KIT and PDGFRA suggest that these transmembranous oncoproteins are present in esophageal melanoma.

In cutaneous melanomas, the percentage of KIT expression varies amongst studies reported by researchers[36]. The percentage of KIT positive cutaneous melanomas in the literature is as follows; 35%[37], 21%[38], 87%[39], 90%[40], 50%[41] and 84%[42]. Sihto et al[36] reported that KIT expression in most human solid tumors, including cutaneous melanomas, was due to KIT gene amplification. Studies of KIT mutations in cutaneous melanoma are scant. Willmore-Payne et al[23] showed only 2% of KIT mutations in cutaneous melanomas. Sihto et al[36] showed no KIT mutations in 14 cutaneous melanomas. In contrast, Curtin et al[14] showed that KIT mutations are present in 39% of mucosal melanomas, in 36% of acral melanomas, in 28% of melanomas on sun-damaged skin, and in 0% of melanomas on non-sun-damaged skin. Beadling et al[37] recently reported that KIT mutations were present in 23% of acral melanomas, 15.6% of mucosal melanomas, 7.7% of conjunctival melanomas, 1.7% of cutaneous melanoma, and in 0% of choroidal melanomas.

PDGFRA protein expression in melanoma has not been performed, to the best of the author’s knowledge. As for PDGFRA mutations, Curtin et al[24] found no PDGFRA mutations in 26 cutaneous melanomas. Sihto et al[36] demonstrated no PDGFRA gene mutations in 14 cutaneous melanomas.

In summary, the author reported two extremely rare cases of amelanotic malignant melanoma of the esophagus with immunohistochemical and genetic analysis of KIT and PDGFRA.