Abstract
Background: Ovarian germ cell tumors (OGCT) account for 2-5% of ovarian malignancies, with an annual incidence of 1:100,000, and typically occur in young women and adolescents. The yolk sac tumor (YST) is the second most common subtype of OGCTs and has an aggressive phenotype. Their rarity in postmenopausal women has the potential to cause initial diagnostic uncertainty and lead to delayed or sub-optimal treatment. In this article, we report two cases. The first case is a 67-year-old woman with a pure YST and the second refers to a 59-year-old patient with YST with neuroendocrine differentiation. We also review and summarise the current literature. Discussion: YSTs in older women, either in association with ovarian epithelial tumors or without an identifiable epithelial precursor, are a challenging clinical situation. The disease is aggressive and the outcome remains poor. Thirty-seven cases, including the two reported in this article, have been described in the literature to date. 12/ 37 described patients with malignant OGCTs died within 8 months of diagnosis. Conclusion: Ovarian cancer with a YST component in postmenopausal women has an aggressive behaviour and adjuvant platinum-based chemotherapy should be considered.
Ovarian germ cell tumors (OGCTs) comprise approximately 15% to 20% of all ovarian neoplasms and 2% to 5% of all ovarian malignancies (1). The most common forms of malignant OGCTs are dysgerminoma, yolk sac tumor (YST) and immature teratoma (2). YSTs usually occur in young women, either occurring in combination with other components, or alone as a pure YST (3). The majority of patients reported with YST are under 30 years of age (4). As germ cells are not histologically identified in the ovaries of postmenopausal patients, an origin of YST from germ cells is most unlikely in this age group.
Four theories describing the pathogenesis of postmenopausal YST have been described: the teratoma theory, retrodifferentiation, the collision theory, and the neometaplasia theory (5-7). Neo-metaplasia, also called aberrant differentiation, refers to carcinomas having the capability for germ cell differentiation, and the germ cell component is thought to derive from somatic mesodermal cells rather than germ cells (8). The majority of YSTs in postmenopausal patients are associated with epithelial ovarian carcinoma and appear to be associated with a poorer outcome. Endometrioid carcinoma is the commonest reported precursor lesion and is usually associated with an endometriotic cyst. The stage of disease and the presence of elevated tumor markers at diagnosis correlate with prognosis. Most reported patients died within 8 months of diagnosis and only a few cases of mainly mixed YSTs were disease-free more than 2 years from the diagnosis. The immunohistochemical markers which are most useful in the differential diagnosis of these cases are α-foetoprotein (AFP) and sal-like protein 4 (SALL4), which are positive in YST and negative in primary ovarian or metastatic intestinal carcinomas. Glypican-3, which also stains some clear cell carcinomas, is thus less useful in the differential diagnosis.
In this study, we report two cases of YST in post menopausal women and also review and summarise the current literature on this topic.
A PubMed search was carried out for eligible articles published from January 1976 until December 2014 using combinations of the following free-text key words: Yolk sack tumors, ovarian germ cell tumors, postmenopause, AFP. Original articles, review articles and case reports were included. The references cited in these articles were also reviewed.
Case Reports
Case 1. A 67-year-old woman presented with a 2-month history of lower abdominal discomfort, and an abdominal mass was palpable on examination. Family history included her father being diagnosed with colorectal cancer and brother with bladder cancer. She had no children, had never taken hormone replacement therapy and was an ex-smoker, having stopped 35 years earlier. Magnetic resonance imaging (MRI) demonstrated a pelvic mass inseparable from the left ovary which was compressing the uterus, peritoneal deposits, free fluid in the pelvis and upper abdominal disease in the splenic hilum. Preoperatively, cancer antigen 125 (Ca125) was raised (700 U/ml), and AFP was not tested. The patient underwent primary debulking surgery with total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), pelvic lymphadenectomy, appendectomy, and partial omentectomy and peritonectomy without macroscopic residual disease. Surgical findings included a mass arising from the left ovary with involvement of the rectum and pelvic peritoneum.
Histopathological findings. The initial pathological examination reported this tumor to be a high-grade clear cell carcinoma affecting the left ovary. Upon review at our Institution, the histological diagnosis was revised to a YST with metastatic deposits in the rectum, both parametria and sigmoid mesentery. Most of the right ovary had a glandular morphology whilst other areas showed solid and papillary patterns (Figure 1). A few perivascular formations (Schiller-Duvall bodies) were identified. There was abundant periodic acid-Schiff (PAS)-positive diastase-sensitive material, consistent with glycogen within the cytoplasm of the neoplastic cells. Many hyaline globules were present which were PAS-D positive. The tumor showed strong diffuse positivity for SALL4 (Figure 2). It also showed patchy strong positivity for glypican-3 and AFP (Figure 3). There were focal glandular structures that resembled embryonic gut structures. Many of which were positive for caudal-related homeobox gene 2 (CDX2). They also showed focal positivity for epithelial membrane antigen (EMA), cytokeratin 7 and 20. The tumor was negative for octamer 3/4 (OCT3/4), CD30, estrogen receptor (ER), Wilm's tumour 1 protein (WT1), Ca125 and calretinin. The tumors, both primary and metastatic, showed no evidence of a carcinomatous component.
Outcome. The postoperative computed tomographic (CT) imaging performed one month after the surgery demonstrated large-volume peritoneal disease, mainly in the lesser omentum, serosal liver and splenic involvement, as well as moderate left hydronephrosis secondary to the peritoneal disease. After an uneventful postoperative recovery, carboplatin in combination with paclitaxel was initially commenced.
Haematoxylin and eosin-stained section of the tumour shows nests, some of which are cribriform, composed of neoplastic cells which have well-demarcated cell margins and pale to clear cytoplasm. Nuclei are large with distinct nucleoli. Mitoses are frequent. Original magnification, ×300.
An MRI scan revealed a good response after 1 cycle of chemotherapy. However, in light of the revised diagnosis, the recommendation was to change to bleomycin, etoposide and cisplatin (BEP) chemotherapy. Postoperative AFP was noted to be 31,014 kU/l and β-human chorionic gonadotrophin (βhCG) 43 mIU/l. Despite the marked clinical response and the dramatic reduction in AFP (15 kU/l) and βhCG (<2 mIU/l) following BEP therapy, within one month, the patient presented with a rising AFP level. The CT scan showed stable appearances without evidence of disease progression. The patient subsequently had a PET scan which confirmed disease adjacent to the splenic hilum and, in addition, several areas of peritoneal disease within the pelvis, measuring in the order of 2-3 cm. The chemotherapy regimen was changed to weekly paclitaxel plus gemcitabine as second line therapy in the context of platinum-refractory disease. A CT scan performed after the third cycle showed further progression with enlargement of the pre-existing peritoneal lesions and likely new peritoneal and liver serosal disease. The AFP level increased significantly (from 619 to 6,241 kU/l). Combination chemotherapy with carboplatin and gemcitabine was then initiated. After the end of the third cycle, the patient experienced significant clinical deterioration. Imaging confirmed small bowel and distal sigmoid obstruction due to the large volume of peritoneal disease. This was not amenable to surgery and the patient died 11 days later, within 12 months of the initial diagnosis.
The neoplastic cells show diffuse and strong positivity for sal-like protein 4.
The tumour is positive for α-foetoprotein.
Demographics of 35 postmenopausal patients with ovarian germ cell tumours.
Case 2. A 59-year-old woman was referred to the Gynaecology Clinic with a 2-month history of abdominal distension, pain, weight loss and anorexia. The patient had no past family history of cancer, her personal medical history included hypertension and depression. She was an ex-smoker. MRI demonstrated a large, heterogeneous 20×27×15 cm mass arising from the pelvis and peritoneal nodularity. The CA125 level at diagnosis was noted to be 266 IU. She underwent TAH with BSO, omentectomy and appendectomy. Intraoperative findings revealed ascites with a 40 cm right ovarian cyst which was adherent to the small bowel loops and rectosigmoid. Her postoperative recovery was complicated by sepsis and she required a further laparotomy, haemofiltration and ventilation support in intensive care.
Histopathological findings. The resection specimen was reported as YST with a glandular configuration and neuroendocrine tumor with a range of differentiations. The glandular areas had a pseudoendometrioid appearance, whereas elsewhere, there was an almost intestinal-type appearance. Morular-like structures were present and there were large areas of necrosis, mesenchymal-like areas with occasional hyaline globules, small foci of osteoid formation and collections of hepatoid cells. The tumor displayed focal positive staining for AFP, glypican-3, SALL4, cytokeratin AE1/3, CDX2 and thyroid transcription factor 1 (TTF1). There was negative staining for EMA, ER, progesterone receptor (PR) and OCT3/4. In many of the sections, there were also areas of neuroendocrine tumor (synaptophysin, CD56 and focally chromogranin positive). Some areas were in keeping with a carcinoid tumor, but there were other parts with atypia and mitotic activity, suggestive of a component of a large cell neuroendocrine carcinoma.
Outcome. Postoperative AFP was measured to be 57 kU/l. The patient was staged as having International Federation of Gynecology and Obstetrics stage II mixed yolk sac and neuroendocrine tumor of the right ovary. Postoperatively, there was no residual disease on imaging. Over the subsequent months, the patient had multiple episodes of sepsis requiring prolonged admission in intensive care. Given the significant morbidity after the surgery, the patient did not receive chemotherapy and the AFP level normalized (7 kU/l) three months after the initial diagnosis. One year later, the patient presented with chest infection and the AFP level was significantly elevated, at over 39,000 kU/l. A CT scan revealed peritoneal disease suggestive of recurrence. Taking into account the significant risk of severe sepsis given the previous history and the patient's limited respiratory reserve, the risks associated with bleomycin (within the BEP chemotherapy regimen) were deemed high. Therefore, treatment with carboplatin and etoposide (EP) was administered. The AFP level was raised at 64,000 kU/l at the time of starting chemotherapy and imaging showed the appearance of right hydronephrosis with the right ureter traced to an occlusive mass lying in the right hemi-pelvis. The serum AFP level declined rapidly after starting EP, falling to 24,500 kU/l after the third course. There was also a significant radiological improvement. Despite a continued fall in AFP, the end of treatment scan showed early progression, with new solid peritoneal lesions and distal compression of the right ureter. Further surgery was recommended but the patient declined this due to the previous postoperative complications she had experienced. Her condition gradually deteriorated clinically and she died 21 months after the initial diagnosis.
Discussion
OGCTs in postmenopausal patients are extremely rare, with only 35 prior published cases reported in the literature (Table I and II). The age at initial presentation ranged from 50 to 86 years (1, 5-31), (Table I). In 21 out of the 35 cases, a malignant epithelial component was identified (1, 5-8, 15-18, 21-23, 25, 27, 29, 30) and in two cases, the epithelial component was entirely benign (12, 28); the oldest patient within these 21 cases was 86 years of age (12). Endometrioid carcinoma was the most common epithelial component, accounting for 12 out of the 21 malignant epithelial cases (5-8, 17, 18, 23, 25, 29, 30). Six of these events were associated with an endometriotic cyst (5-7, 17, 18, 23). The other types of epithelial tumors which can be associated with YSTs are less commonly described. A mucinous element was detected in three patients (1, 6, 12). Histopathology was compatible with both clear cell adenocarcinoma and YST in three cases (22, 23), with papillary serous carcinoma (16, 29) and carcinosarcoma (17, 21) in two cases each, and with low-grade serous carcinoma (23) and serous cystadenoma (28) in two patients, respectively. Interestingly, clear cell carcinoma is also a tumor sometimes associated with a precursor endometriotic cyst, carcinosarcoma, and also endometriosis (17). There were also mixed cases identified with more than one epithelial type, including mucinous cystadenoma (6), endometrioid adenofibroma (17), clear cell carcinoma (23) and papillary serous carcinoma (29) in addition to endometrioid carcinoma. Eleven cases involved pure YST histology (9, 10, 11, 13, 14, 19, 20, 23, 26, 29, 31), with the oldest reported patient with pure YST being 86 years old (26).
There is limited knowledge concerning the diagnosis, natural history, treatment and outcome of postmenopausal YST. Arriving at the correct diagnosis can be challenging as AFP is not routinely tested in postmenopausal women. In postmenopausal women with an ovarian mass and an elevated serum AFP level, a neoplasm of this type should be suspected. Problems can arise in the accurate histological identification of cases with an epithelial component. The older age of the patients likely contributes to the lack of consideration of YST in the differential diagnosis. The first of our reported cases was initially diagnosed as a high-grade clear cell carcinoma. Further review and sampling revealed the YST and there was no definite carcinomatous component.
Positive staining for AFP is the most characteristic immunohistochemical finding in YST. Positive staining of tumor cell cytoplasm, secretory material within cysts and glands, and some hyaline bodies is found in more than 75% of YSTs. Other stains that are typically positive in YST include SALL4 (32) which is nuclear, and glypican-3, (33, 34) which is a cytoplasmic stain. Strong and diffuse expression of SALL4 is sensitive and specific for germ cell tumors, but in addition to YST, SALL4 stains positively in dysgerminoma, the germ cell component of gonadoblastoma, embryonal carcinoma, some immature teratomas (32) and in AFP-producing foetal-type gastric carcinoma (35). It is considered to be particularly useful in distinguishing YST from ovarian clear cell adenocarcinoma. Both our cases showed diffuse strong nuclear expression of SALL4 in the YST component, supporting its diagnosis in light of the morphology. Glypican-3, an oncofoetal protein expressed in foetal liver and malignant tumors of hepatocytic lineage, is more sensitive than AFP but not as specific. Positivity of glypican-3 in clear cell carcinoma appears variable and when positive does not reliably distinguish it from YST (33, 34, 36). Lack of glypican-3 expression may be more helpful as it favours, although in isolation is not diagnostic of, clear cell carcinoma. Staining for glypican-3 can also be seen in choriocarcinoma and in some teratomas (37). CDX2, an intestine-specific transcription factor, is found in most cases of colorectal cancer and thus could be useful for detecting intestinal differentiation in cases of YST. Its positivity in both our patients is in accordance with the literature, but it is neither sensitive nor specific for the diagnosis of YST (38). OCT3/4 is positive in dysgerminoma and embryonal carcinoma but negative in YST, as it was in our two cases. CD30, which shows membranous staining in embryonal carcinoma, is negative in YST (39) additionally to epithelial markers CK7 and EMA (3).
Summary of the characteristics of 35 postmenopausal patients with ovarian germ cell tumours.
With regard to the microscopic appearance, numerous patterns of growth have been described, mixtures of which are present in most tumors (40). The most common and distinctive patterns are the reticular, or microcystic, and the endodermal, also known as pseudopapillary pattern. Schiller-Duval bodies are most often associated with the latter and are diagnostic of YSTs, also described in our first case. Glands of intestinal type are occasionally seen in YSTs and can mimic a primary or metastatic mucinous tumor. The hepatoid pattern, presented in our second case, is morphologically characterized by large cells resembling liver cells (41, 42).
The most common presenting signs and symptoms are a rapidly enlarging pelvic mass and pain. Even though malignant OGCTs are highly aggressive, cure is usually achievable with surgery and combination chemotherapy. BEP chemotherapy is the first-line treatment most commonly recommended. For women with malignant OGCTs treated after the introduction of cisplatin-based chemotherapy, the 5-year survival rate approaches 90% (43). The cure rates for patients with early-stage malignant OGCT approach 100%, and even in advanced-stage disease are at least 75% (44). Platinum-based adjuvant chemotherapy aimed at treating both epithelial ovarian neoplasms and germ cell tumors, as these components are identifiable or were postulated to be a part of the tumor at one time, has also been used. Adjuvant chemotherapy with the combination of carboplatin and paclitaxel was administered in some patients. Results from five reported cases treated aggressively in this context suggest that the outcome may have improved (8, 23, 25, 27, 30). Disease-free survival from 12 to 48 months was reported.
The prognosis of OGCT in postmenopausal women is poor, even for patients with early-stage disease. Fifteen out of 30 patients with available staging were diagnosed with stage I disease (1, 5-8, 11-13, 17, 18, 23, 25, 27) but only six of them (40%) were alive for more than 20 months (5, 8, 11, 12, 23, 25). Seven out of the 23 reported patients (30.4%) who presented with ovarian YST associated with epithelial ovarian tumors (1, 7, 17, 18, 21, 23) and four out of 11 patients (36.3%) with YST without an identifiable epithelial component (9, 10, 19, 20) experienced an initial biochemical response to treatment but subsequently died of disease after less than 8 months from the initial diagnosis. Serum markers may normalise during chemotherapy, but this may reflect regression of only one component of the mixed lesion. Therefore, in these patients, a second-look laparotomy may be indicated if there is residual disease following chemotherapy. Both our patients died of their disease at 12 and 21 months, respectively, after diagnosis, which is in accordance with other similar cases reported in the literature.
Because of its rarity, prognostic factors for YST remain unclear. In a retrospective study, increasing stage and elevated tumor markers were shown to be independent poor prognostic indicators in malignant OGCT. In 19 out of the 21 postmenopausal patients with YST, the AFP level was markedly increased (1, 5-8, 13, 15-19, 23, 26, 27, 30, 31). Clinical outcome information was available for 16 of these patients: 10 patients (1, 6, 7, 17-19, 23) died within 15 months (62.5%) and six (5, 8, 15, 23, 30) were disease-free more than 20 months after their diagnosis (37.5%). An ascites volume of <100 ml and residual tumor measuring <1 cm have been reported to be associated with a better prognosis of YST (45). At present, it is unclear why relapsed malignant OGCT seems to behave so differently from relapsed testicular germ cell tumor, and additional research is warranted.
Conclusion
We describe two cases of YST in postmenopausal women, bringing the total number of reported cases to 37 patients. To the best of our knowledge, we report the first YST associated with a neuroendocrine ovarian tumor with a range of differentiations.
We highlight the importance of the immunohistochemical analysis and measuring serum AFP to define the correct diagnosis and raise the possibility of endometriosis, or malignancies derived from endometriosis as precursor factors. These patients have poor outcome even if presenting with early-stage disease, whether or not an epithelial component is detected. Aggressive adjuvant therapy with platinum-based agents are recommended, but further research is needed to determine why the outcome from this disease is so poor in this older patient group.
Acknowledgements
The Authors would like to acknowledge support from the Royal Marsden/ICR NIHR Specialist Biomedical Research Centre.
Dr. Boussios is clinical research fellow funded by the Hellenic Society of Medical Oncology (HeSMO).
- Received July 31, 2015.
- Revision received September 16, 2015.
- Accepted September 25, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
