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Home , Cystadenocarcinoma, Dysgerminoma, Embryonal carcinoma, Ovarian germ cell tumors

ANTICANCER RESEARCH 35: 6713-6722 (2015)

Malignant Ovarian Tumors in Postmenopausal Patients: The Royal Marsden Experience and Literature Review

STERGIOS BOUSSIOS1, AYOMA ATTYGALLE2, STEVE HAZELL2, MICHELE MOSCHETTA1, JENNIFER MCLACHLAN1, ALICIA OKINES1 and SUSANA BANERJEE1

1Gynaecology Unit, The Royal Marsden NHS Foundation Trust, London, U.K.; 2Department of Histopathology, Royal Marsden Hospital, London, U.K.

Abstract. Background: (OGCT) components, or alone as a pure YST (3). The majority of account for 2-5% of ovarian , with an annual patients reported with YST are under 30 years of age (4). As incidence of 1:100,000, and typically occur in young germ cells are not histologically identified in the of women and adolescents. The yolk sac tumor (YST) is the postmenopausal patients, an origin of YST from germ cells is second most common subtype of OGCTs and has an most unlikely in this age group. aggressive phenotype. Their rarity in postmenopausal Four theories describing the pathogenesis of women has the potential to cause initial diagnostic postmenopausal YST have been described: the uncertainty and lead to delayed or sub-optimal treatment. theory, retrodifferentiation, the collision theory, and the In this article, we report two cases. The first case is a 67- neometaplasia theory (5-7). Neo-metaplasia, also called year-old woman with a pure YST and the second refers to a aberrant differentiation, refers to having the 59-year-old patient with YST with neuroendocrine capability for germ cell differentiation, and the germ cell differentiation. We also review and summarise the current component is thought to derive from somatic mesodermal literature. Discussion: YSTs in older women, either in cells rather than germ cells (8). The majority of YSTs in association with ovarian epithelial tumors or without an postmenopausal patients are associated with epithelial identifiable epithelial precursor, are a challenging clinical ovarian and appear to be associated with a situation. The disease is aggressive and the outcome poorer outcome. Endometrioid carcinoma is the commonest remains poor. Thirty-seven cases, including the two reported precursor lesion and is usually associated with an reported in this article, have been described in the endometriotic . The stage of disease and the presence literature to date. 12/ 37 described patients with malignant of elevated tumor markers at diagnosis correlate with OGCTs died within 8 months of diagnosis. Conclusion: prognosis. Most reported patients died within 8 months of Ovarian with a YST component in postmenopausal diagnosis and only a few cases of mainly mixed YSTs were women has an aggressive behaviour and adjuvant platinum- disease-free more than 2 years from the diagnosis. The based should be considered. immunohistochemical markers which are most useful in the differential diagnosis of these cases are α-foetoprotein Ovarian germ cell tumors (OGCTs) comprise approximately (AFP) and sal-like protein 4 (SALL4), which are positive 15% to 20% of all ovarian and 2% to 5% of all in YST and negative in primary ovarian or metastatic ovarian malignancies (1). The most common forms of intestinal carcinomas. Glypican-3, which also stains some malignant OGCTs are , yolk sac tumor (YST) clear cell carcinomas, is thus less useful in the differential and (2). YSTs usually occur in young diagnosis. women, either occurring in combination with other 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 Correspondence to: Dr. Susana Banerjee MBBS MA RCP, Ph.D., published from January 1976 until December 2014 using The Royal Marsden NHS Foundation Trust, Unit, combinations of the following free-text key words: Yolk sack Fulham Rd, London, SW3 6JJ, United Kingdom. Tel: +44 tumors, ovarian germ cell tumors, postmenopause, AFP. 2086613979, e-mail: [email protected] Original articles, review articles and case reports were Key Words: Yolk sac tumor, ovarian germ cell, postmenopausal, included. The references cited in these articles were also α-fetoprotein. reviewed.

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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 which was compressing the uterus, peritoneal deposits, free fluid in the 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 (TAH), bilateral salpingo- (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 Figure 1. Haematoxylin and eosin-stained section of the tumour shows octamer 3/4 (OCT3/4), CD30, estrogen receptor (ER), Wilm’s nests, some of which are cribriform, composed of neoplastic cells which tumour 1 protein (WT1), Ca125 and calretinin. The tumors, have well-demarcated cell margins and pale to clear cytoplasm. Nuclei both primary and metastatic, showed no evidence of a are large with distinct nucleoli. Mitoses are frequent. Original magnification, ×300. carcinomatous component.

Outcome. The postoperative computed tomographic (CT) imaging performed one month after the surgery demonstrated An MRI scan revealed a good response after 1 cycle of large-volume peritoneal disease, mainly in the lesser chemotherapy. However, in light of the revised diagnosis, the omentum, serosal and splenic involvement, as well as recommendation was to change to , and moderate left hydronephrosis secondary to the peritoneal (BEP) chemotherapy. Postoperative AFP was noted to disease. After an uneventful postoperative recovery, be 31,014 kU/l and β-human chorionic gonadotrophin (βhCG) in combination with was initially 43 mIU/l. Despite the marked clinical response and the dramatic commenced. reduction in AFP (15 kU/l) and βhCG (<2 mIU/l) following

6714 Boussios et al: Two Cases of Yolk Sac Tumours in Postmenopausal Women

Figure 2. The neoplastic cells show diffuse and strong positivity for sal-like protein 4.

Figure 3. The tumour is positive for α-foetoprotein.

6715 ANTICANCER RESEARCH 35: 6713-6722 (2015)

Table I. Demographics of 35 postmenopausal patients with ovarian germ cell tumours.

Author Year of No. of Age at Stage Histology Treatment Chemotherapy Outcome (Ref) publication cases diagnosis (years)

Arai et al. (1) 1999 1 71 (I) Mixed: MC cystadeno- No TAH, BSO EP DOD at 6M carcinoma-YST Kamoi et al. (5) 2002 1 54 IC Mixed: YST + EM Yes Tumour Ca(ip) followed DF at 21M debulking by PeEP × 5 Lopez et al. (6) 2003 1 51 IC Mixed: EM -YST, Yes TAH, BSO, BEP × 3 DOD at 10M MC omentectomy Rutgers et al. (7) 1987 1 50 IA Mixed: EST + EM Yes TAH, BSO, MOC×5 pre- DOD at 8M omentectomy, operatively and peritoneal washings VP×1 post- operatively Abe et al. (8) 2008 1 52 IC Mixed: YST + EM No TAH, BSO, BEP × 3 DF at 20M omentectomy, pelvic followed and para-aortic by TCa × 3 lymphadenectomy Brown et al. (9) 1976 1 57 III Pure: EST No TAH, BSO, None DOD at 3M omentectomy Ferracini et al. (10) 1979 1 63 N/A Pure: EST No TAH, tumour None DOD 2D post- debulking operatively Cisło et al. (11) 1984 1 50 IC Pure: EST No TAH, BSO MOC DOD at 22M Mazur et al. (12) 1988 1 82 IA Mixed: MC No TAH, BSO, None DF at 24M cystadenofibroma-YST omentectomy Kinoshita et al. (13) 1990 1 62 IA Pure: EST No TAH, BSO, VPeP × 5 N/A omentectomy Pliskow et al. (14) 1993 1 54 N/A Pure: EST No TAH, BSO, BEP × 3 DF at 24M omentectomy Kammerer-Doak 1996 1 53 N/A Mixed: EST + No TAH, BSO, BEP × 3 DF at 60M et al. (15) omentectomy, appendicectomy, pelvic and para- aortic LN Bx Takizawa et al. (16) 1996 1 69 III Mixed: EST + No BSO, partial P × 2 (ip) DOD at 24M papillary serous omentectomy followed by carcinoma CAP × 6. Second line CaE × 2 due to biochemical recurrence Nogales et al. (17) 1996 4 64 IA Mixed: EST + EM No TAH, BSO MOC × 3 DOD at 14M 71 IA Mixed: EST + Yes TAH, BSO P-based × 6 DF at 12M EM + EAF 71 III Mixed: EST + EM No TAH, BSO P-based × 1 DOD at 3M 73 III Mixed: EST + No LSO, omentectomy, None DOD at 5M carcinosarcoma appendicectomy, and uterine Bx Horiuchi et al. (18) 1998 1 53 IA Mixed: EST + EM Yes TAH, BSO, VPeMC × 6 DOD at 6M omentectomy, pelvic LN Bx Oh et al. (19) 2001 1 75 IIIC Pure: EST No TAH, BSO, EP-based × 3 DOD at 4M sigmoid colectomy, omentectomy, pelvic LN Bx Filiz et al. (20) 2003 1 76 II Pure: EST No TAH, BSO, BEP × 4 DOD at 6M omentectomy, pelvic and para-aortic LN Bx

Table I. Continued

6716 Boussios et al: Two Cases of Yolk Sac Tumours in Postmenopausal Women

Table I. Continued

Author Year of No. of Age at Stage Histology Endometriosis Treatment Chemotherapy Outcome (Ref) publication cases diagnosis (years)

García-Galvis 2008 1 69 IV Mixed: EST + No Tumour debulking None DOD 10D OF (21) carcinosarcoma and omentectomy postoperatively Zaloudek C (22) 2008 1 59 III Mixed: CCAC No TAH, BSO, N/A N/A – YST omentectomy and tumour debulking Roth et al. (23) 2011 4 67 IIIC Mixed: YST + LGSC No Partial Adjuvant, DOD 10D omentectomy N/A agents postoperatively and tumour debulking 48 IA Mixed: EM + Yes TAH, BSO DF at 24M CCAC + YST 49 IIIA Mixed: CCAC + No TAH, BSO, DOD at 15M YST omentectomy 60 IC Pure: EST No TAH, BSO, TCa DF at 14M omentectomy, appendicectomy and LN Bx Hembah-Hilekaan 2012 1 58 III Pure: No Infra-colic BEP × 2 DOD at 1M et al. (24) dysgerminoma omentectomy with tumour debulking Giuliani et al. (25) 2012 1 73 IA Mixed: YST + EM No BSO and TCa × 6 DF at 22M omentectomy Lange et al. (26) 2012 1 86 IIIC Pure: EST No TAH, BSO, BEP × 4 N/A omentectomy, peritoneal stripping Meguro et al. (27) 2013 1 58 I Mixed: AFP No TAH, BSO, TCa × 6 DF at 12M producing omentectomy with adenofibroma showing germ cell differentiation Sukumaran 2013 1 52 III Mixed: YST- No Surgical resection N/A N/A et al. (28) serous cystadenoma of the tumour Roma et al. (29) 2014 2 61 N/A Mixed: papillary No TAH, BSO and staging Bx (ip) × 6 Rec at 7M serous with minor components of EM and YST 70 N/A Pure: EST Yes TAH, BSO and 6 cycles Rec at 7M staging Bx Koi et al. (30) 2014 1 56 IIIC Mixed: YST + EM No TAH, BSO, pelvic BEP × 2. DF at 48M lymphadenectomy, Second line appendectomy and chemotherapy partial omentectomy, TCa × 6 and peritonectomy Parker et al. (31) 2014 1 60 III Pure: YST No Tumour debulking BEP × 2 Rec 17D hemi-colectomy, followed post- resection of the by POMeB operatively terminal ileum –MCE but remains and caecum, under FU ileostomy

YST: Yolk sac tumour, EST: endodermal sinus tumour, EM: endometrioid carcinoma, EAF: endometrioid adenofibroma, MC: mucinous, LGSC: low-grade serous carcinoma, CCAC: clear cell adenocarcinoma, TAH: total abdominal hysterectomy, BSO: bilateral salpingo-oophorectomy, Bx: biopsy, LN: lymph nodes, M: dactinomycin, O: vincristine, C: cyclophosphamide, V: vinblastine, P: cisplatin Pe: pepleomycin, A: adriamycin Ca: carboplatin, B: bleomycin, E: etoposide, T: taxane, Me: methotrexate, DOD: died from disease, M: months, D: days, DF: disease-free, Rec: recurrence, N/A: not available, ip: intraperitoneal, FU: follow-up.

6717 ANTICANCER RESEARCH 35: 6713-6722 (2015)

BEP therapy, within one month, the patient presented with a Outcome. Postoperative AFP was measured to be 57 kU/l. rising AFP level. The CT scan showed stable appearances The patient was staged as having International Federation of without evidence of disease progression. The patient Gynecology and Obstetrics stage II mixed yolk sac and subsequently had a PET scan which confirmed disease adjacent of the right ovary. Postoperatively, to the splenic hilum and, in addition, several areas of peritoneal there was no residual disease on imaging. Over the disease within the pelvis, measuring in the order of 2-3 cm. The subsequent months, the patient had multiple episodes of chemotherapy regimen was changed to weekly paclitaxel plus sepsis requiring prolonged admission in intensive care. Given as second line therapy in the context of platinum- the significant morbidity after the surgery, the patient did not refractory disease. A CT scan performed after the third cycle receive chemotherapy and the AFP level normalized (7 kU/l) showed further progression with enlargement of the pre-existing three months after the initial diagnosis. One year later, the peritoneal lesions and likely new peritoneal and liver serosal patient presented with chest infection and the AFP level was disease. The AFP level increased significantly (from 619 to significantly elevated, at over 39,000 kU/l. A CT scan 6,241 kU/l). Combination chemotherapy with carboplatin and revealed peritoneal disease suggestive of recurrence. Taking gemcitabine was then initiated. After the end of the third cycle, into account the significant risk of severe sepsis given the the patient experienced significant clinical deterioration. previous history and the patient’s limited respiratory reserve, Imaging confirmed small bowel and distal sigmoid obstruction the risks associated with bleomycin (within the BEP due to the large volume of peritoneal disease. This was not chemotherapy regimen) were deemed high. Therefore, amenable to surgery and the patient died 11 days later, within treatment with carboplatin and etoposide (EP) was 12 months of the initial diagnosis. administered. The AFP level was raised at 64,000 kU/l at the time of starting chemotherapy and imaging showed the Case 2. A 59-year-old woman was referred to the appearance of right hydronephrosis with the right ureter Gynaecology Clinic with a 2-month history of abdominal traced to an occlusive mass lying in the right hemi-pelvis. distension, pain, and . The patient had The serum AFP level declined rapidly after starting EP, no past family history of cancer, her personal medical history falling to 24,500 kU/l after the third course. There was also included hypertension and depression. She was an ex- a significant radiological improvement. Despite a continued smoker. MRI demonstrated a large, heterogeneous 20×27×15 fall in AFP, the end of treatment scan showed early cm mass arising from the pelvis and peritoneal nodularity. progression, with new solid peritoneal lesions and distal The CA125 level at diagnosis was noted to be 266 IU. She compression of the right ureter. Further surgery was underwent TAH with BSO, omentectomy and appendectomy. recommended but the patient declined this due to the Intraoperative findings revealed with a 40 cm right previous postoperative complications she had experienced. ovarian cyst which was adherent to the small bowel loops Her condition gradually deteriorated clinically and she died and rectosigmoid. Her postoperative recovery was 21 months after the initial diagnosis. complicated by sepsis and she required a further , haemofiltration and ventilation support in intensive care. Discussion

Histopathological findings. The resection specimen was OGCTs in postmenopausal patients are extremely rare, with reported as YST with a glandular configuration and only 35 prior published cases reported in the literature (Table neuroendocrine tumor with a range of differentiations. The I and II). The age at initial presentation ranged from 50 to 86 glandular areas had a pseudoendometrioid appearance, years (1, 5-31), (Table I). In 21 out of the 35 cases, a whereas elsewhere, there was an almost intestinal-type malignant epithelial component was identified (1, 5-8, 15-18, appearance. Morular-like structures were present and there 21-23, 25, 27, 29, 30) and in two cases, the epithelial were large areas of , mesenchymal-like areas with component was entirely benign (12, 28); the oldest patient occasional hyaline globules, small foci of osteoid formation within these 21 cases was 86 years of age (12). Endometrioid and collections of hepatoid cells. The tumor displayed focal carcinoma was the most common epithelial component, positive staining for AFP, glypican-3, SALL4, cytokeratin accounting for 12 out of the 21 malignant epithelial cases (5- AE1/3, CDX2 and thyroid factor 1 (TTF1). 8, 17, 18, 23, 25, 29, 30). Six of these events were associated There was negative staining for EMA, ER, progesterone with an endometriotic cyst (5-7, 17, 18, 23). The other types receptor (PR) and OCT3/4. In many of the sections, there of epithelial tumors which can be associated with YSTs are were also areas of neuroendocrine tumor (, less commonly described. A mucinous element was detected CD56 and focally chromogranin positive). Some areas were in three patients (1, 6, 12). Histopathology was compatible in keeping with a tumor, but there were other parts with both clear cell adenocarcinoma and YST in three cases with atypia and mitotic activity, suggestive of a component (22, 23), with papillary serous carcinoma (16, 29) and of a large cell neuroendocrine carcinoma. carcinosarcoma (17, 21) in two cases each, and with low-

6718 Boussios et al: Two Cases of Yolk Sac Tumours in Postmenopausal Women grade serous carcinoma (23) and serous cystadenoma (28) in Table II. Summary of the characteristics of 35 postmenopausal patients two patients, respectively. Interestingly, clear cell carcinoma with ovarian germ cell tumours. is also a tumor sometimes associated with a precursor Characteristic Number of % endometriotic cyst, carcinosarcoma, and also endometriosis patients (17). There were also mixed cases identified with more than one epithelial type, including (6), Age, years endometrioid adenofibroma (17), clear cell carcinoma (23) Median=62.2 Range=50-86 and papillary serous carcinoma (29) in addition to endometrioid carcinoma. Eleven cases involved pure YST Stage at diagnosis histology (9, 10, 11, 13, 14, 19, 20, 23, 26, 29, 31), with the I 15 42.9 oldest reported patient with pure YST being 86 years old (26). II 1 2.9 There is limited knowledge concerning the diagnosis, III 13 37.1 IV 1 2.9 natural history, treatment and outcome of postmenopausal Uncertain exact stage 5 14.3 YST. Arriving at the correct diagnosis can be challenging as AFP is not routinely tested in postmenopausal women. In Histological subtype postmenopausal women with an ovarian mass and an Pure YST 11 31.4 elevated serum AFP level, a of this type should be Mixed 23 65.7 Mixed: EST + EM 12 34.3 suspected. Problems can arise in the accurate histological Mixed: EST + mucinous component 3 8.6 identification of cases with an epithelial component. The Mixed: EST + papillary serous 2 5.7 older age of the patients likely contributes to the lack of Mixed: EST + carcinosarcoma 2 5.7 consideration of YST in the differential diagnosis. The first Mixed: EST + more than one component 4 11.4 of our reported cases was initially diagnosed as a high-grade Dysgerminoma 1 2.9 clear cell carcinoma. Further review and sampling revealed Baseline tumour markers the YST and there was no definite carcinomatous component. AFP elevated 18 13 Mixed 85.7 Positive staining for AFP is the most characteristic 5 Pure immunohistochemical finding in YST. Positive staining of hCG and AFP elevated 1 Mixed 4.8 tumor cell cytoplasm, secretory material within and hCG and AFP normal 2 Mixed 9.5 Unknown 14 40 , and some hyaline bodies is found in more than 75% of YSTs. Other stains that are typically positive in YST Surgery include SALL4 (32) which is nuclear, and glypican-3, (33, 34) Oophorectomy (unilateral or bilateral) 3 8.6 which is a cytoplasmic stain. Strong and diffuse expression of Debulking surgery (including TAH and BSO) 25 71.4 Suboptimal debulking surgery 7 20 SALL4 is sensitive and specific for germ cell tumors, but in addition to YST, SALL4 stains positively in dysgerminoma, Outcome the germ cell component of gonadoblastoma, embryonal DF at 48-60M 2 Mixed 5.7 carcinoma, some immature (32) and in AFP- DF at 20-24M 6 5 Mixed 17.1 producing foetal-type gastric carcinoma (35). It is considered 1 Pure DF at 12-14M 3 2 Mixed 8.6 to be particularly useful in distinguishing YST from ovarian 1 Pure clear cell adenocarcinoma. Both our cases showed diffuse DOD at 22-24M 2 1 Mixed 5.7 strong nuclear expression of SALL4 in the YST component, 1 Pure supporting its diagnosis in light of the morphology. Glypican- DOD at 10-15M 3 Mixed 8.6 3, an oncofoetal protein expressed in foetal liver and malignant DOD at 5-8M 5 4 Mixed 14.3 1 Pure tumors of hepatocytic lineage, is more sensitive than AFP but DOD at 3-4M 3 1 Mixed 8.6 not as specific. Positivity of glypican-3 in clear cell carcinoma 2 Pure appears variable and when positive does not reliably DOD at 1M 4 2 Mixed 11.4 distinguish it from YST (33, 34, 36). Lack of glypican-3 2 Pure expression may be more helpful as it favours, although in Rec at 6-8 M 2 1 Pure 5.7 1 Mixed isolation is not diagnostic of, clear cell carcinoma. Staining N/A 4 11.4 for glypican-3 can also be seen in and in Ongoing FU 1 2.9 some teratomas (37). CDX2, an intestine-specific transcription factor, is found in most cases of colorectal cancer and thus YST: Yolk sac tumour, EST: endodermal sinus tumour, EM: could be useful for detecting intestinal differentiation in cases endometrioid carcinoma, AFP: α-foetoprotein, hCG: β-human chorionic gonadotrophin, TAH: total abdominal hysterectomy, BSO:bilateral of YST. Its positivity in both our patients is in accordance with salpingo-oophorectomy, DOD: died from disease, DF: disease-free, M: the literature, but it is neither sensitive nor specific for the months, Rec: recurrence, N/A: not available, FU: follow-up.

6719 ANTICANCER RESEARCH 35: 6713-6722 (2015) diagnosis of YST (38). OCT3/4 is positive in dysgerminoma accordance with other similar cases reported in the literature. and embryonal carcinoma but negative in YST, as it was in our Because of its rarity, prognostic factors for YST remain two cases. CD30, which shows membranous staining in unclear. In a retrospective study, increasing stage and embryonal carcinoma, is negative in YST (39) additionally to elevated tumor markers were shown to be independent poor epithelial markers CK7 and EMA (3). prognostic indicators in malignant OGCT. In 19 out of the With regard to the microscopic appearance, numerous 21 postmenopausal patients with YST, the AFP level was patterns of growth have been described, mixtures of which are markedly increased (1, 5-8, 13, 15-19, 23, 26, 27, 30, 31). present in most tumors (40). The most common and distinctive Clinical outcome information was available for 16 of these patterns are the reticular, or microcystic, and the endodermal, patients: 10 patients (1, 6, 7, 17-19, 23) died within 15 also known as pseudopapillary pattern. Schiller-Duval bodies months (62.5%) and six (5, 8, 15, 23, 30) were disease-free are most often associated with the latter and are diagnostic of more than 20 months after their diagnosis (37.5%). An YSTs, also described in our first case. Glands of intestinal type ascites volume of <100 ml and residual tumor measuring <1 are occasionally seen in YSTs and can mimic a primary or cm have been reported to be associated with a better metastatic mucinous tumor. The hepatoid pattern, presented in prognosis of YST (45). At present, it is unclear why relapsed our second case, is morphologically characterized by large malignant OGCT seems to behave so differently from cells resembling liver cells (41, 42). relapsed testicular , and additional research is The most common presenting are a warranted. rapidly enlarging pelvic mass and pain. Even though malignant OGCTs are highly aggressive, cure is usually Conclusion achievable with surgery and combination chemotherapy. BEP chemotherapy is the first-line treatment most commonly We describe two cases of YST in postmenopausal women, recommended. For women with malignant OGCTs treated bringing the total number of reported cases to 37 patients. To after the introduction of cisplatin-based chemotherapy, the 5- the best of our knowledge, we report the first YST associated year survival rate approaches 90% (43). The cure rates for with a neuroendocrine with a range of patients with early-stage malignant OGCT approach 100%, differentiations. and even in advanced-stage disease are at least 75% (44). We highlight the importance of the immunohistochemical Platinum-based adjuvant chemotherapy aimed at treating both analysis and measuring serum AFP to define the correct epithelial ovarian neoplasms and germ cell tumors, as these diagnosis and raise the possibility of endometriosis, or components are identifiable or were postulated to be a part of malignancies derived from endometriosis as precursor the tumor at one time, has also been used. Adjuvant factors. These patients have poor outcome even if presenting chemotherapy with the combination of carboplatin and with early-stage disease, whether or not an epithelial paclitaxel was administered in some patients. Results from five component is detected. Aggressive with reported cases treated aggressively in this context suggest that platinum-based agents are recommended, but further the outcome may have improved (8, 23, 25, 27, 30). Disease- research is needed to determine why the outcome from this free survival from 12 to 48 months was reported. disease is so poor in this older patient group. The prognosis of OGCT in postmenopausal women is poor, even for patients with early-stage disease. Fifteen out Acknowledgements of 30 patients with available staging were diagnosed with stage I disease (1, 5-8, 11-13, 17, 18, 23, 25, 27) but only The Authors would like to acknowledge support from the Royal Marsden/ICR NIHR Specialist Biomedical Research Centre. six of them (40%) were alive for more than 20 months (5, 8, Dr. Boussios is clinical research fellow funded by the Hellenic 11, 12, 23, 25). Seven out of the 23 reported patients (30.4%) Society of Medical (HeSMO). who presented with ovarian YST associated with epithelial ovarian tumors (1, 7, 17, 18, 21, 23) and four out of 11 References patients (36.3%) with YST without an identifiable epithelial component (9, 10, 19, 20) experienced an initial biochemical 1 Arai T, Kitayama Y and Koda K: Ovarian mucinous response to treatment but subsequently died of disease after with yolk sac tumor in a 71-year-old less than 8 months from the initial diagnosis. Serum markers woman. Int J Gynecol Pathol 18(3): 277-280, 1999. may normalise during chemotherapy, but this may reflect 2 Gershenson DM, Del Junco G, Copeland LJ and Rutledge FN: regression of only one component of the mixed lesion. Mixed germ cell tumors of the ovary. Obstet Gynecol 64(2): 200-206, 1984. Therefore, in these patients, a second-look laparotomy may 3 Ramalingam P, Malpica A, Silva EG, Gershenson DM, Liu JL and be indicated if there is residual disease following Deavers MT: The use of cytokeratin 7 and EMA in differentiating chemotherapy. Both our patients died of their disease at 12 ovarian yolk sac tumors from endometrioid and clear cell and 21 months, respectively, after diagnosis, which is in carcinomas. Am J Surg Pathol 28(11): 1499-1505, 2004.

6720 Boussios et al: Two Cases of Yolk Sac Tumours in Postmenopausal Women

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37 Zynger DL, Everton MJ, Dimov ND, Chou PM and Yang XJ: 42 Devouassoux-Shisheboran M, Schammel DP and Tavassoli FA: Expression of glypican-3 in ovarian and extragonadal germ cell Ovarian hepatoid yolk sac tumors: morphological, immunohisto- tumors. Am J Clin Pathol 130(2): 224-230, 2008. chemical and ultrastructural features. Histopathology 34(5): 462- 38 Bing Z, Pasha T, Tomaszewski JE and Zhang P: CDX2 469, 1999. expression in yolk sac component of testicular germ cell tumors. 43 Solheim O, Gershenson DM, Tropé CG, Rokkones E, Sun CC, Int J Surg Pathol 17(5): 373-377, 2009. Weedon-Fekjaer H and Fosså SD: Prognostic factors in 39 Chang MC, Vargas SO, Hornick JL, Hirsch MS, Crum CP and malignant ovarian germ cell tumors (The Surveillance, Nucci MR: Embryonic stem cell transcription factors and D2-40 Epidemiology and End Results experience 1978-2010). Eur J (podoplanin) as diagnostic immunohistochemical markers in Cancer 50(11): 1942-1950, 2014. ovarian germ cell tumors. Int J Gynecol Pathol 28(4): 347-355, 44 Gershenson DM: Management of ovarian germ cell tumors. J 2009. Clin Oncol 25(20): 2938-2943, 2007. 40 Kurman RJ and Norris HJ: Endodermal sinus tumor of the 45 Umezu T, Kajiyama H, Terauchi M, Shibata K, Ino K, Nawa A ovary: a clinical and pathologic analysis of 71 cases. Cancer and Kikkawa F: Long-term outcome and prognostic factors for 38(6): 2404-2419, 1976. yolk sac tumor of the ovary. Nagoya J Med Sci 70(1-2): 29-34, 41 Prat J, Bhan AK, Dickersin GR, Robboy SJ and Scully RE: 2008. Hepatoid yolk sac tumor of the ovary (endodermal sinus tumor with hepatoid differentiation): a light microscopic, ultrastructural Received July 31, 2015 and immunohistochemical study of seven cases. Cancer 50(11): Revised September 16, 2015 2355-2368, 1982. Accepted September 25, 2015

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