Primary Malignant Amelanotic Melanoma in the Female Genital Tract: A Report of Six Cases and a Review of the Literature

Clinical Characteristics

The typical MFGT lesion manifests with pigments, either brown or black. Clinicians usually make a first melanoma judgment from these pigments. AMFGT differs from MFGT in that the former appears without pigments and is not easily identified clinically from inflammatory lesions or other malignancies. A case of AMFGT in the vulva was reported to be misdiagnosed as vulvar lichen sclerosus et atrophicus ^[1]. Pizzichetta et al.^[2], found that most amelanotic melanomas are actually partially devoid of pigment and some contain a predominance of reddish, sulfur-containing pheomelanin over brown-black eumelanin. Thus the lesion may present with a grayish, yellowish or reddish color, often with the pigmentation present at the periphery of the lesion^[2,3]. One patient with AMFGT in the vulva in our study had a tumor lesion that was virtually a transparent red; however, the micro-satellite lesions around the affected area did have brown pigments. So, for these non-pigmented lesions with encircled pigments, clinicians should be on the alert for AMFGT.

MFGT can recur as an AMFGT and vice versa. Another case in our study was originally a vulvar melanoma. After a vulvar wide excision, she had two recurrences; the second proved to be a recurrence as an AMFGT in her vulva. Conversely, Oguri et al,^[4] in 2004, reported a case of vaginal amelanotic melanoma which recurred as a typical melanoma. This phenomenon indicates that some melanoma cell clones can lose or increase their ability to produce melanin, so that variable quantities of melanin observed during the melanoma’s procession and conversion between melanoma is veritable ^[3].

Diagnosis

Histological examinations of typical MFGT specimens, using H&E histochemical staining, will confirm a melanoma diagnosis once tumor cells with large amounts of melanin granules in the cytoplasm are found. However, for AMFGT, there are few melanin granules in the tumor cells. Therefore it has been reported that amelanotic melanoma may be easily confused pathologically with other malignances, such as chorioepithelioma, lymphoma, adenocarcinoma, poorly differentiated sarcomas etc ^[5,6]. In our study, 4 patients were preliminarily diagnosed through routine H&E staining as chorioepithelioma, sarcoma, adenocarcinoma or lymphoma. This common misdiagnosis should arouse pathologists’ awareness.

The role of immunohistochemical staining in the diagnosis of melanomas, especially in AMFGT^[7], has become increasing important. The most common immunohistochemical staining markers are HMB-45, S-100 protein and vimentin. In our 4 misdiagnosed cases, 2 showed positive immunohistochemical staining for both the S-100 protein and HMB-45, thereby correcting the diagnosis. Oguri et al,^[5] presented a case of amelanotic melanoma of the vagina, which was initially suspected to be a non-epithelial malignant tumor. Subsequently the case was correctly diagnosed by positive HMB-45 and S-100 protein immunohistochemical staining. The surgical specimens removed from all 6 cases received combined immunohistochemical staining. All cases were positive for both S-100 and vimentin. Five cases received immunohistochemical staining for HMB-45 and 3 of them were positive.

In Gupta’s report^[7] of 26 cases of vaginal melanoma mentioned, 6 cases involved non-pigmented melanoma. Of these, all cases were positive for S-100 and 3 cases were positive for HMB-45. For these 3 cases, MART-1 and tyrosine kinase were 2 other significant immunohistochemical staining markers for AMFGT.

A complete melanoma diagnosis should also include the evaluation of the AJCC stage and Breslow classification. So an excisional biopsy with enough depth is recommended to help in evaluating the tumor invasion depth ^[8]. In our study no patients were recognized as AMFGT positive from their first medical visit, and instead received a superficial biopsy with a biopsy forceps, which was insufficient in evaluating the tumor invasion depth and AJCC stage. This superficial biopsy mode is not recommended for melanoma cases. Due to the cryptic nature of AMFGT, it’s hard to decide the range of excision. Recently Busam^[9] and Pizzichetta^[2] et al. reported respectively that a confocal scanning laser microscope and dermatoscope were utilized to determine the range of lesion in amelanotic melanoma, which may be of great help in making a diagnosis of this disease.

Treatment and Prognosis

The treatment for AMFGT is currently the same as that for MFGT. The main method is surgery with some adjuvant treatment including chemotherapy, radiotherapy and biotherapy. But the overall therapeutic efficacy for AMFGT is poor^[10]. Although all patients in our study had radical therapy, 4 patients had a tumor recurrence and 3 of them died (at 13, 18 and 19 months) after the initial diagnosis. The outcomes were worse than that of MFGT reported by our hospital^[11]. In our study the patients were staged among Ia to IIa (Federation International of Gynecology and Obstetrics Staging Guidelines). However, no patients were recognized as AMFGT at their first medical visit, and all received a superficial biopsy with a biopsy forceps, which was insufficient in evaluating the tumor invasion depth, AJCC stage and prognosis. We know that a misdiagnosis increases the difficulty of treatments^[12]. One of our cases was originally diagnosed as a “vaginal sarcoma”. Though 3 cycles of systemic chemotherapy combined with intracavity radiotherapy was given, the tumor was not controlled. Therefore avoiding misdiagnosis is important for appropriate treatment.