Mesonephric adenocarcinomas in female genital tract

Abstract Mesonephric adenocarcinoma (MNAC) is a very rare tumor that originates from mesonephric duct remnants of the female genital tract. Only a few cases were reported in the literature, and most of them occurred in the cervix, extremely rare in the uterine body and ovary. MNAC was rarely reported to arise in the uterine corpus, but never was reported in the ovary. Mesonephric-like adenocarcinomas are recently suggested to describe these neoplasms arising from the uterine corpus and ovary. Due to the rareness of the disease, little is known regarding clinical characteristics, pathological diagnosis, prognosis, and optimal management strategy of MNAC in the female reproductive system. We report a series of MNACs arising from the vagina, cervix, uterine corpus, ovary, and fallopian tube, to summarize the clinical characteristics, pathological diagnosis, treatment, and prognosis. We retrospectively analyzed all MNACs in the female genital tract derived from our institute from January 2010 till January 2020. Patients’ clinical details and follow-up were obtained from hospital records and scans were obtained from picture archiving and communication system. A total of 11 patients were included. The median age of onset of symptoms was 52 years. All patients underwent total hysterectomy and bilateral salpingo-oophorectomy, and lymph node dissections were performed in 7/11 (63.6%) patients. Two/eleven (18.2%) received neoadjuvant chemotherapy before surgery and 7/11 (63.6%) received adjuvant chemotherapy after primary surgery. Of the 11 patients, only 1 patient received adjuvant radiation therapy. One patient died at the end point of this study, 9 patients (81.8%) survived and 1 patient was lost to follow-up. The mean follow-up duration was 33.5 months. Although there is no consensus for the optimal treatment of this rare disease, radical surgery is considered to be the initial choice for localized lesion. Given the high malignancy, the majority of MNAC or mesonephric-like adenocarcinoma patients who underwent adjuvant chemotherapy received 4 to 8 cycles of carboplatin/paclitaxel as a first-line treatment after primary surgery with a median progression-free survival of 12 months. Treatment for recurrent disease in these patients included gemcitabine, carboplatin, and paclitaxel. Radiation was very limited in the treatment of the disease.


Introduction
Mesonephric adenocarcinoma (MNAC) is an extremely rare and highly malignant tumor in the female reproductive system. It is considered to originate from the embryonal remnants of mesonephric ducts (also known as Wolffian ducts). [1,2] During embryonic development, the females have 2 sets of paired primitive reproductive ducts: the para-mesonephric (Müllerian) and the mesonephric (Wolffian) ducts. In the embryologic females, Müllerian ducts become the female reproductive ducts, while the mesonephric ducts degenerate. [3] However, vestiges of mesonephric ducts may persist along the female genital tract in the form of epithelial inclusions which are called mesonephric remnants. [4] The embryological remnants are found pre-dominantly in the para-ovarian region (epoophoron and paroophoron) and deep in the cervical stroma in the lateral walls. Therefore, MNACs in the female genital tract occur most commonly in the cervix and vagina, and less frequently in the upper female genital tract. [5] MNACs was rarely reported to arise in the uterine corpus, but was never reported in the ovary. It was reported that adenocarcinomas of endometrium and ovary shared morphologic, immuonphenotypic, and molecular features with MNAC, but were lack of association with mesonepheric remnants or hyperplasia. [6] Hence, mesonephric-like adenocarcinomas (MLAs) are recently defined as tumors exhibiting the classic morphologic features of mesonephric carcinoma, but occurring outside of the cervix and without convincing mesonephric remnants. [4,[7][8][9] Due to the paucity of available data, little is known regarding the clinical characteristics, pathological diagnosis, prognosis, and optimal management strategy of MNAC and MLA in the female reproductive system. To add to existing literature, we performed a retrospective review of 11 cases of MNAC and MLA diagnosed and treated at a single institution between January 2010 and January 2020. The purpose of this case series is to summarize the clinical characteristics, pathological diagnosis, treatment, and prognosis of MNAC and MLA in the female genital tract.

Materials and methods
All MNACs and MLAs were retrieved from the Anatomical Pathology Department at West China Second University Hospital, Sichuan University. We retrospectively analyzed all MNACs in the female reproductive system diagnosed at our institute from January 2010 to January 2020 (The disease is nearly undiagnosed before 2010 in our hospital because of a lack of awareness of the disease). Patients' clinical characteristics and follow-up were obtained from hospital records and scans were obtained from picture archiving and communication system. The age at diagnosis, presenting symptom, surgical approach, FIGO stage, chemotherapy regimen, histopathology, and follow-up of all the patients were analyzed. All surgical specimens were reevaluated by 2 specialized gynecologic pathologists. According to the diagnostic criteria for MNAC, patients whose surgical specimens showed characteristic morphologic features of MNAC as well as either immunohistochemical confirmation or molecular confirmation, were included in this study. Patients with the following conditions were excluded: 1 or 2 specialized gynecologic pathologists deny the diagnosis, patients without survival data or complete follow-up data.
Progression-free survival (PFS) was defined as the time interval from initial surgery to the first radiologic or biopsy-proven disease recurrence, or the last follow-up visit in the absence of recurrent disease. Overall survival was measured as the time interval from initial surgery to death.
All experimental protocols were approved by the ethics committee of West China Second University Hospital, and the methods were carried out in accordance with the relevant guidelines and regulations. Informed consent was obtained from all participants.

Results
A total of 15 patients were retrieved. Among them, 1 was excluded after being confirmed by 2 pathologists, 3 patients without the survival data were excluded. Eleven patients who met the inclusion criteria were ultimately included.  Table 1.
The median age of these patients when diagnosed with MNAC or MLA was 52 years old, ranging from 29 to 75 years old. Among them, the median age of patients with uterine MLA was 62 years old. As for clinical presentation observed in this study, patients with ovarian MLA or oviducal MNAC initially presented with abdominal pain or pelvic pain, patients with uterine MLA and cervical MNAC initially presented with vaginal bleeding, and patient with vaginal MNAC initially presented with vaginal discomfort. Nine of the 11 patients had a preoperative CA-125 drawn with 1 patient having an elevated measurement (Case number 5, Table 1). Clinical stage among these patients was IA (1 patient), IB (5 patients), ifosfamide and cisplatin (2 patients), IIIA (1 patients), IIIC (1 patient), and IVB (1 patient).
As for tumor histology, the pathologic features for MNAC or MLA are characterized histologically by a variety of architectural patterns such as glandular and tubular, glandular, and solid in Table 1 Clinicopathologic features of mesonephric adenocarcinoma in female genital tract.   1C). Some of the tumors (2/11 cases) exhibited mainly solid and a focal glandular architecture (Fig. 1D). Mesonephric remnants ( Fig. 2A), mesonephric hyperplasia (Fig. 2B) and hyperplasia into cancerous nests (Fig. 2C) were histologically found in the oviducal case, while no mesonephric remnants was found in any of the 2 ovarian cases. Immunohistochemically, all cases tested were positive with PAX8 ( Fig. 3A). Ten of 11, 7 of 11, and 9 of 11 cases exhibited some degree of immunoreactivity with GATA3 ( Fig. 3B), CD10 (Fig. 3C), and calretinin ( Fig. 3D), respectively. In all CD10positive cases, the staining was luminal. Most of the cases exhibited nuclear TTF-1 expression (10/11 cases were positive, Fig. 3E). All cases were totally negative with ER ( Fig. 3F) and PR (Fig. 3G), and all tumors exhibited "wild type" immunoreactivity with p53 (Fig. 3H). All of the uterine neoplasms pre-dominantly involved the endometrium where they appeared to arise, with subsequent invasion into the myometrium. None of uterine MLA involved the myometrium without endometrial involvement.

Discussion
MNAC or MLA is an extremely rare and highly malignant tumor in the female genital tract. Currently, little is known about the clinical characteristics, pathological diagnosis, prognosis, and optimal management strategy of MNAC and MLA in the female reproductive system. Due to the rareness of the disease, current study about MNAC or MLA is very little and pre-dominantly limited to case reports. In addition, these studies have demonstrated inconsistent findings. To add to existing literature, we performed a retrospective review of 11 cases of MNAC or MLA diagnosed and treated at a single institution between 2010 and 2020, and this study aimed to summarize the clinical characteristics, pathological diagnosis, treatment, and prognosis of MNAC or MLA in female genital tract. Most of MNACs in female genital tract are incidental findings. Neither MNAC nor MLA has specific clinical manifestations. In our study, MNACs occurred in the cervix or uterine corpus mainly presented with vaginal bleeding or vaginal discharge, and MNAC of the fallopian tube or ovarian MLA mainly presented with abdominal pain or discomfort. The levels of serum tumor markers in patients with MNAC or MLA may be within normal range. Nine of 11 patients had a pre-operative CA125 drawn with 1patient having an elevated measurement in this study (Table 1). Therefore, the pre-operative diagnosis of MNAC or MLA is extremely difficult and definite diagnosis almost depends on postoperative histology and immunohistochemistry.
Due to the paucity of available data, there is no established guideline about standard therapy of MNAC or MLA. However, a radical surgery is considered to be the initial choice for localized disease. In the current study, all the patients underwent hysterectomy and bilateral salpingo-oophorectomy, and 6/11 patients received lymphadenectomy. Of the 5 patients without lymphadenectomy, 2 patients were diagnosed with late stage MNAC (≥FIGO stage III), lymphadenectomy is not beneficial to these patients and may increase the risk associated with the operation. Omentectomy was performed in patients with ovarian MLA or MNAC of fallopian tube.
MNACs might be very aggressive, even when early stage. A recent study including 31 cases of MNAC reported that 82% of the patients were at FIGO stage IB when initial diagnosis, but one-third of the patients with FIGO stage I disease developed recurrence even after radical surgery. Distant metastases and local recurrence were frequent findings in this study, and the median time to recurrence was 2.1 years. [10] In another study, the recurrence rate among patients with FIGO stage I MNAC was 32%. [11] Distant metastases at initial diagnosis was found in less than 5% of MNAC cases, but a malignant clinical course has been reported in about 40% of patients. [12,13] Recently, a multi- Figure 3. Immunohistochemically, all cases tested were positive with PAX8 (A). Ten of 11, 7 of 11, and 9 of 11 cases exhibited some degree of immunoreactivity with GATA3 (B), CD10 (C), and calretinin (D), respectively. In all CD10-positive cases, the staining was luminal. Ten of 11 cases were positive with TTF1 (E). All tumors were totally negative with ER (F) and PR (G), and all tumors exhibited wild-type staining with p53 (H). Staining method: immunohistochemical staining. Original magnification: (A-E) Â200, (F-H) Â400.  (Table 1). NACT was performed in the patients with uterine MNAC, whose FIGO stage were IIIC and IV. Regimens based on paclitaxel and platinum-derivatives formed the main body of the combination of NACT and PACT. There was very few patients reported to treat with radiation. Of the 11 patients, only 1 patients in this study received adjuvant radiotherapy after surgery in this study. Radiation was very limited in the treatment of the disease.
There is very little research about chemotherapy regimen in recurrent MNAC. A recent study showed a recurrent MNAC case had good response to the combination chemotherapy of carboplatin and paclitaxel. [15] Of the 3 patients who recurred in this study, 1 patient died before receiving salvage treatment, 1 was lost to followup immediately following being diagnosed with tumor recurrence, and 1 received second surgery followed by a new chemotherapy regimen. The patient who had been given chemotherapy with carboplatin plus paclitaxel after initial surgery, rapidly developed a distant relapse, hence a new chemotherapy combination with gemcitabine and carboplatin was administered to treat this patient after the second resection of metastatic lesions, and the patient remains with no evidence of disease recurrence with 22 months of follow-up. Based on the lack of patients in the current study, the role of chemotherapy in recurrent MNAC or MLA remains unclear, but this represents an area that warrants future research.

Conclusion
In this contemporary review of 11 patients with MNAC or MLA of the female genital tract, radical surgery is considered to be the initial choice for localized disease. Given the high malignancy, the majority of MNAC or MLA patients who underwent adjuvant chemotherapy received 4 to 8 cycles of carboplatin plus paclitaxel as first-line treatment after primary surgery. MNAC or MLA might be very aggressive, even when early stage. Recurrence rate was lower than expected for early stage disease. Treatment for recurrent disease in these patients included gemcitabine, carboplatin, and paclitaxel. Radiation is very limited in the treatment of the disease.