Malignant melanoma of the female genital tract diagnosed by cervicovaginal smear: A rare case from the Middle East

INTRODUCTION

Malignant melanoma is a rare form of cancer in the Middle East, with an average age-standardized incidence rate of 1.66/100,000 population- significantly lower than the global high reported in Australia at 54.11/100,000.^[1] In Oman, melanoma ranks among the lowest worldwide, with an age-standardized incidence of just 0.5/100,000 in 2019.^[2]

Gynecological melanomas are exceedingly rare, accounting for only 0.3% of all malignant melanomas and fewer than 3% of all vaginal carcinomas.^[3] Detecting such a rare malignancy via a Pap smear presents a significant challenge, not only due to its rarity, but also because of melanoma’s diverse cytomorphologic appearances. Furthermore, the Pap test is primarily designed to screen for squamous intraepithelial lesions, making incidental detection of nonepithelial malignancies such as melanoma even more difficult.^[4]

In this report, we present a rare case of malignant melanoma diagnosed through a vault/vaginal Pap smear in a Middle Eastern woman referred from a rural hospital. We highlight the cytologic clues that contributed to the diagnosis and provide a brief literature review on melanoma in the Middle East. On August 1^st, 2025, we conducted a PubMed search using the terms “melanoma,” “female genital tract,” “Middle East,” and “Arab world” covering the previous two decades. The search was limited to the English-language publications and full-text articles. No reported cases of malignant melanoma of the female genital tract from the Middle East and North Africa (MENA) region were identified. To the best of our knowledge, this is one of the very limited documented cases of malignant melanoma involving the female genital tract diagnosed through Pap smear in a Middle Eastern patient.

CASE REPORT

A 61-year-old postmenopausal woman (G10P10), pale brown skin type, presented with vaginal bleeding to a gynecologist at a regional hospital. Her last childbirth had occurred 24 years prior. She had previously undergone a vaginal hysterectomy due to 2^nd° uterovaginal prolapse.

On speculum examination, the vaginal vault appeared healthy; however, a 3 cm polypoidal, bluish-colored lesion was noted on the lower part of the posterior vaginal wall. The lesion bled on touch. Differential diagnoses at the time included a thrombosed polyp or an endometrioma. Per rectal examination revealed no connection to the anterior rectal wall. There was no prior history of skin or other melanomas, no family history of malignancies and no imaging studies were provided at the time.

A vaginal/vault Pap smear was obtained using the ThinPrep^® technique (Hologic, USA) and referred to the reference cytopathology laboratory.

Cytological findings

Cytological evaluation revealed numerous singly dispersed small to medium-sized cells, with occasional discohesive clusters [Figure 1a]. The cells showed eccentrically placed nuclei, prominent nucleoli [Figure 1b], occasional binucleation [Figure 1c], and dusty brown pigmented cytoplasm of melanin pigment [Figure 1d]. Nuclear pseudo-inclusions, which are a common characteristic of melanoma, were not seen in this case. In the absence of a history of melanoma and rarity of such a diagnosis in this anatomical location, and potential cytomorphologic overlap with other carcinomas, the final cytology report was rendered as: “Positive for malignancy. Malignant pigmented cells are present. A melanocytic lesion is considered in the differential diagnosis.

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Figure 1: (a) Loose sheet of malignant cells with enlarged, and hyperchromatic nuclei (Pap stain, ×200). (b) Scattered malignant cells with eccentrically placed, hyperchromatic nuclei, and prominent nucleoli. Note, intranuclear pseudo-inclusions were not present in this case (Pap stain, ×400). (c) Occasional singly scattered binucleated malignant cells with prominent nucleoli were identified (Pap stain, ×400). (d) Isolated malignant cells showing dusty cytoplasmic pigment. The arrows indicate melanin pigment (Pap stain, ×400).

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Radiological and histopathological findings

The patient was referred to the gynecologic oncology department at Royal Hospital, Muscat for further investigations.

The patient had a pelvic magnetic resonance imaging, which showed a well-defined, mildly T2 hyperintense polypoid lesion arising from the posterior vaginal wall and extending within the vaginal lumen [Figure 2a]. Also, the axial T1-weighted imaging post contrast delayed phase demonstrated hyperintense foci within the lesion on the plain T1, suggestive of melanin pigmentation, and it demonstrates mild enhancement on the post contrast examination [Figure 2b].

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Figure 2: Magnetic resonance imaging of the primary lesion at the initial diagnosis. (a) Axial T2 weighted image demonstrating a well-defined mildly T2 hyperintense polypoid lesion arising from the posterior vaginal wall and extending within the vaginal lumen (red arrows). (b) Axial T1-weighted imaging post contrast delayed phase suggestive of melanin pigmentation and it demonstrates mild enhancement on the post contrast examination (red arrows).

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Histological examination of the vaginal wall lesion demonstrated fragments of stratified squamous epithelium with an underlying neoplastic lesion composed of sheets of large atypical epithelioid and spindle-shaped cells with abundant eosinophilic cytoplasm, marked nuclear pleomorphism, prominent nucleoli, and a mitotic index of 6 mitosis/2 mm² [Figure 3a]. Many of the cells have dusty brown pigment. The Breslow thickness was 4 mm. Immunohistochemistry was performed using a ready-to-use cytokeratin AE1/AE3 (Lot no. 83588), HMB-45 (Lot no. 11670753), and Melan-A (Lot no. 41653908) monoclonal antibodies and S100 (Lot no. 83418) polyclonal antibody reagents from Dako Omnis (Agilent Dako, California, USA). The assay was run on an automated BOND staining system (Leica, Wetzlar, Germany) according to the manufacturer’s instructions. The tumor cells were negative for epithelial marker of cytokeratin AE1/AE3 [Figure 3b], while strongly positive for melanocytic markers HMB-45 [Figure 3c], S100 [Figure 3d], and Melan-A [Figure 3e], supporting a diagnosis of malignant melanoma.

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Figure 3: (a) Biopsy tissue section demonstrating atypical epithelioid and spindleshaped cells arranged in sheets, with prominent nucleoli and marked nuclear pleomorphism (Hematoxylin and Eosin stain, ×400) 50 μm. (b) The malignant cells were negative for cytokeratins AE1/AE3 (×400) 50 μm, (c) positive for Human Melanoma Black 45 (×400) 50 μm, (d) positive for S100 (×400) 50 μm, and (e) positive for Melan A (×400) 50 μm.

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DISCUSSION

Malignant melanoma arises from melanocytes that are found at the epidermal-dermal junction of the skin, typically when genetic mutations take place in neural crest cells that lead to overproliferation of melanocytes.^[11] The overall incidence of gynecological melanomas is very rare, with only 0.3% of all malignant melanomas reported.^[3] This can be attributed to the limited blood supply and the fibrous stroma of the female reproductive organs.^[4]

Our patient is in her sixth decade of life, an age group commonly reported in previous cases of vaginal melanoma.^[12] Clinically, per vaginal bleeding associated with an ulcerated lesion is a well-recognized symptom. However, studies indicate that the presence of ulceration mainly contributes to the bloodstained tumor diathesis observed in cytologic smears, rather than significantly increasing the likelihood of obtaining exfoliated tumor cells.^[13,14]

Cytologically, melanomas can mimic a wide range of malignancies, particularly with squamous cell carcinoma, due to overlap features. In our case, the presence of pigmented, eccentrically placed nuclei with prominent nucleoli and occasional binucleation raised suspicion for a melanocytic lesion. However, in the absence of a prior history of melanoma and with no classic cytologic features such as nuclear pseudoinclusions, a definitive diagnosis based on cytology alone was challenging. Hence, a cautious and descriptive cytology report was issued, prompting further tissue evaluation.

It should be noted that the absence of nuclear pseudoinclusions (NPIs) in some melanocytic cells reflects the variability of cytological features observed in malignant melanoma. NPIs represent cytoplasmic invaginations into the nucleus and have been described in a range of neoplastic conditions. One study suggested that NPI formation may be related to increased Golgi apparatus activity in melanoma cells.^[15] Furthermore, another study examining 50 melanoma cases reported NPIs in 56% of tumors. This finding indicates that while NPIs are relatively common in melanoma, their presence is insufficiently specific to distinguish malignant melanoma from benign melanocytic lesions. However, NPIs may still be helpful as a criterion in differentiating melanocytic from non-melanocytic tumors.^[16]

Furthermore, the cytomorphologic variability of melanoma presents a diagnostic challenge on Pap smears. Particularly, in cases of amelanotic melanoma, which can be misdiagnosed as squamous cell carcinoma due to its rarity and the relative frequency of squamous lesions in the female genital tract.^[13] However, when melanin pigment is present, it must also be distinguished from other pigments, primarily hemosiderin, an iron storage compound found in macrophages during red blood cell breakdown and lipofuscin, a pigment derived chiefly from the breakdown products of lipids, usually those derived from the cell membrane. The key differentiating features are that melanin tends to appear as a brown, finely granular substance with a dusky yellow appearance, while hemosiderin typically appears golden yellow, more crystalline, and coarsely granular. Lipofuscin tend to be yellow to golden-brown without a dusty appearance in Pap stain. Special stains can aid in differentiating these pigments, such as Fontana Masson for melanin, Prussian blue for iron, and Sudan Black B for lipofuscin.^[4]

The background of a cytology smear can offer important diagnostic clues, such as inflammation, necrosis, or hemorrhage, which may support the suspicion of malignancy, including melanoma. In our case, however, the smear background was notably clean as expected, since we employed liquid-based cytology (LBC). This observation aligns with findings from a study that compared the cytomorphological characteristics of extra-genital metastases using LBC versus conventional smears.^[17]

The absence of a known history of prior malignancies, along with limited clinical and radiological information, made the diagnosis of malignant melanoma particularly challenging. Following the initial Pap smear, where a melanocytic lesion was considered in the differential, the patient underwent further evaluation. Histopathological examination, supported by immunohistochemistry, proved critical in confirming the diagnosis. The tumor cells expressed melanocytic markers HMB-45, S100, and Melan-A, while cytokeratin markers were negative, confirming malignant melanoma. This underscores the importance of correlating cytologic impressions with histopathological and immunohistochemical confirmation, particularly in rare tumors.

Gynecological malignant melanoma is an aggressive tumor with a poor overall prognosis, with estimated overall survival rates of 24% at 2 years and 15% at 5 years.^[18] Surgery remains the standard treatment whenever feasible, typically followed by adjuvant therapy such as radiotherapy, chemotherapy, or targeted immunotherapy. Surgical management may involve wide local excision or radical resection, depending on disease stage, to achieve negative tumor margins. Routine regional lymph node dissection is generally not recommended because lymph node metastasis is relatively uncommon in gynecological melanomas.^[19]

Radiotherapy is most often offered to patients with advanced disease who are not surgical candidates or to those with post-operative recurrence or metastasis, and it is rarely used as an adjuvant therapy following surgery. The role of adjuvant chemotherapy remains controversial, as studies have reported inconsistent effects on overall survival.^[19,20] In contrast, recent evidence highlights the benefits of immune checkpoint inhibitors such as nivolumab and pembrolizumab in advanced or metastatic melanoma. For example, one study described a 55-year-old woman with vaginal melanoma and adrenal metastasis who experienced a reduction of both primary and metastatic lesions after combined radiotherapy, anti-angiogenic therapy, and immunotherapy.^[21] Another report noted favourable outcomes in advanced vaginal melanoma treated with surgery followed by adjuvant nivolumab.^[22] These findings underscore the promising role of immunotherapy compared with traditional adjuvant radiotherapy or chemotherapy.

Our patient underwent a total vaginectomy with removal of the labia minora, without regional lymph node dissection or sentinel lymph node biopsy, as no evidence of lymphadenopathy was indicated preoperatively. A postoperative positron emission tomography scan showed no evidence of residual or metastatic disease. She is currently receiving adjuvant nivolumab and is doing well at the time of this report.

SUMMARY

This case report affirms the possibility of detection of melanoma in Pap smears and raises awareness among the cytopathology community in the Middle East about such cases, despite their rarity, particularly in the female genital tract. Statistics show that malignant melanoma cases are rising globally and in the Middle East. Therefore, both cytotechnologists and cytopathologists should maintain a high index of suspicion for uncommon entities, including melanoma, even in routine screening samples.