Mesonephric-like adenocarcinoma of the ovary

Mesonephric-like adenocarcinoma is a new class of rare subtypes of the female reproductive system. Its clinical symptoms are similar to other types of ovarian tumors. The diagnosis is based on pathological and immunohistochemical methods. The main treatment option is surgery combined with chemotherapy. Few cases have been reported at home and abroad. We reported a case of a 45-year-old woman with a cystic solid mass in the left adnexa. The postoperative pathological diagnosis was mesonephric-like adenocarcinoma of the left ovary and mature cystic teratoma (partial infiltration of the small intestine). This case had no specific clinical symptoms. Immunohistochemical findings showed positive results of GATA3, TTF1, CD10, ER, and PR. Paclitaxel and carboplatin chemotherapy were given after the operation. Currently, no specific criteria are available for diagnosis and treatment of the disease. This article aims to improve the understanding of clinicians in this disease and create a basis for clinical diagnosis and treatment.

syndromes are similar to other types of ovarian cancer.No symptoms were usually observed in the early stage, while the main symptoms in the late stage are abdominal distension, abdominal mass, ascites, and other gastrointestinal symptoms.Its morphology, immunohistochemistry, and molecular characteristics are similar to mesonephric adenocarcinoma.Postoperative pathology is the golden standard for the diagnosis of ovarian MLA [2].Currently, surgery is the first choice of treatment, followed by adjuvant chemotherapy [3].This article aims to improve the understanding of clinicians in this disease and create a basis for clinical diagnosis and treatment.

Introduction
Mesonephric-like adenocarcinoma (MLA) is a new and rare subtype of female reproductive system tumors.The origin of MLA has not been determined.Some scholars believe MLA originates from remnants of mesonephros adjacent to the ovary, while others suggest that it may originate from the Mullerian epithelium and then differentiate along the mesonephric pathway [1].Its clinical with a lower uterine segment transverse incision, a laparoscopic total hysterectomy, right ovarian cyst removal surgery, bilateral salpingectomy, abnormal focus in the pelvic cavity, pelvic adhesion separation, and intestinal adhesion separation surgery (due to chocolate cyst on the right ovary) 5 years ago.The postoperative recovery was good.The patient was found during a physical examination 5 years ago to have a left adnexal mass measuring approximately 1 cm × 1 cm, which persisted without significant enlargement.The patient underwent a B-scan ultrasonography 1 month ago, showing a solid mixed pelvic echo area of 5.0 cm × 3.8 cm × 4.7 cm, with a clear boundary and regular morphology.CDFI: Rich blood flow signals can be detected within the arterial spectrum, with the arterial resistive index (RI) at 0.64.A free, nocturnal dark area was found in the pelvic cavity at a depth of about 1.7 cm [See Fig. 1].The patient had a significantly larger left appendage mass than before and felt occasional symptoms of lower abdominal pain, nausea, and vomiting and was hospitalized.Examinations after hospitalization were as follows.Pelvic MRI (routine + enhanced): The left pelvic region had a mass of abnormal signal foci, with the largest cross-section being about 5.0 × 4.2 cm, clear lesion boundary, and not homogeneous signal.T1WI showed low iso-intensity signals, T2WI showed slightly high signal intensity, DWI showed high signal intensity, and the enhancement was unevenly strengthened.The boundary between the lesion and the left adnexa was not clear.It was considered a malignant tumor of left adnexal origin [See Fig. 2].CT of the whole abdomen (routine + enhanced): A soft-tissue mass shadow was observed on the left side of the pelvis, with a maximum cross-section of about 4.7 × 4.1 cm.The lesion boundary was not clear.The enhancement showed obvious inhomogeneous strengthening.The intestinal walls of the small intestine, colon, and rectum did not show obvious abnormal thickening, and the intestinal lumen did not show obvious dilatation [See Fig. 3].Tumor markers: CEA 2.0 ng/mL, AFP: 3.75 ng/mL, CA125 100.7 U/mL↑, CA199 266 U/mL↑, CA50: 203.76 U/mL, HEF: 114.3 pmol/L, SCC: 0.9 ng/mL, neuron-specific enolase 13.51ng/mL (all within the normal range).Based on the patient's medical history and examination results, the preliminary diagnosis was a possible ovarian tumor.After a total hysterectomy, Laparoscopic surgery was performed under general anesthesia on March 15, 2023.During the surgery, the uterus and right adnexa were absent, no obvious ascites were seen in the pelvis, and extensive dense adhesions were observed between the sigmoid colon, small intestine, rectum, and its mesentery and both pelvic walls, pelvic floor, and vesico-peritoneal anticlinal folds.After the separation of membranous adhesions between small bowel loops, the left ovary was found to be enlarged in size at about 5 cm × 4 cm × 4 cm.Two small fat-like nodules were seen in the mesentery of the small intestine, with a diameter of about 0.3cn or 0.4 cm, and several hard nodules could be palpated in the pelvic peritoneum of the left pelvis (at the adhesion to the Fig. 2 A cluster of abnormal signal lesions is seen in the left pelvic area, with a maximum cross-section of approximately 5.0 × 4.2 cm.The boundary is still clear, and the signal is uneven.It is iso-hypointense on T1WI and slightly hyperintense on T2WI.(A) DWI is hyperintense (A).Enhancement is uneven, and the boundary between the lesion and the left adnexa is unclear.(B).The red arrow indicates the location of the tumor Fig. 1 B-ultrasound image.Solid mixed pelvic echo area of 5.0 cm × 3.8 cm × 4.7 cm, with a clear boundary and regular morphology (A).CDFI: Rich blood flow signals can be detected within the arterial spectrum, with the arterial resistive index (RI) at 0.64.A free, nocturnal dark area was found in the pelvic cavity at a depth of about 1.7 cm (B) left ovary), with a diameter of about 0.3 to 0.5 cm.The surface of the right peritoneum, greater omentum, liver, and diaphragm was smooth.The left ovary was filled with cystic, solid tumor tissue, gray-white in color, with bad and brittle texture.Intraoperative rapid pathology: The left ovary tumor gland hyperplasia was active with cellular heterogeneous junctional changes.Part of the complex gland had a disorder with necrosis, part of the tumor glands had carcinoma, and the tumor tissue had a small amount of morphology and mild squamous epithelium, which should be further clarified through routine checks.It was decided to perform laparoscopic unilateral salpingo-oophorectomy, laparoscopic pelvic lymph node dissection, para-abdominal aortic lymph node dissection, omentectomy, partial resection of the small intestine, and resection of peritoneal lesions.Immunohistochemistry: GATA-3 (small foci +), TTF-1 (+), CD10 (small foci +), Vim (+), ER (partial +), PR (small foci +), No malignant tumor cells were found in the ascites, and there was no lymph node metastasis.FIGO staging is IIIA2, The patient's tumor markers gradually decreased after surgery, with CA125 at 37.69 U/mL and CA199 at 66.48 U/mL.Six courses of paclitaxel + carboplatin chemotherapy were proposed after surgery.No obvious

Discussion
Based on a systematic literature search using the terms "mesonephric-like adenocarcinoma" and "ovary" in the PubMed, Wanfang, and CNKI databases, 19 mesonephric-like adenocarcinoma of the ovary cases were reported, as shown in Table 1.

Pathogenesis
Mesonephric-like adenocarcinoma and mesonephricduct adenocarcinoma are rare malignancies of the female reproductive system.Current studies suggest that mesonephric-duct adenocarcinoma is of mesonephric origin, often occurring in the cervix and vagina, and is associated with mesonephric ductal remnants and mesonephric ductal hyperplasia.Mesonephric ductal remnants may be seen around the tumor tissue.Mesonephric-like adenocarcinoma, a new class of rare subtypes included in the WHO (2020) Classification of Tumors of the Female Reproductive System, does not have mesonephric ductal remnants around the tumor tissue but has histologic, immunohistochemical, and molecular features similar to those of mesonephric-duct adenocarcinoma [1].The histologic origin of mesonephric-like adenocarcinoma has been controversial.It has been suggested that it may originate from the epithelium of the Müllerian duct and then differentiate along the mesonephric pathway [2].Among the 39 cases of ovarian mesonephric-like adenocarcinoma statistically analyzed by Deolet E [3]  found that mesonephric-like adenocarcinomas and endometrial carcinomas, plasmacytoid junctional tumors, and low-grade plasmacytoid carcinomas of the ovary share common mutations in the KRAS and NRAS genes, which also supports the idea that mesonephric-like adenocarcinoma (MLA) is of the Mullerian origin [4][5][6][7].In this case, the patient had a history of endometriosis (EMS), and the coexistence of ovarian-like adenocarcinoma and mature cystic teratoma of the ovary in this pathologic tissue suggested that the mesonephriclike adenocarcinoma in the ovary may originate in the Mullerian duct.

Clinical manifestations and pathology
Mesonephric-like adenocarcinoma (MLA) of the ovary is extremely rare clinically, and there are few related reports at home and abroad.Its clinical manifestations are not significantly different from other types of ovarian cancers, often asymptomatic in the early stage, and chronic pelvic pain and abnormal uterine bleeding, postmenopausal irregular bleeding, abdominal distention, or asymptomatic in the late stage.The confirmation of diagnosis depends on pathological and immunohistochemical methods [8].Histologically, mesonephric-like adenocarcinoma may show different patterns, such as reticular, papillary, tubular, gonadal, glandular, glomeruloid, fusiform, and sieve-like, and the same tumor often has a mixture of two or more growth modalities.Eosinophilic colloid-like material is commonly found in the lumen of the tubules [9][10][11].Cytologically, tumor cells are flat, cuboidal, and columnar, mildly to moderately heterogeneous, while highly heterogeneous is uncommon.The cytoplasm is eosinophilic; nuclei are flat or ovoid, with vesicular nuclei, nuclear grooves, and nuclear overlap visible, without squamous, ciliated, and mucinous chemotaxis, and there is no mesonephric remnant in the periphery [12].Immunohistochemistry is important for its diagnosis.Mesonephric-like adenocarcinoma is often positive for calretinin, GATA-3, CD10, and TTF-1, sometimes positive for P53, and negative for ER and PR.PR is a more reliable negative marker compared with ER [13].Studies have shown that GATA3 and/or thyroid  transcription factor 1 (TTF1) are considered as its markers [3].Molecularly, G12V, and G12D are the most common KRAS mutations in mesonephric-like adenocarcinoma, and concurrent ARID1A and PIK3CA mutations are relatively common, with 1q copy number gain being the most common [2,4,14,15].Some of them also had a 1p loss.p53 expression adopts a wild-type pattern, p16 is patchy and WT1 is negative.However, no PTEN mutations/deletions were observed, microsatellite was unstable, which is different from the mesonephric-duct adenocarcinoma [16][17][18].Studies have shown that the combined testing of CA125, CA199, and CEA in patients with ovarian malignant tumors can improve the accuracy of early diagnosis of ovarian cancer.In this case, the patient demonstrated preoperative elevation of CA125 and CA199 and postoperative declines, which can help predict the disease progression and prognosis evaluation [19][20][21].

Treatment
Studies have shown that mesonephric-like adenocarcinoma is highly invasive and can recur and metastasize at an early stage.39% of patients with mesonephric-like adenocarcinoma of the ovary were at stages II-IV at the time of diagnosis, and 43% of patients had lymphatic metastases.Tumors are more likely to metastasize when they have a diameter of > 4 cm, unclear tumor boundary, relatively high clinical stage (III-IV), large areas of necrosis, high nuclear fission index (> 10/10HPF), and lymphovascular invasion [12].There is currently no uniformly recommended surgical method, and the general approach is total hysterectomy with bilateral adnexectomy, omentectomy, and pelvic lymphadenectomy.After surgery, chemotherapy, radiotherapy, or combined radiotherapy is used.Paclitaxel combined with carboplatin is generally recommended as the first-line chemotherapy regimen [22].Inhibition of the RAS/MAPK pathway can also be a therapeutic modality when the mesonephriclike adenocarcinoma is combined with KRAS/NRAS mutations [23].After standard treatment, 42% of patients may still experience a recurrence, and the most common sites of recurrence are the lung, omentum majus, liver, ossa pubis, perihepatic, mesentery, and peritoneum regions [22].

Conclusion
Mesonephric-like adenocarcinoma of the ovary is a rare gynecologic malignancy that is easy to be misdiagnosed and underdiagnosed clinically, and the current diagnosis mainly relies on immunohistochemistry of postoperative pathology.Due to its rarity and non-standardized treatment yet, we expect the discovery of specific factors and indicators that can help with the diagnosis of this disease, which facilitates the development of clinical diagnostic criteria and treatment protocols for this disease.Ultimately, the disease can be detected and treated at an early stage to benefit the patients.

Fig. 6 (Fig. 5
Fig. 6 (Part of the small intestine) Focal infiltration was observed in the intrinsic muscular layer of the intestinal wall, and the upper and lower margins were negative

Table 1
Review of the literature on mesonephric-like adenocarcinoma (MLA)