Primary Yolk Sac Tumor of the Endometrium-----A Case Report and Literature Review


 BackgroundPrimary yolk sac tumor (YST) of the endometrium is extremely rare. We report a case of endometrial YST and review the literature to provide a comprehensive understanding of the diagnosis and management of primary YST of the endometrium.Methods A 43-year-old woman with primary YST of the endometrium is described. We summarize the clinical characteristics, treatments and prognosis of the case reported herein and 29 cases from the literature.ResultsIn a total of 30 primary endometrial YSTs, the average patient age was 52 years (range, 24-87 y). The mean tumor size was 6.94 cm (range 1.3-19.0 cm). Increasing serum levels of AFP were observed in all but one patient. Stage I was more common (12/30, 40%), followed by stages II (5/30, 17%), III (6/30, 20%) and IV (7/30, 23%). Of all 30 patients, 17 (57%) had pure endometrial YST, and 13 (43%) had a concomitant somatic neoplasm representing between <10% and 90% of the tumor, of which endometrial adenocarcinoma was the most common. Patients with pure YST were younger than those with concomitant somatic tumors (ranging from 24-68 years, mean 44.41 years vs. range 28-87 years, mean 61.92 years, P=0.008). Endometrial YSTs with somatic neoplasms had a poorer prognosis than pure YSTs.ConclusionPrimary YST of the endometrium is an extremely rare disease. Surgery combined with adjuvant chemotherapy is the most effective treatment. A late stage and combined somatic components may indicate a poor prognosis.


Abstract
Background Primary yolk sac tumor (YST) of the endometrium is extremely rare. We report a case of endometrial YST and review the literature to provide a comprehensive understanding of the diagnosis and management of primary YST of the endometrium.

Methods
A 43-year-old woman with primary YST of the endometrium is described. We summarize the clinical characteristics, treatments and prognosis of the case reported herein and 29 cases from the literature.

Results
In a total of 30 primary endometrial YSTs, the average patient age was 52 years (range, 24-87 y). The mean tumor size was 6.94 cm (range 1.3-19.0 cm).

Conclusion
Primary YST of the endometrium is an extremely rare disease. Surgery combined with adjuvant chemotherapy is the most effective treatment. A late stage and combined somatic components may indicate a poor prognosis.

Background
Yolk sac tumor (YST), also known as an endodermal sinus tumor, is the third most common form of malignant ovarian germ cell neoplasms, followed by dysgerminoma and immature teratomas [1]. It is one of the most common malignant ovarian neoplasms of childhood, adolescence, and early adulthood.
Although YST usually originates from the gonads (ovary and testis), it occasionally arises from midline extragonadal regions, such as the sacrococcygeal region, mediastinum, and retroperitoneum. Approximately 20% of female patients experience extragonadal YST (EGYST) [2], and the vagina is the most common site of YST growth in infants and young children [3]. Primary YST of the endometrium is very rare [4]. The rst case of primary YST of the endometrium was reported in 1980. [3] To the best of our knowledge, only 29 cases have been reported in the literature to date. We report a new case of primary endometrial YST and have a systematic review of the literature.

Case Presentation
Clinical history A 43-year-old woman was admitted with abnormal vaginal bleeding for 2 months and epigastric pain for 4 months. In the local hospital, she received a transvaginal ultrasound, which showed a hyperechoic endometrial mass. A 4 cm prominent mass was observed on the left side of the uterine isthmus by hysteroscopy. A pelvic computerized tomography (CT) scan revealed a uterine mass with no obvious enlarged lymph nodes. No apparent abnormalities were observed on the abdominal and chest CT scans. A gynecological examination indicated no obvious abnormalities in the abdomen and vagina. An abnormal increasing level of AFP (1465 µg/ml, reference level < 20 ng/ml) was observed. The serum β-HCG, CA125, CA199 and CEA levels were normal. The dilatation and curettage specimen was diagnosed as endometrial carcinoma. To further treatment, the dilatation and curettage specimen was subjected for a consultation diagnosis as primary YST of the endometrium in our hospital.
The patient underwent total abdominal hysterectomy with bilateral salpingectomy, bilateral ovary biopsies, bilateral pelvic lymphadenectomy, para-aortic lymphadenectomy, omentectomy and appendectomy. The intraoperative exploration revealed that the uterus was enlarged equivalent to 50 gestational days.
No abnormalities were observed on the surface of the uterus, bilateral ovaries or oviducts, and no enlargement or hardening of the pelvic and abdominal paraaortic lymph nodes was observed.
The serum level of AFP decreased to 193.4 ng/ml on the rst day after the operation. Adjuvant chemotherapy with bleomycin, etoposide, and cisplatin (BEP) was performed for 6 cycles. The tumor response was monitored by serial determination of the serum level of AFP, which was normal before the rst cycle of chemotherapy. The serum level of AFP was monitored and abdominal and pelvic MRI scans were taken every 3 months after chemotherapy. The patient remains alive and disease free 15 months after the completion of chemotherapy via a telephone follow-up.

Pathologic ndings
Grossly, the uterus measured 12.5 × 9.5 × 5.5 cm. An area of hemorrhage and necrosis was observed at the lower uterine segment. The residual tumor in ltrated the super cial myometrium, less than half of the myometrium. The tumor did not involved the cervix, fallopian tubes, bilateral ovaries or omentum.
The tumor did not exhibit lymph node metastasis (including 12 pelvic lymph nodes and 3 para-aortic lymph nodes). The patient was classi ed as stage IA according to the FIGO staging system [5].
Microscopically, pure endometrial YST without any other type of germ cell tumor or somatic carcinoma components was found (Fig. 1). A reticular pattern coexisted with papillary growth. The reticulum was a labyrinth of channels lined by primitive cells expanding to form microcysts with attened, clear atypical epithelial cells. Papillary growth displayed papillary brovascular structures in which a central blood vessel with tumor cells projects into the surrounding space (endodermal sinuses, Schiller-Duval bodies (S-D bodies)). Hyaline globules were observed in the cells. The stroma was hypocellular and myxoid.

Results
The description of primary YST of the endometrium in the literature is limited to case reports and small series. After systematically reviewing and screening the literature, 19 citations were found. The clinicopathological features, therapies and prognosis of 30 cases (the present case and 29 cases from the literature) are summarized in Table 1.

Discussion
The histogenesis of extragonadal YST remains speculative and controversial. There are four potential mechanisms by which a germ cell neoplasm can arise in the endometrium [6]. The rst is the aberrant migration of primordial germ cells in a lateral direction during embryogenesis, which can remain in the basal layer of the endometrium for many years. The second potential mechanism is metastasis from occult ovarian YST. Residual fetal tissues remaining in the uterus because of an incomplete abortion and somatic cells that have undergone aberrant differentiation by which YST originates in unusual sites are the other two potential mechanisms.
We summarized 30 primary endometrial YSTs: the present case and 29 cases from the literature. Patients with pure YSTs were younger than those with a concomitant somatic tumor. Therefore, pure endometrial YST and endometrial YST with somatic tumors may have had different histogeneses. Pure endometrial YSTs may originate from pluripotent germ cells, while endometrial YSTs with somatic tumors may arise from malignant pluripotent somatic stem cells or possibly via "retrodifferentiation", by which a differentiated cell transforms into a more primitive form [7]. Reports of ovarian YST arising from an endometrioid carcinoma support this hypothesis [8][9][10]. YSTs of the female genital tract in older adults are commonly derived from somatic epithelial neoplasms [11].
AFP, a special tumor marker elevated in the vast majority of patients with tumors containing a YST component, is essential for the diagnosis and monitoring of progressiveness. In the overwhelming most endometrial YSTs, AFP is used as a signi cant follow-up indicator, but only a few patients had normal serum AFP levels [12].
Since primary endometrial YST is rare, pathologists who lack experience and are not familiar with the morphology of YST may make an incorrect diagnosis, especially in biopsy specimens. Moreover, its immunohistochemical pro le overlaps between that of YST and carcinoma. AE1/AE3 is positive in both carcinoma and YST, as observed in the current case, and is not a good marker for differential diagnosis [13]. Both HNF-1β and PAX8 can be positive in YST and thus result in an incorrect diagnosis of clear cell carcinoma [14]. However, both marker commonly are patchy positive in YSTs rather than diffuse positive in clear cell carcinoma. SALL4, as a sensitive marker for germ cell tumors, is a useful marker for diagnosis when combined with GPC-3 and AFP [15]. Hence, a panel of markers is necessary for the diagnosis of YST at rare sites.
Given the rarity of primary endometrial YSTs, there is no consensus on the treatment of this extremely rare tumor. Surgery combined with adjuvant chemotherapy is the main treatment. However, the speci c resection range remains controversial, and whether ovaries are preserved still needs further study. Among the 30 patients described herein, unilateral ovary reservation was reported in only one patient [16], and bilateral ovary reservation was reported in 2 patients [17] , [18]. Rossi described a 30-year-old woman with stage II primary endometrial YST treated with simple total hysterectomy [18], preserving the bilateral ovary. The patient remained free of disease for more than 6 years after completion of the therapy. Tao reported a similar case, a 27-year-old woman with stage IA disease [17] who remained free of disease for 14 months after surgery. Wang described a 29-year-old woman with stage II disease who preserved her right adnexa to maintain endocrine function [16] and was alive without recurrence for 39 months. This fact revealed the possibility of treating a young patient with early-stage primary YST of the endometrium with surgery to conserve the ovary. The surgeons effectively retained the patient's ovarian endocrine function and improved her quality of life.
For germ cell tumors, including ovarian YST, the BEP regimen results in high cure rates, even for advanced-stage tumors [19]. However, the outcome for EGYST, especially in endometrial tissue, is less certain.

Conclusion
Primary YST of the endometrium, a highly malignant germ cell tumor, is extremely rare. Surgery combined with postoperative chemotherapy is considered effective for the treatment of primary endometrial YST. YST combined with somatic neoplasms may have a worse prognosis. However, additional cases need to be reported to further understand these rare tumors.

Declarations
All procedures followed were in accordance with the ethical standards of the Iwate Medical University and with the Helsinki Declaration. Substitute for informed consent (approval of the institutional review board of Iwate Medical University) was obtained from all patients for being included in the study, as below: This study was approved by the institutional review board Facility Ethical Committee (Fudan University Cancer Center Ethics Committee, China; approval No. 050432-4-121B, 13 December 2012).

Consent for publication
Not applicable.