Correspondence *Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore

Email mdchoky@nus.edu.sg

The case

The patient, a 48-year-old Chinese woman, first presented in March 2006 with a 2-month history of progressive dysphagia for solids and (less frequently) liquids. She had minimal weight loss since the onset of symptoms and had no family history of cancer. She was not taking any medications, had no history of any illness, and was a nonsmoker.

Physical examination was normal and revealed no skin lesions. Proctoscopic, pelvic, and ears, nose and throat examinations were all clear. Initial esophagogastroduodenoscopy found a large, pigmented, polypoidal, intraluminal mass that almost occluded the entire esophageal passage at about 20 cm from the upper incisors (Figure 1). A CT scan showed a mass in the esophagus that did not extend outside the esophageal wall. There was no significant hilar or mediastinal lymphadenopathy. No pleural effusion was evident but slight shadowing on the lingular segment of the left upper lobe of the lungs indicated possible pneumonitis. The abdomen was normal.

Figure 1 Three videoendoscopic views of the esophagus of a 48-year-old female with a 2-month history of dysphagia

A large pigmented multilobular intraluminal mass at approximately 20 cm from the oral incisors is shown.

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Endoscopic polypectomy was performed 3 days later with injection of methylene blue and adrenaline into the polyp base before the procedure. The excised black, fleshy, ulcerated mass, which was removed in three pieces, measured 4.5 3.2 2.2 cm in total (Figure 2). Histologic examination revealed highly pleomorphic, plump, spindled tumor cells arranged in solid nests and sheets (Figure 3). The cells had large, round-to-oval vesicular nuclei, prominent nucleoli and abundant mitoses. Many cells were laden with brown cytoplasmic melanin granules; this finding was confirmed immunohistochemically by staining with the monoclonal antibody marker for melanoma, HMB 45 (Figure 4A,B). The overlying stratified squamous epithelium was ulcerated and, although no obvious evidence of junctional activity was discernible in this area, there were scattered melanin-containing cells among the adjacent stratified squamous epithelium. A histopathologic diagnosis of malignant melanoma was made.

Figure 2 Gross image of a highly pigmented, ulcerated and hemorrhagic tumor excised from the esophagus of a 48-year-old woman

The tumor measures 4.5 3.2 2.2 cm on reconstruction.

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Figure 3 Histologic section of the resected esophageal mass

A subepithelial pigmented cellular tumor is shown (stained with hematoxylin and eosin, magnification 150).

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Figure 4 Histologic section and immunostaining of the resected esophageal tumor

(A) Sheets of pleomorphic plump, spindled cells exhibiting large round-to-oval vesicular nuclei, prominent nucleoli, abundant mitoses, and brown cytoplasmic granules (stained with hemoxylin and eosin, magnification 400). (B) The presence of melanin confirmed by immunostaining with HMB 45 (Immunostain, magnification 400)

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Fluorodeoxyglucose–PET (FDG-PET) scans revealed no signs of residual melanoma or distant metastasis. Conventional esophagogastroduodenoscopy revealed three distinct pigmented, polypoid lesions (Figure 5) at 24 cm, 22 cm and 18 cm from the incisors, which were believed to be the remnants of the originally presented main and satellite tumors. The patient was referred for re-evaluation with endoscopic ultrasonography (EUS); a 20 MHz transendoscopic ultrasound probe was used. With this technique, the lesions appeared hypoechoic, and involved the submucosal layer. A near-total esophagectomy (Figure 6) with esophagogastric anastomosis was performed 1 month later. The patient was discharged on the sixth postoperative day. Microscopically, small nests of tumor were found at the proximal surgical margin. Postoperative radiation therapy is being considered.

Figure 5 Endoscopic view of three pigmented satellite polypoid lesions in a patient with malignant melanoma

Residues of the excised tumor at 18 cm, 22 cm and 24 cm from the incisors are shown.

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Figure 6 Resected specimen of the esophagus of a patient diagnosed with malignant melanoma

Hyperpigmented remnants of the original lesions are shown.

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Discussion of diagnosis

Primary malignant melanoma of the esophagus is an extremely rare, non-epithelial neoplasm, with an incidence of 0.0036 cases per million people each year.¹ Before June 2005, there were only 262 documented cases in the world literature.² Esophageal melanomas account for about 0.1–0.2% of all esophageal cancers, and 0.5% of noncutaneous melanomas.^{3, 4}Almost 90% of cases occur in the middle or distal third of the esophagus, usually as a solitary tumor, but multiple lesions have been reported in 12% of cases.^{4, 5} Most patients are symptomatic on presentation, and dysphagia is the most common symptom, followed by weight loss, substernal or epigastric discomfort, and melena. The duration of symptoms before presentation is short—approximately 3 months—in most cases.^{3, 4, 6} Very little is known about the etiology of malignant melanoma because of the rarity of the disease; however, melanocytosis has been indicated as a predisposing factor.⁷

Endoscopically, esophageal melanoma lesions appear as intraluminal, polypoid, and (usually, but not necessarily), pigmented, irregular masses, which might also be ulcerated.^{1, 8} Diagnosis on endoscopy is often difficult, particularly for amelanotic lesions, because of their similarity to epithelial carcinomas—although the latter are more likely to occur in the proximal rather than the distal two-thirds of the esophagus. In this case, initial esophagogastroduodenoscopy revealed a pigmented, multilobular mass that was characteristic of esophageal melanoma. The surprisingly huge size of the tumor in relation to the short onset of the patient's symptoms suggested that it was a rapidly developing tumor, rather than a more insidious, gradual-growing type. The diagnosis of esophageal melanoma was confirmed histologically and immunohistochemically by typical cytologic features and the presence of melanin pigment, respectively.^{1, 9} The absence of cutaneous, ocular, or mucosal melatonic lesions elsewhere in the body indicated a primary rather than a secondary melanoma.

Different imaging techniques were used to help stage this patient's tumor pre-operatively. CT revealed the absence of tumor infiltration beyond the esophageal wall, and excluded the presence of distant metastasis, but could not be used to differentiate mucosal versus submucosal involvement, or to assess regional lymphadenopathy. On the basis of this staging modality alone, a conservative piecemeal polypectomy was performed, rather than a radical esophagectomy. FDG-PET scanning is an efficient and well-known diagnostic tool in various malignant disorders. It is of proven value in the detection of metastases in patients with cutaneous melanoma; however, little is known about its value for esophageal melanoma.^{10, 11} In this patient, the results of FDG-PET were normal after the initial endoscopic polypectomy, despite the presence of residual disease in the esophagus, which was clearly demonstrated on subsequent endoscopy and confirmed intraoperatively. In this case, FDG-PET seemed less useful than EUS in the detection of residual esophageal disease. One reason for this observation might be that the residual lesions were too small to be detected by FDG-PET. It has been shown that FDG-PET is of limited use in the detection of micrometastases and small lesions (<10 mm).^{12, 13} This finding, as reported, is the key reason behind most false-negative FDG-PET results.¹³

EUS has revolutionalized the tumor staging of many gastrointestinal malignancies. Locoregional evaluation by EUS has been shown to be useful in the diagnosis and preoperative staging (for resectability) of esophageal melanoma.¹⁴ As this case demonstrated, EUS clearly defined the intramural extent of the lesions, which typically appeared hypoechoic. Owing to the EUS findings in this patient, a near-total esophagectomy was performed.

Treatment and management

Primary esophageal melanoma is notorious for its aggressiveness, and its rapid dissemination to multiple organs, tissues and lymph nodes by means of the lymphatic system and blood vessels. Most cases are extensive at diagnosis and synchronous metastases are found in almost half of patients. Prognosis is generally dismal; only 30% of patients survive beyond 1 year after diagnosis, and the 5-year survival rate is less than 5%.^{9, 15, 16} Current therapeutic options are limited, and usually involve radical surgery or palliative treatment. Surgical excision with discretionary lymphadenectomy is the treatment of choice for operable melanomas, but total or near-total esophagectomy offers the best survival outcome (about 5 years, versus 9 months for local resection).⁴ Therapeutic options such as radiotherapy, chemotherapy and immunotherapy provide limited benefits, even when used in conjunction with surgery. They are generally not recommended as first-line treatment options for patients with primary esophageal melanoma, except when surgical resection of the tumor is not feasible. Other newer treatment modalities, such as intraluminal brachytherapy and laser photoablation, are promising, but the long-term outcomes of these methods remain to be established.^{17, 18} A near-total esophagectomy was performed in this case because a total esophagectomy would have entailed a laryngopharyngoesophagectomy as it is not possible to anastomose at the level of the laryngeal introitus. A near-total esophagectomy leaves a stump of about 2–3 cm of cervical esophagus for the esophagogastric anastomosis, which in this case was performed in the neck, notwithstanding that there were still microscopic nests of disease at the proximal surgical margin. Although we recognize that post-operative radiotherapy might not be sufficient to treat this patient, who has tumor involvement at the surgical margin, it is the least-invasive option given her poor prognosis.

Conclusion

This rare case of primary malignant esophageal melanoma presented with three separate lesions. Endoscopic polypectomy failed to eliminate the disease and near-total esophagectomy was performed. In this case, EUS was shown to be more useful than CT and FDG-PET scans in the regional detection of the residual melanoma, as well as in the determination of its extent of invasion.

Acknowledgments

We would like to thank A Thomas of Parkway Laboratory Services Ltd, Singapore, for her contribution of a histology slide, and J Wong for her editorial assistance.

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Subject areas under which this article appears: Cancer | Upper gastrointestinal tract