Primary malignant melanoma of the cervix: a rare disease

Abstract

Malignant melanoma (MM) arising primarily in the cervix is exceedingly rare and has a poor prognosis. We report the case of a primary MM of the cervix in a 64-year-old woman with vaginal bleeding. She presented with a cervical amelanotic lesion which on biopsy rendered the diagnosis of MM. The patient was staged as International Federation of Gynecology and Obstetrics IIB and underwent Wertheim-Meigshysterectomy followed by brachytherapy. One year later, she was diagnosed with a large pelvic relapse for which surgery was performed. She then presented with a vaginal relapse and an isolated hepatic lesion, both of which were proposed for surgery. The diagnosis of MM of the cervix is a clinical and pathological challenge due to its rarity and overlapping features. Cytology cannot accurately diagnose it. Moreover, amelanotic MMs must be distinguished from other poorly differentiated carcinomas by diagnosis that ultimately relies on immunohistochemical staining. Radical surgery is the only treatment showing predictive benefit.

Background

Mucosal malignant melanoma (MM) has a low incidence and only 2% are diagnosed in the gynaecological tract.¹ Primary MMs of the cervix are rare with around 80 cases described.²

Diagnosing primary cervical MM is often difficult. Clinical presentation mimics other cervical malignancies, usually exhibiting discharge or abnormal bleeding.³ They can have an asymptomatic initial growth until the lesions ulcerate or become infected.⁴ Colposcopic observation can detect a coloured exofitic lesion.⁵ Cervical screening tests like cytology are often incapable of detecting MMs because they are highly observer dependent and because of the rarity of the disease.⁶ Therefore, histological evaluation of the lesions is crucial, and immunohistochemical staining proves very helpful in differentiating lesions. Another important issue is to be certain that the lesion is not metastatic. Other primary sites must be excluded, like cutaneous, other mucosal or ocular. Staging is also important for prognosis and treatment, although frequently presenting in advanced stages. Most authors use the International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer due to similar metastatic spreading. Tumor, Node, Metastasis (TNM) system does not specify staging for mucosal melanomas other than head and neck.^{7 8}

Mucosal MMs are usually coloured; however, in 35%–45% of the cases, they develop as colourless lesions, so they are called amelanotic MMs.^{9 10} Their identification involves a difficult clinical and pathological diagnosis. The differential diagnosis with other poorly differentiated squamous cell carcinomas, lymphomas or sarcomas must be attended.¹¹ Immunohistochemical staining is crucial in confirming the diagnosis, combining S100 sensitivity, HBM45 specificity and MelanA staining.²

Therefore, the rarity of this disease, the difficulty associated with the diagnosis and the lack of evidence regarding treatment make case reports a valuable tool in deciding patient management.

We report the case of a 64-year-old woman diagnosed with a primary amelanotic cervical MM, FIGO IIB, treated with radical hysterectomy.

Case presentation

A multiparous, HIV-negative, postmenopausal 64-year-old woman was attending a private gynaecologist due to a low-grade squamous intraepithelial lesion detected in screening cytology in August 2014. Medical history revealed arterial hypertension, adenomatous intestinal polyps and urinary effort incontinence. Gynaecological history showed two voluntary abortions and an endometrial polyp resection in 2012. The patient’s mother died due to cutaneous MM.

A previous colposcopic evaluation was available, performed in October 2014, presenting with an atrophic cervix and no other findings (figure 1).

Figure 1.

Colposcopy assessments in October 2014.

In January 2015, she presented with postmenopausal vaginal bleeding and dyspareunia. A transvaginal ultrasound reported a thickened endometrium (8×7 mm), and she was referred to the cervical pathology unit.

Investigations

Colposcopy was reported as adequate, type 3 Transformation Zone (TZ) with a polypoid exofitic pale lesion at 6 o’clock. This lesion was ulcerated and showed spontaneous bleeding, suggesting invasion, so a biopsy was performed (figure 2).

Figure 2.

Colposcopy assessments in January 2015.

Microscopic examination showed a highly cellular neoplasm composed of epithelioid cells with round to oval hyperchromatic nuclei, prominent nucleoli and granular cytoplasm. The neoplastic cells exhibited a high degree of nuclear pleomorphism and mitotic activity. On immunohistochemistry, the tumour cells were positive for HMB-45, S100 protein and MelanA, and negative for cytokeratins. The diagnosis of MM was rendered.

The patient was referred to gynaecological oncology department, and the disease was staged with a thoracoabdominal CT and pelvic MRI. A follow-up colposcopy showed a noticeable increase in the lesion size (figure 3). MRI reported a cervical lesion in the posterior lip with 3.1x1.2×2.9 cm and suspected anterior parametrial extension. CT scan was unremarkable.

Figure 3.

Colposcopy assessments in January 2015, 18 days after figure 2.

In March 2015, the patient was referred to Instituto Português de Oncologia do Porto, a Portuguese comprehensive oncology centre. The gynaecological evaluation reported a cervical exofitic amelanotic and necrotic lesion, with 3 cm in diameter and suspected micronodular invasion of the right parametrium. A thorough evaluation of vaginal walls did not show any satellite lesions. The patient was staged as a proximal FIGO IIB and underwent ¹⁸F-FDG (fludeoxyglucose) positron emission tomography (PET) scan that showed no other hypermetabolic lesions. A second look of the samples in the pathology department confirmed the diagnosis (figures 4–7). The case was then discussed in a gynaecology multidisciplinary tumour board with the presence of dermato-oncology, concluding on a primary melanoma of the cervix.

Figure 4.

Microscopic examination showed a highly cellular neoplasm exhibiting a high mitotic activity (H&E).

Figure 5.

Immunohistochemistry: the tumour cells were positive for HMB45.

Figure 6.

Immunohistochemistry: the tumour cells were positive for Melan-A.

Figure 7.

Immunohistochemistry: the tumour cells were positive for S100 protein.

Treatment

A radical surgical approach was proposed to the patient with her acceptance. On 31 March 2015, she underwent a Wertheim-Meigs hysterectomy with an uneventful recovery. Gross pathological examination showed a lesion measuring 85x45×40 mm (figure 8). The final histopathology report verified the presence of a nodular MM with ulceration (Breslow thickness of 13 mm). There was a brisk lymphocytic response, and the mitotic count was up to 54 per 10 high-power fields. There were no features of regression, microsatellite lesions or perineural invasion. Lymphovascular invasion was identified. The tumour invaded the vagina and was resected with a 4 mm clear peripheral microscopic cuff margin. All of the 15 lymph nodes and parametrial soft tissue were free of disease.

Figure 8.

Gross examination of the surgical specimen showing a polypoid pale lesion in the posterior quadrants of the cervix.

The patient was observed in a postoperative gynaecology consultation, in May 2015, where an imagiological restaging was ordered, showing no distant metastasis and vaginal brachytherapy was proposed in the tumour board due to close margins. In the first radio-oncology evaluation, in June 2016, a solid nodule of about 1 cm was observed in the vaginal vault, and the biopsy confirmed early relapse. PET-CT showed isolated uptake on the biopsied nodule, and in July 2015 resection was performed with a deep 1 mm clear microscopic margin. After discharge, she underwent brachytherapy that was completed in September 2015.

Outcome and follow-up

The patient maintained surveillance at our institution. In May 2016, she presented with a pigmented vaginal lesion that was biopsied revealing reactive pigmentation of basal keratinocytes. In July, she was admitted to the gynaecology ward due to abdominal pain, emesis and constipation. Abdominal radiography showed small-bowel distension and air-fluid levels. The patient presented with de novo anaemia (9.3 mg/dL), a slightly elevated lactate dehydrogenase (LDH) (G1, ULN (Upper limit of normal) = 248 U) and no other relevant analytical findings. Symptoms were controlled after medical treatment. A PET-CT showed a large pelvic mass with small bowel invasion and several hypermetabolic lombo-aortic lymph nodes. In September 2016, she underwent enterectomy and mass resection with no residual disease. Gross examination revealed a 60 mm intestinal ulcero-infiltrative lesion. Histopathological examination confirmed it to be a metastatic MM with free surgical resection margins. In December, she presented with a suspected vaginal relapse, and a PET-CT showed an isolated hepatic lesion. The tumour board proposed resection of both lesions.

Discussion

MMs can affect other locations outside the skin, and mucosal melanomas are a rare example. They can be found in oral, oesophageal, gastric, anal, gynaecological mucosa and others.¹ However, they represent less than 1.5% of all MM cases because cutaneous forms are the most prevalent.¹² Mucosal MMs are more frequent in women, probably due to gynaecological MMs,¹³ and these arise mostly in the vulva and vagina. Primary cervical MM is a very rare entity, with 78 cases reported in the literature.² Contrary to cutaneous melanomas, little is known about the genetic predisposition of mucosal MM, although it has been shown to develop in a familial setting.¹⁴

Mucosal melanomas, including cervical MMs, do not have established treatment guidelines because of its rarity. However, it has become common ground that an optimal surgery is the most important step. Radical hysterectomy with wide margins and regional lymphadenectomy are the preferred approaches.^15–17 Chemotherapy and radiation have been used with no proven benefit. Radiation therapy is often reserved for unsatisfactory surgical margins, locally advanced disease, involved lymph nodes or palliative intent, as MMs are usually radioresistant.¹⁸ Conventional MM chemotherapy offered some objective responses but with no survival benefit.¹⁶ Immunotherapy could be a treatment option in the future.

Cervical MM usually presents as locally advanced and less frequently as stage IV disease. Nonetheless, prognosis is very poor due to tumour aggressiveness, local relapse, frequently unresectable disease and poor outcome with systemic or radiation therapy. The median overall survival of published reports (78 cases) was 12 months (0.1–168 months) with two long survivors (13 and 14 years). Most of the women died 3 years after diagnosis.²

Learning points.

• Primary melanoma of the cervix is an exceedingly rare disease and frequently a hard one to diagnose due to uncharacteristic clinical and histological presentation.

• Differential diagnosis between primary and secondary cervical malignant melanomas (MMs) must be made evaluating other more common locations for primary MMs.

• Optimal radical surgery is the best approach for these tumours. Close follow-up is necessary for early diagnosis and treatment of disease relapse. Chemotherapy and radiotherapy, with variable and unpredictable outcomes, should be used with palliative intent and to control symptoms.

• Referral to a specialised centre and inclusion in clinical trials are crucial to adequately treat and follow-up mucosal MMs.