SLCT is also referred to as androblastoma, and it is an extremely uncommon neoplasm, accounting for only about 1% of all ovarian sex cord stromal tumors and 0.2–0.5% of all ovarian tumorsc[9]. It occurs more often in young females between 20 and 30 years of age with an average age of 25 years and occasionally in children and menopausal women. SLCT was even reported in a 12-month-old infant[10], and the younger the patients, the lower the differentiation degree[1, 2]. SLCT typically occurs unilaterally, mostly confined to the ovary and seldom form distant metastases (2.5%) to other organsc[11, 12, 7, 1]. As most ovarian SLCT cells can synthesize androgens, approximately 25–77% of patients may present with defeminization (e.g., oligomenorrhea, amenorrhea and breast atrophy) followed by virilization (e.g., hoarseness of voice, hirsutism, facial acne and clitoromegaly)[13].Chang et al.[14] showed that a serum testosterone level of ༞6.9 nmol/L (200 ng/dL) indicated the presence of androgen-producing tumors mostly in the ovary or adrenal gland. Ovarian SLCTs should be considered in virilized patients with markedly elevated serum testosterone levels and space occupying lesions of the ovary. However, some patients may have no endocrine abnormalities but have a tumor diameter of > 10 cm, poor pathological differentiation and a high rupture risk, and these patients are often admitted due to abdominal distension and pain[7]. However, patients requiring emergency surgery for acute abdominal pain account for < 15% of all ovarian SLCT patients, which can be caused by ovarian torsion, rupture or hemorrhage of the mass[15]. In our case, the young female was hospitalized for intermittent pain in the right lower quadrant of the abdomen and the presence of a large mass in the pelvic cavity, but no obvious manifestations of high androgen levels and hyperandrogenism were noted. Intraoperative exploration showed that the tumor was ruptured and wrapped, and postoperative pathological examination showed moderately or poorly differentiated ovarian SLCT with heterologous elements.Manifestations of high androgen levels are rarely reported in SLCT patients with heterologous elements, and in most circumstances, ovarian SLCT patients are first admitted to the hospital for abdominal signs and symptoms caused by ovarian tumors[4–6],which is in agreement with the case reported here.
However, although the presence of clinical manifestations of high androgen levels in some patients contributes to preoperative diagnosis of SLCT, the diagnosis of SLCT is usually established by histopathological examination. Grossly, it appears as a large solid, cystic or solid-cystic mass[1]. According to the differentiation of tubular structures composed of Sertoli cells, the percentage of primordial gonads, the number of Leydig cells and the presence or absence of heterologous elements, SLCTs can be subdivided into well, moderately and poorly differentiated SLCTs with or without heterologous elements and/or retiform pattern, and heterologous elements are more likely to be present in moderately or poorly differentiated tumors or tumors with a retiform patternc[10, 16, 1, 17, 12]. Sertoli cells can secrete high amounts of estrogen and small amounts of progesterone and androgen, while Leydig cells can secrete high amounts of androgen and small amounts of estrogen and progesterone. Thus, the clinical manifestations of SLCTs are closely associated with the percentage of different histological types of tumors and the hormones secreted by tumor cells. In our case, the patient had only a small number of Leydig cells but a large number of Sertoli cells, which agreed well with the observation of no significant increase in androgen levels in this patient. The combination of H&E and immunohistochemical staining is considered the most reliable method for diagnosis of SLCTs. Microscopic examination revealed many eosinophilic Leydig cells interspersed with Sertoli cells in small clusters, and immunohistochemical staining revealed positive staining for CK, CD99, CD10, Vimentin and α-inhibin, indicating the possibility of ovarian SLCT. Sertoli cells were round shaped with scanty cytoplasm, deeply stained nuclei, nuclear pleomorphism, no obvious tubular structure and a flake distribution, which was determined to be moderately or poorly differentiated ovarian SLCT. In addition, two heterologous elements, mucinous epithelium and liposarcoma, were also identified. Notably, SLCT with liposarcoma has rarely been reported in the literature.
Heterologous elements are present in approximately 20% of ovarian SLCTs and can be further separated into endodermal elements and mesenchymal elements[18].The former are represented by endodermal type mucin-secreting epithelium and hepatocyte-like cells, while the latter are represented by immature cartilage and skeletal muscles.Mucinous epithelium is the most common heterologous element accounting for 20% of moderately differentiated ovarian SLCTs. The intestinal type mucinous epithelium is predominant over other types of mucinous epithelium, which is commonly accompanied by goblet cells and occasionally by argyrophil cells and exhibits neuroendocrine differentiation[1, 8].Heterologous elements such as skeletal muscle, bone and cartilage are rare, and hepatocyte-like cells are even rarer[19].However, the histogenesis of heterologous elements remains controversial and not fully understood, which may be related to the mesenchymal metaplasia of tumour cells[20]. The tumor may also be a mixed Mullerian tumor or derived from teratoma[21].As these heterologous elements can be derived from different embryonic layers, the morphological changes of SLCTs are more extensive than any other ovarian tumors except teratoma[22].In our case, the pathological examination after the first surgery revealed the presence of goblet cells intermingled with tall columnar cells, implying the presence of intestinal type mucinous epithelium. A large number of naive adipocytes were also observed and their nuclei were pushed to the periphery of the cell by vacuoles, giving the cell a typical signet ring appearance. Cells were round or ellipse shaped with chicken feet-like capillary networks and occasionally lipoblasts, implying the presence of liposarcoma. The pathological examination after the second surgery showed no mucinous epithelium, and HE staining showed some fat-like cells with deeply stained nuclei. The immunohistochemical staining showed positive staining for MDM2 and CDK4, with a sensitivity of 80–97% and a specificity of 64–93% for MDM2 and a sensitivity of 68.9–92% and a specificity of 95–100% for CDK4, respectively[23–25].For these reasons, the patient was diagnosed to have only liposarcoma. Notably, this heterologous element has rarely been reported in the literature.
Some patients would visit the hospital for abdominal pain or mass, and it is difficult to make an early diagnosis of ovarian SLCTs. However, serum AFP levels may be elevated in moderately or poorly differentiated SLCTs or SLCTs with heterologous elements[26]. AFP is a fetal globulin synthesized by the fetal liver and yolk sac during early pregnancy, which is often considered a marker of primary liver cancer. However, serum AFP levels can also be elevated in some gynecological diseases, germ cell tumors and immature teratoma, especially in endodermal sinus tumor, which can be used for preoperative diagnosis and evaluation of therapeutic efficacy and prognosis[27–30]. The increase in serum AFP levels in ovarian SLCTs can be related to various cells such as sertoli cells, leydig cells, gastrointestinal type epithelium and hepatocytes[31], but the mechanism remains largely unknown.WATANABE et al.[31] first reported heterologous gastrointestinal epithelium expression of AFP in a poorly differentiated SLCT, which was also the first case of AFP production by heterologous gastrointestinal epithelium in SLCT. We reviewed reported cases of SLCTs with heterologous elements and elevated serum AFP levels, including the age at the time of diagnosis, causes of first hospitalization, surgery type, SLCT type, presence or absence of heterologous elements, immunohistochemical staining of AFP, serum AFP levels before and after surgery, androgen levels before and after surgery, postoperative chemotherapy and follow-up outcomes.
A total of 25 SLCT patients (including our case) with heterologous elements and elevated serum AFP levels were identified in PUBMED (Table 1). All of these patients presented with elevated serum AFP levels, and immunohistochemical staining showed positive staining for AFP in 92% (23/25) patients and negative staining for AFP in 8% (2/25) patients, respectively. Leydig cells, Sertoli cells, gastrointestinal type mucinous epithelium and hepatocytes were positively stained in 16% (4/25), 8% (2/25), 24% (6/25) and 44% (11/25) patients, respectively, indicating that the increase in serum AFP levels might be associated with AFP in tumor cells. It is important to note that serum AFP levels are elevated to > 1000 ng/ml in patients with AFP-positive Sertoli cells and hepatocytes. However, it is possible that the so-called AFP-positive Sertoli cells in SLCT are basically areas of primitive heterologous intestinal elements, which is similar to the AFP-positive endodermal elements in teratoma[5].The negative immunohistochemical staining for AFP can also be attributed to the presence of only a small amount of heterologous elements[32].In our case, the serum AFP levels were elevated to ༞400 ng/ml before the first surgery, and immunohistochemical staining showed negative staining for AFP in Sertoli and Leydig cells but strongly positive staining for AFP in mucinous epithelium (Fig. 5). The serum AFP levels returned to normal within half a year after surgery with no evidence of recurrence. Thus, the increase in serum AFP levels may be associated with the presence of mucinous epithelium. The patient became pregnant naturally 4 years later, but recurrence occurred in the opposite ovary with a serum AFP level of about 160 ng/ml. The pathological examination showed no mucinous epithelium. However, the serum AFP levels of pregnant women may also increase due to the presence of the fetus, which often becomes detectable at 16 weeks of gestation, reaches a maximum at 32–34 weeks of gestation, and decreases to normal after childbirth. Note that the serum AFP levels would not exceed 400 ng/ml. The results at 4-month follow up showed neither abnormal symptoms nor elevated serum AFP levels. For this reason, the increase in serum AFP levels during the gestation could not be caused by tumors, but it is likely to be the physiological characteristics of the gestation period. The review of the 25 cases also showed that the serum AFP levels were reduced to normal after surgery, but increased again with tumor recurrence in 2 cases. Thus, the increase in serum AFP levels is likely to be related to the presence of heterologous elements in tumor tissues. The increase in serum AFP levels may have important implications for preoperative determination of the presence of heterologous elements and evaluation of the prognosis of SLCTs.
Table 1
Cases of SLCT Associated With Raised Serum AFP and heterologous elements (Literature Review)
| References | No. Case | Age | Clinical | Sur | G (cm) | Differ /AFP(+) | Heter | T Pre& Post (ng/dl) | AFP Pre& Post (ng/mL) | Chemo | follow-up |
| Singh et al.[1] | 1 | 17 y | secondary amenorrhea, hirsuitism and hoarseness of voice 1yr | NA | 10 x 6 x 5, CS | MD /Leydig | GIEP with dysplasia; R-Sar | Pre: 350; Post 6W: 140; | Pre : 40; Post 6W: 14; | NA | A&W,6W |
| Watanabe et al.[2] | 1 | 20 y | abdominal enlargement;irregular menstrual cycles for 1y | RSO | 30max;CS | NA /GIEP | • GIEP | NA | Pre: 306 Post: normal | Taxol; carboplatin | Recurrence,second laparotomy, second line chemotherapy, in remission |
| Singh et al.[3] | 1 | 12 y | slowly worsening abdominal pain of 2w | RSO | 11.7 x 10.1 x 7.9;CS; confined R | PD /Leydig | R-Sar and glandular | Pre : normal Post : normal | Pre: 77.1 Post 6W: 4.3 | BEPx4 cycles | A&W,20M |
| Al-Hussaini et al.[4] | 6 | 27 y 20 y 15 y 18 y 18 year 15 y | NA | NA | 22 11 27 14 13 8 | PD/IME MD/IME PD/IME MD/IME Retiform/Leydig MD/None | IME IME IME IME IME IME | NA | Pre:411 Pre:100 Pre:137 Pre:685 Pre:35.3 Pre:185 (Post:AII DN) | NA | NA |
| Motoyama et al.[5] | 1 | 18 y | amenorrhea 6 yr;virilism | LSO | 40×20×15 | MD + Retiform /Sertoli cells | IME | Pre:520 Post:normal | Pre:1443 Post:normal | BVCx3 cycles | A&W |
| Ikota et al.[6] | 1 | 12 y | appetite loss, diarrhea, abdominal enlargement 1M | LSO, | 27 × 15 × 10 | MPD /immature hepat | GIEP, immature hepat | Pre:0.31 Post: NA | Pre: 1349.4 Post 10W:normal | BEPx3 cycles | A&W 2.5 yr |
| Young et al.[7] | 1 | 13 y | Abdominal swelling and pain | BSO | 30 x 20 x 10 | PD with Retiform /hepat | IME, hepat, SM | NA | Pre:14000 Post 4M:25 Post 7M:3800 | BVCx2 cycles with Cy-actD-D x2 cycles | ( after operation) 7M Recurrence ;9M Died |
| Chadha et al.[8] | 2 | 16 y 11 M | Amenorrhea 4M Acute abdominal pain | BSO RSO | 12 x11 x16,CS 10 x 9 x 6 | NA /Sertoli cell Retiform / hepat | GIEP Resembling hepat cell | normal NA | Pre:4500 Post:430 Pre:1500 Post :200 Post 4M:3500 Post 5M:7000 Post 6M:11700 Post 2nd operation 4d:9000 | NA Cy-actD-Vx10 cycles | Post 1y pregnancy; A&W 2y Post 2nd : A&W 1.5y |
| Liang et al.[9] | 1 | 15 y | constipation 8M | LSO | 26 x 24 x 14 | NA / hepat differentiation | mucinous epithelium, hepat differ | Normal | Pre: elevated Post:NA | NA | NA |
| Mooney et al.[10] | 5 | 44 74 18 23 15 | NA | NA | NA | Retiform/hepat MD + Retiform/hepat PD + Retiform/ hepat MD + Retiform/hepat PD + Retiform/ hepat | Hepat Hepat + sar Hepat + cartilage Hepat Hepat + Sar recurrent | NA | Pre:NA but elevated Post:NA | NA | NA |
| Horta et al.[11] | 1 | 19 y | diffuse abdominal pain and bloating | RSO | 8.2 x 7.5 x 6.5, CS | PD /Not found | IME | NA | Pre:46.3 Post:normal | BEP | A&W 4M |
| 20.Jang et al.[12] | 1 | 26 | Amenorrhea 3M,masculine voice, pelvic mass | NA | 11×9×9 ,CS, filled with mucoid material | MD + retiform /Leydig cell | IME | Pre:90 Post:normal | Pre:56.6 Post:normal | BEP x3 cycles | A&W 6M |
| 21.lo´pez-arias et al.[13] | 1 | 28 | abdominal pain, a right adnexal mass | RSO | 13 ,CS | retiform /Hepat | Hepat | NA( without virilization) | Pre:636 Post 1W:150 Post 5M:0.89 | NA | NA |
| 22.Liggins et al.[14] | 1 | 40 | progressive left lower abdominal pain 5y | BSO | 13 | NA /Hepat | Hepat, carcinoid tumor | NA | Pre:NA but elevated Post:normal | carboplatin and paclitaxel x2 cycles | A&W 20M |
| Present Case | 1 | 18 | Right lower abdominal pain | LSO | 15 x 12 x 11,CS | PD /IME | IME, Lipoblastoma | Normal | Pre: 442.6 Post 5M: 1.9 | DP x10 cycles | ( after operation) 4y pregnancy and Re, Post 2nd: A&W 4M |
Up to now, there is no uniformly accepted treatment for ovarian SLCTs[33], and surgical excision is the preferred treatment of choice[34]. Unilateral adnexectomy or ovarian cystectomy can result in favorable clinical outcomes in early-stage or highly differentiated SLCT patients who wished to retain fertility[35, 36]; while advanced or poorly differentiated SLCT patients may benefit more from unilateral adnexectomy + staging operations such as omentectomy, appendectomy and lymphadenectomy of the pelvic cavity. The combination of chemotherapy and cellular immunity can be considered after the surgery. Despite this, controversy still exists about the necessity of lymphadenectomy of the pelvic cavity.Brown et al.[37] showed that a lymph node metastasis was rare in SCSTs, thus indicating that lymphadenectomy could be omitted when staging patients with ovarian SCSTs. Young and Scully found that 19% of tumors with heterologous elements were considered malignant clinically[1].Postoperative chemotherapy is generally required in patients with poor prognosis such as advanced tumors, moderately or poorly differentiated tumors, presence of heterologous elements, and tumor rupture [3, 1, 2, 7],but its efficacy needs to be further evaluated in clinical trails[34, 33, 7, 14]. The combination of bleomycin, etoposide and cisplatin (BEP) is regarded as standard chemotherapy of SCSTs[38, 39], and other chemotherapy regimens include cisplatin, doxorubicin and cyclophosphamide (CAP), and cisplatin, vinblastine and bleomycin (PVB)[40].Currently, there is no chemotherapy regimen specifically for heterologous elements in SCSTs. No specific treatment is required for patients in whom gastrointestinal type mucinous epithelium has no significant effect on the prognosis, but it remains unknown whether it is required for malignant interstitial cell tumors with heterologous elements. Further well-designed and large-sample clinical trials are warranted to investigate the effects of age, fertility potential and presence of heterologous elements. In this case, unilateral adnexectomy was performed in the first surgery (her fertility was retained) but lymph nodes were not removed, and DP chemotherapy was administered for 6 cycles and triptorelin was injected to preserve her ovarian function. The patient became naturally pregnant 3 years after the surgery. Unfortunately, tumor recurred in the opposite ovary. Ovarian cystectomy was performed, and future surgery and auxiliary chemotherapy were scheduled at an appropriate time in order to improve the long-term survival of the patient.
Postoperative adjuvant chemotherapy is recommended for ovarian SLCTs with heterologous elements, but it would cause irreversible ovarian damage and even premature ovarian failure in young patients, which highlights the need to preserve ovarian function before and after chemotherapy[1–3]. The DOC and DDP used in this case may directly or indirectly affect the maturation and development of oocytes and even cause premature ovarian failure[41, 42]. It is reported that the use of gonadotropin-releasing hormone (GnRH) agonist before DOC chemotherapy could result in a 86.8% reduction in docetaxel-induced ovarian damage[43].In our case, triptorelin was injected to preserve the ovarian function of the patient, which could arrest the development and maturation of primordial follicles during chemotherapy and reduce the damage to the ovary and the sensitivity to cytotoxic drugs, and consequently contributed to preserve the ovarian function[44] and reduce the risk of premature ovarian failure of the patient. A full-term baby was born, indicating that the administration of GnRH-a during operation can be useful to preserve the ovarian function.
In general, ovarian SLCTs are relatively inactive with a detection rate of 18%. It has been reported that all well differentiated tumors were benign, and 11% of moderately differentiated tumors, 59% of poorly differentiated tumors and 19% of tumors were malignant[1].The long-term prognosis is closely associated with clinical stage, tumor size, differentiation degree, cell proliferation index, tumor rupture and presence or absence of heterologous elements, and those patients with tumors of > 15 cm, poorly differentiated tumors, nuclear division and a reticular pattern are likely to have poorer prognosis [33, 45].The 5-year survival rate was 100% in patients with highly differentiated ovarian SLCTs but only 80% in patients with poorly differentiated ovarian SLCTs. It has also been reported that the survival rate was 95% in stage Ⅰ patients but almost 0 in stage Ⅲ/IV patients[1, 14].The gastrointestinal type epithelium has no significant effect on the prognosis, but malignant stromal components such as rhabdomyosarcoma and chondrosarcoma can result in poor prognosis[46–48].Thus, there is a need for more intensive follow up for those ovarian SLCT patients with heterologous elements, which will significantly contribute to early detection and treatment. In our case, the patient was diagnosed to have stage Ⅲc ovarian SLCT with liposarcoma and a large ruptured mass was found during the surgery, all of which were considered poor prognostic factors. The patient was closely followed up for 2 years but lost to follow up for 1 year. However, recurrence occurred in the opposite ovary during the early pregnancy three years after the operation, but happily a full-term baby was born. The mass of the right ovary was removed and no recurrence was found at 6-month follow up. It is evident that these favorable outcomes are of importance for the patient and her famlily members.