Two Cases of Primary Melanoma of the Uterine Cervix

Introduction

Primary mucosal melanomas of the female genital tract account for approximately 3% of all melanomas diagnosed in women [1], with most developing in the vulva or vagina. Involvement of the uterine cervix is rare, accounting for only 3% to 9% of cases [2]. Cervical melanomas are more likely to recur or metastasize and have a higher mortality rate compared with vulvar melanomas. Non-vulvar melanomas are significantly associated with high-risk clinicopathologic features, including increased tumor thickness, ulceration, and lymph node metastasis [3,4]. Cervical melanoma is typically observed in postmenopausal women between 60 and 70 years old [5], although an article reported a mean patient age of 56 years old [6]. Scholars had previously assumed that primary melanoma could not exist in the cervix due to the lack of melanocytes in the cervical mucosal membrane, but this assumption was invalidated when a previous study observed melanin-containing cells in the uterine cervix of 3.5% of their participants [7]. In addition to causing melanoma, melanocytic cells in the cervix can also result in pigmented lesions, including blue nevi and benign lentigines [8]. Primary malignant melanoma of the cervix is indicated by junctional activity in the epithelium adjacent to the lesion [9]. Neoplastic cells of the metastatic cervical melanoma localized below the basement membrane do not cause epithelial junctional activity [10]. Cases without junctional change or other primary malignant melanoma are categorized as primary cervical melanoma, because superficial ulceration and repeated biopsy can mask junctional activity [11–13].

The risk factors for cervical melanoma remain unclear. Mucosal melanomas are most common among people of Asian descent, whereas genitourinary mucosal melanomas are most common among people of European descent [14]. A case of cervical melanoma that developed 9 years after the patient received external beam radiotherapy for cervical squamous cell carcinoma was reported, suggesting that the melanoma may have been induced by radiotherapy. However, the link between ionizing radiation and melanoma remains unclear [15].

This article aims to provide further insight into this rare disease. The clinical presentation, diagnostic approaches – including imaging studies and pathological features – staging, and management strategies are discussed in the following sections.

Case Reports

CASE 1:

A 69-year-old woman with no known underlying diseases, a gynecologic history of gravida 2, para 2 (vaginal deliveries), and menopause at age 55, presented with a 1-month history of massive vaginal bleeding. She had never undergone a Pap smear. She denied abdominal pain, abdominal fullness, or increased vaginal discharge, but reported symptoms of fatigue and dizziness. Laboratory test revealed anemia (hemoglobin: 9.1 g/dL). Physical examination revealed a bulky cervical mass accompanied by nodular lesions on the vaginal wall, raising suspicion for either cervical or vaginal cancer. Transvaginal sonography confirmed a cervical mass measuring approximately 7 cm and a 2-cm pelvic mass. Cervical biopsy confirmed the diagnosis of malignant melanoma, demonstrating uniform neoplastic epithelioid cells with melanin pigment deposition (Figure 1). Immunohistochemical staining showed strong cytoplasmic positivity for HMB-45 (Figure 2). To exclude the possibility of metastatic melanoma to the cervix from another primary site, comprehensive skin and ophthalmologic examinations were performed, both of which found no evidence of other primary lesions. Computed tomography (CT) and positron-emission tomography (PET) scans (Figure 3A–3D) revealed extensive metastasis, including invasion into the lower third of the vagina, uterus, left parametrial tissue, and left pelvic wall. Additionally, multiple bone metastases and bilateral lung involvement were detected. The metastatic pattern resembled that typically seen in advanced cervical cancer, further supporting the diagnosis of primary cervical melanoma. The clinical staging was determined to be cT4N1M1b, FIGO Stage IVB. Cystoscopy followed by transurethral resection of a bladder tumor confirmed metastatic melanoma involvement of the bladder on pathological examination (Figures 4, 5). Following a multidisciplinary discussion, the patient started concurrent chemoradiotherapy including volumetric modulated arc therapy (VMAT) 5000 cGY in 25 fractions, followed by nivolumab therapy (100 mg via intravenous infusion). However, renal function deteriorated due to tumor invasion of the left ureter, resulting in hydronephrosis. A percutaneous nephrostomy (PCN) was placed to relieve the obstruction. Three months after the initial diagnosis, she developed shortness of breath. Imaging revealed progression of lung metastases with associated pleural effusion. Despite treatment efforts, she died 4 months after diagnosis due to the extent of metastatic disease.

CASE 2:

A 75-year-old patient with underlying disease of diabetes mellitus, hypertension, Alzheimer disease, presented with irregular vaginal bleeding for 1 month. She denied pelvic pain, vaginal discharge, urinary symptoms, gastrointestinal complaints, fatigue, weight loss, or decreased appetite. There was no known family history of cancer. Pelvic examination revealed a cervical mass with parametrium invasion, raising high suspicion for cervical cancer. However, due to the pigmented appearance of the cervical lesion, melanoma could not be ruled out. A cervical biopsy was performed. A diagnostic immunohistochemical panel confirmed the melanocytic origin of the tumor, with positive staining for S-100 protein, Human Melanoma Black-45 (HMB-45), and Melanoma antigen (Melan-A), confirming malignant melanoma. Comprehensive dermatologic and ophthalmologic examinations revealed no evidence of a primary melanoma elsewhere. Magnetic resonance imaging (MRI) (Figure 6A–6C) and PET scans indicated a 7-cm cervical tumor with invasion into the parametrium and lower third of the vagina and right pelvic lymphadenopathy. The pattern of metastasis was consistent with cervical cancer, supporting the diagnosis of primary cervical melanoma. She was diagnosed with primary cervical melanoma, staged as cT3N1M0, FIGO stage IIIc.

Given the bulky tumor and advanced stage, concurrent chemoradiotherapy was initiated as a neoadjuvant approach to reduce tumor size. Initial treatment consisted of concurrent chemoradiotherapy (6000 cGy total), followed by radical hysterectomy (Figures 7, 8) and bilateral pelvic lymph node dissection. Hematoxylin and eosin (H&E) staining (Figure 9A, 9B) revealed pleomorphic epithelioid tumor cells arranged in sheet-like patterns. A diagnostic immunohistochemical panel for melanoma – including S-100, HMB-45 (Figure 10), Melan-A, and SRY-related HMG-box gene 10 (SOX10) (Figure 11) – demonstrated positive staining in the tumor cells, further supporting the diagnosis of malignant melanoma. Due to positive surgical margins, salvage brachytherapy (2000 cGy in 4 fractions) was performed after surgery. The first recurrence was found 17 months later when a CT scan revealed a right pelvic wall nodule, which was treated with debulking surgery and 6 cycles of nivolumab 200 mg. The disease remained stable for 3 years. However, she later presented with recurrent irregular vaginal bleeding and a tenesmus-like sensation. MRI revealed multiple metastases, including vaginal, presacral, and bilateral para-aortic lesions. Due to the extent of metastasis, surgical intervention was not indicated. Palliative chemoradiotherapy was initiated but later discontinued due to poor patient tolerance. resulting in patient transfer to hospice for palliative care. She was subsequently transferred to hospice care, where she died 7 years after the initial diagnosis due to disease progression.

Discussion

Most studies have reported that patients with cervical melanoma were symptomatic when diagnosed, with vaginal bleeding observed in approximately 85% of these patients. Other symptoms included vaginal discharge, abdominal pain, dyspareunia, and post-coital bleeding [16,6]. Inspection with a speculum is a crucial first step in evaluating the presence of cervical melanoma, the gross appearance of which typically presents as a variably pigmented, exophytic polypoid mass [17,18]. Among the methods used for diagnosis, the most common is cervical biopsy. During colposcopic examination, cervical melanoma may present as small, purpura-like spots [17]. Additionally, the use of cervical smear liquid-based cytology and colposcopy-guided fine-needle aspiration cytology for diagnosis has also been reported [19,20]. In both of our cases, cervical biopsy combined with immunohistochemical staining was sufficient to confirm the diagnosis of cervical melanoma. PET scans and MRI were subsequently used to determine the pattern of metastasis, which resembled that of cervical carcinoma. These findings are consistent with the diagnostic criteria for primary cervical melanoma proposed by Norris and Taylor, which include: the presence of melanin in the normal cervical epithelium, junctional activity in the cervical epithelium adjacent to the lesion, absence of melanoma in other parts of the body, and a metastatic pattern similar to that of cervical carcinoma [21]. Findings from the diagnostic work-up for cervical melanoma indicate the extent of the disease and are used to rule out conditions caused by other primary lesions. Due to limited blood supply, only 20% of cervical melanoma are the result of metastasis [22]. The diagnostic evaluation process includes a thorough skin examination and ophthalmological assessment to exclude primary cutaneous or ocular melanoma that may have metastasized. Additionally, serum lactate dehydrogenase levels are measured, and MRI, whole-body CT, and PET scans are conducted to assess disease progression and detect any distant metastases [1]. The unique properties of melanin allow clinicians to effectively distinguish melanoma from other tumors in MRI findings. On T1-weighted images, melanin exhibits a high signal intensity on T1-weighted images and a low signal intensity on T2-weighted images. This distinct signal pattern, which results from the paramagnetic nature of melanin, enables clinicians to distinguish melanoma from other lesions, contributing to more accurate diagnosis and treatment planning [23].

The pathological features of malignant cervical melanoma often consist of either spindle-shaped or epithelioid cells that display pleomorphism, a high mitotic index, hyperchromatic nuclei, and, possibly, intranuclear cytoplasmic inclusions or multinucleated giant cells [12]. Approximately 55% of mucosal melanomas have detectable melanin pigment, whereas those remaining may be amelanotic, which can be more challenging to diagnose. Immunohistochemical stains are more specific and reliable compared with traditional diagnostic methods like the Masson-Fontana stain, especially in amelanotic melanoma [17]. Positive staining for HMB-45, Melan-A (MART-1), and S-100 protein and negative staining for epithelial markers is characteristic of malignant cervical melanoma [12].

The FIGO staging system is widely used for cervical melanoma due to its similar clinical presentation and spreading pattern to cervical carcinoma [16,24] [16]. According to a literature review by Pusceddu et al, 41% of cases have been diagnosed at FIGO Stage I and 34.4% at FIGO Stage II, indicating that cervical melanoma tends to be detected at an early stage [16].

Despite the lack of consensus on clinical management, surgical intervention following comparable approaches to those used for cervical carcinoma is the most common treatment. Radical hysterectomy, upper vaginectomy, and pelvic lymphadenectomy are among the procedures that are performed. Achieving clear surgical margins – ideally at least 2 cm – is crucial to reducing recurrence risk and optimizing outcomes. Although clinicians disagree on the necessity of pelvic lymphadenectomy, this approach is generally recommended for comprehensive staging and assessing potential lymphatic spread, which guides further treatment decisions and provides valuable prognostic information [9,25]. A literature review indicated that surgical intervention has a significant relationship with patient prognosis. Although some studies have found that patients who undergo radical hysterectomy and lymphadenectomy have higher survival rates, others have suggested that any surgical procedure, regardless of type, is correlated with improved outcomes [26–29]. The literature review also indicated a lack of consensus regarding the effectiveness of adjuvant treatment. Some studies have suggested that patients who undergo surgery do not experience significant survival benefits from adjuvant therapy, while others have indicated improved outcomes for patients receiving adjuvant treatments, particularly those involving a combination of chemotherapy and immunotherapy [27,28].

For advanced or metastatic cervical malignant melanoma, chemotherapy protocols similar to those used for skin melanoma can be applied. Dacarbazine is the most commonly used FDA-approved agent and can be administered alone or in combination with other chemotherapeutic drugs, achieving an effective response rate of approximately 15% to 20%. However, these responses are often transient, and other polychemotherapy regimens have not shown a significant survival benefit [30,31].

Although melanoma is radio-resistant, radiotherapy can be used as adjuvant therapy, particularly for cases in which the parametrium is infiltrated, pelvic lymph nodes are involved, or surgical margins are not achieved. Additionally, radiotherapy can provide palliative local control in advanced or recurrent cases, aiding symptom management and improving quality of life [32].

Over the past few decades, several key immunotherapies have been developed to treat melanoma. Interleukin-2 (IL-2) and interferon-alpha (IFN-α) are approved adjuvant treatments for high-risk patients with melanoma, despite the potential for severe toxicities and adverse effects and debate surrounding patient selection criteria [32,33]. Recent studies have focused on reducing adverse effects and enhancing the therapeutic index by combining IL-2 and IFN-α with chemotherapy, which has demonstrated improved response rates [34,35]. In addition, immune checkpoint inhibitors have become a widely used treatment option. Ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, was shown to yield improvements in overall survival for patients with metastatic melanoma [36]. One study found a favorable response when ipilimumab was combined with concurrent radiotherapy in cases of female lower genital tract mucosal melanoma [37]. Immune checkpoint inhibitors targeting programmed cell death-1(PD-1) and programmed death-ligand 1(PD-L1), which are approved by the FDA for treating melanoma, have revolutionized melanoma management but received only limited application in female genital mucosal melanoma due to the low incidence of this disease. One study suggested that anti-PD-1 therapies were associated with better overall survival compared with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatments in metastatic melanoma of the female reproductive tract [38]. Additionally, some studies have indicated that certain genital melanomas respond to immune checkpoint inhibitors regardless of their PD-L1 immunohistochemistry status [4,39]. With regard to cervical melanoma specifically, a small number of case reports document the use of immunotherapy. In 6 reported cases, all patients underwent radical hysterectomy with or without bilateral pelvic lymph node dissection. Among them, 4 received anti-PD-1 therapy, 1 received an anti-CTLA-4 agent, and 1 received a combination of both. Despite these interventions, all patients experienced disease progression and ultimately succumbed to the disease [40–45], highlighting the need for further investigation into the effectiveness of these therapies in the context of cervical melanoma.

The selection of treatment in our cases was particularly challenging due to the absence of standardized guidelines for cervical melanoma. However, as highlighted in the literature, surgical intervention – especially when achieving clear margins – is associated with improved survival outcomes. In Case 2, concurrent chemoradiotherapy was administered as a neoadjuvant approach to reduce tumor size, which facilitated a margin-negative surgical resection, followed by radical hysterectomy and bilateral pelvic lymph node dissection. This aligns with findings from recent reviews, reinforcing that surgical resection remains the cornerstone of treatment for cervical melanoma. Due to the presence of positive surgical margins and lymph node metastasis, adjuvant radiotherapy was administered postoperatively in Case 2. Upon recurrence, the patient received anti-PD-1 immunotherapy. Immunotherapy was selected over chemotherapy because of its more favorable adverse effect profile, particularly considering the patient’s advanced age and limited tolerance for treatment. A similar treatment course was reported by Noguchi et al, who described a stage IIIA cervical melanoma case treated with anti-PD-1 antibodies following the development of multiple metastases after recurrence [45]. In contrast, Case 1 involved a tumor that was extensively disseminated and unresectable. Therefore, concurrent chemoradiotherapy (CCRT) was offered with palliative intent – to control tumor bleeding and alleviate left-sided obstructive uropathy. In conclusion, treatment strategies for cervical melanoma remain diverse and are largely extrapolated from other melanoma types or cervical cancers. Individualized treatment plans are essential and should be tailored to the patient’s overall condition, disease extent, and symptom burden.

Cervical melanoma has a poor prognosis, especially when visceral metastases occur early [24], with primary prognostic factors that include age, tumor stage and thickness, and lymphatic invasion [1,16,26,27]. The mean survival time is 36.5 months for Stage I, 20 months for Stage II, 10 months for Stage III, and 6 months for Stage IV, indicating a substantial prognosis decline as the disease progresses [28]. This trend is consistent with our cases. In Case 1, distant metastases were already present at diagnosis. Moreover, surgical intervention is associated with improved outcomes, yet it was not feasible in this case due to the advanced disease. In contrast, although Case 2 involved an older patient with multiple comorbidities, complete surgical staging and adjuvant brachytherapy resulted in initial disease stability. These findings emphasize that disease stage and the ability to perform surgery are closely linked to patient prognosis.

In Case 1, the disease progression was unusually aggressive, raising interest in the tumor’s molecular profile. The BRAF oncogene, which activates the MAPK pathway and promotes tumorigenesis, is commonly mutated in cutaneous melanomas but less frequently in mucosal melanomas – approximately 6% [46]. However, the absence of a BRAF mutation also limits the applicability of targeted therapies. Immunohistochemical staining in Case 1 did not detect BRAF mutation, suggesting that the rapid disease progression was likely due to the advanced stage at presentation and widespread distant involvement, rather than specific genetic drivers.

Conclusions

There is still no established standard protocol for the treatment of cervical melanoma. The FIGO staging system is widely used for staging the disease and is closely linked to prognosis. Surgical intervention, including radical hysterectomy and bilateral pelvic lymphadenectomy, has shown potential to improve outcomes by achieving clear margins. However, the role of adjuvant therapy remains a topic of debate. Chemotherapy and radiotherapy are commonly utilized in cases of metastatic disease or for palliative control, but their efficacy is limited. Immunotherapy has emerged as a promising treatment, with agents such as IL-2, IFN-α, anti-CTLA-4, and anti-PD-1 inhibitors demonstrating potential in improving survival outcomes for advanced and metastatic melanoma. Further research is needed to develop standardized treatment protocols. Raising awareness among clinicians and improving early diagnostic strategies are also crucial to enhancing survival rates and quality of life for patients with this rare and challenging malignancy.