Mesonephric duct remnants in the cervix are found in approximately 22% of adult females . However, tumours from mesonephric remnants rarely occur in the female genital tract. Nogales divided the mesonephric ducts into two distinct regions: an upper zone, including the rete ovarii; and a lower zone, containing the cervix and vagina . Tumours in these areas are usually morphologically distinct. As early as 1939, Schiller named the mesonephric duct tumour as mesonephroma . Then, researchers reported several cases that were histologically similar to the tumor Schiller reported [15-17]. Herbst and Scully reported clear cell carcinoma of the vagina and suggested that it originated in the Müllerian rather than the mesonephric duct . However, Allyn et al reported 36 cases of mesonephric tumours in the vagina and proposed that mesonephric tumours should be classified into 2 types: endodermal sinus tumours and clear cell carcinomas . To date, so-called mesonephroma is usually referred to as mesonephric carcinoma or mesonephric adenocarcinoma.
Mesonephric adenocarcinoma is a rare malignant tumour in the female reproductive tract that originates from the remnants of the mesonephric duct. To the best of our knowledge, 55 cases of cervical MNAC have been reported in the literature (Table 1). Among the 55 cases reviewed in this paper, ages ranged from 24 to 76 years, with an average age of 54.2 years. The most common clinical manifestation of MNAC is abnormal vaginal bleeding . Among cases, 19 had vaginal bleeding, including 13 cases of postmenopausal vaginal bleeding and 8 cases of menorrhagia. The most common histological type was adenocarcinoma (49/55), of which 4/49 cases had spindle cell components, 5 cases were malignant mesonephric mixed tumours (MMMTs), and 1 case was mixed adenoneuroendocrine carcinoma (MNAC + NEC). Follow-up information was available for 37 patients; 6 (16%) died of the disease, 7 (19%) were alive with the disease, and 24 (65%) had no evidence of the disease.
The mesonephric remnants of the cervix have been incidentally found during uterectomy. The remnants occasionally proliferate but rarely develop into MNAC. At present, five types of cervical mesonephric lesions have been reported: mesonephric remnants, lobular mesonephric hyperplasia, diffuse mesonephric hyperplasia, mesonephric ductal hyperplasia, and mesonephric carcinoma . Mesonephric remnants usually comprise a ductal structure covered by a single layer of ciliated cuboidal epithelium. Eosinophilic secretion is found in the lumen. Mesonephric hyperplasia can be divided into three categories according to the microscopic morphology: lobular hyperplasia, diffuse hyperplasia, and ductal hyperplasia. It is easy to misdiagnose adenocarcinoma when the number of mesonephric tubes is large and dispersed, but the luminal cells show no atypia or mitoses. The lobular and ductal hyperplasia types are common, but diffuse hyperplasia is rare. Ductal hyperplasia is characterized by large ducts, and microscopic papillary changes are often seen in the epithelium [21,22].
The diagnosis of MNAC is challenging, especially for biopsy materials and frozen sections. Because of the papillary, solid components and squamous epithelial growth pattern, the lesion is often misdiagnosed as a high-grade carcinoma, such as clear cell carcinoma, serous carcinoma, squamous cell carcinoma or carcinosarcoma. Various morphologic patterns can be seen in MNAC, such as tubular, glandular, papillary and reticular patterns. The histologic features of our case were solid and squamous epithelial growth patterns. Initially, the tumour was misdiagnosed as squamous cell carcinoma due to the absence of immunohistochemistry analysis. The differential diagnosis of MNAC depends on its location and microscopic appearance. The diagnosis is easily made when mesonephric remnants and/or hyperplasia are found near the tumour. However, when the tumour shows a complete or major tubular growth pattern, it should be distinguished from diffuse mesonephric hyperplasia. The crowded growth pattern of glands, malignant nuclear features and presence of perineural or vascular invasion support the diagnosis of carcinoma. When MNAC grows into the lateral wall of the uterus, the differential diagnosis includes endometrial-like carcinoma, serous carcinoma, clear cell carcinoma, endometrial stromal tumour and MMMT. MNAC is particularly easy to confuse with clear cell carcinoma. Clear cell adenocarcinoma of the cervix and vagina usually occurs in young women treated with diethylstilbestrol and displays varying degrees of cystic, papillary, clear cells and nail cells. These features are not common in MNAC. In addition, MNAC may exhibit smooth muscle or endometrial stromal differentiation and express desmin and actin. The differential diagnosis of MNAC includes endometrial stromal nodules and low-grade stromal sarcoma. Although the latter tumour may show a tubular or nest pattern, it is characterized by a uniform distribution of cells, such as proliferative endometrial stromal cells, with fine vascularization and vascular space invasion, characteristics not found in MNAC.
The immunochemical features of MNAC usually include diffusely and strongly positive for CD10, CK7, and EMA. PAX8 is strongly expressed in both benign and malignant mesonephric lesions, whereas PAX8 is expressed in various ways in common pathological types of cervical adenocarcinoma. Because PAX8 is expressed in many types of cervical lesions, it is not reliable for differentiating between benign and malignant cervical lesions . PAX2 expression is often absent in MNAC and cervical adenocarcinoma, but PAX2 is diffusely positive in mesonephric hyperplasia, which can be employed as an important way to distinguish mesonephric hyperplasia and MNAC . Other markers, including calretinin, inhibin and androgen receptor (AR), show varying positivity. CEA and CK20 exhibit negative expression patterns. In mesonephric adenocarcinoma, ER and PR are negative or locally positive [25-27]. GATA3, a transcription factor that plays an important role in embryogenesis development and differentiation, is highly sensitive and specific for mesonephric lesions. Because it is positive in all mesonephric remnants, hyperplasia and MNAC and rarely or not expressed in cervical adenocarcinoma, expression of GATA3 may be a marker of mesonephric lesions [28-30]. In addition, TTF-1 may be positive in mesonephric adenocarcinoma, though it is generally considered a biomarker of lung cancer and thyroid cancer . HNF1β (hepatocyte nuclear factor 1-beta), a marker of clear cell carcinoma, may also be expressed in MNAC .
Chromosome copy number changes have been reported in mesonephric adenocarcinoma. In a series of reports, 1q gain was the most common copy number change in MNAC [9, 3]. Moreover, a gain of 1q is also the most common copy number change in endometrial carcinoma . Therefore, genes at 1q may play an important role in the occurrence and development of mesonephric adenocarcinoma. According to one study, chromosome 1q21.2, which contains the anti-apoptotic gene MCL1, is focally amplified in approximately 10% of all cancers . With regard to MNAC, current data suggest that 1q and 10q gains may be an indicator of poor prognosis and may increase the risk of metastasis [3, 9]. In addition to chromosome changes, gene mutations are also common in MNAC.
KRAS mutation is the most common molecular change in mesonephric adenocarcinomas. According to one study, 12 of 17 cases were confirmed to have KRAS mutations, and the chromatin remodelling gene ARID1A/B was also frequently mutated (8/17) . Common genetic aberrations such as PTEN and PIK3CA in endometrial carcinoma and other types of cervical adenocarcinoma have not been reported in MNAC. TP53 is a rare mutation in mesonephric adenocarcinoma and other cervical adenocarcinomas, but more than 90% of endometrial serous carcinomas have TP53 aberrations. Therefore, KRAS mutations combined with the lack of PIK3CA, PTEN and TP53 mutations would support the diagnosis of MNAC.
Because cervical MNAC is rare, its biological behaviour and prognosis are not clear. It has been reported that the prognosis of MNAC is worse than that of other histological types: the recurrence rate of stage I MNAC is 32%, whereas that of early cervical adenocarcinoma and cervical squamous cell carcinoma are 16% and 11%, respectively [5, 34]. A retrospective study showed that 15 of 48 cases had recurrences, with an average recurrence time of 2.8 years; the recurrence sites were diverse, most of which involved the pelvic cavity and abdominal cavity, with only 2 cases having lung metastasis .