Gynecologic Oncology Reports 4 (2013) 56–59

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Case Report

Central primary primitive neuroectodermal tumor (cPNET) arising from an ovarian mature cystic teratoma in pregnancy: A case report and review of medical literature Yong Kuei Lim a,⁎, Chee Wai Ku b, Gek Choo Teo c, Sheow Lei Lim a, Chee Seng Tee d a

KK Women's and Children's Hospital, Department of Gynaecological Oncology, 100 Bukit Timah Road, Singapore 229899, Singapore Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore c KK Women's and Children's Hospital, Department of Pathology and Laboratory Medicine, 100 Bukit Timah Road, Singapore 229899, Singapore d KK Women's and Children's Hospital, Division of Obstetrics and Gynaecology, 100 Bukit Timah Road, Singapore 229899, Singapore b

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Article history: Received 21 November 2012 Accepted 11 January 2013 Available online 23 January 2013 Keywords: Primitive neuroectodermal tumor Ovary Chemotherapy Pregnancy

Introduction Primary primitive neuroectodermal tumor (PNET) of the ovary is a rare entity. PNETs may be classified under 2 broad categories with differing clinical characteristics, immunohistochemical profiles and genetics: (i) central PNET (cPNET) and (ii) peripheral PNET (pPNET). PNETs in general are aggressive cancers associated with a high mortality (Kovar, 1998). We present a case of a patient diagnosed with cPNET arising from a mature cystic teratoma during pregnancy, managed with fertility-preserving surgery. Case report A 27 year old nulliparous Chinese woman presented to her obstetrician at 12 weeks of gestation. Ultrasound showed a left triloculated cyst measuring 8.9× 7 cm and serum tumor markers (CA-125, CEA and AFP) were normal. She underwent an open ovarian cystectomy at 14 weeks of gestation in June 2009. There was an iatrogenic capsular rupture during the cystectomy. Gross examination of the resected ovarian cyst revealed locules containing sebaceous material and hairs (Fig. 1). The largest locule showed a mural nodule measuring 8 × 5 × 3 cm, with adipose, cartilaginous and bony areas. Histological examination of the ovarian cyst ⁎ Corresponding author. E-mail address: [email protected] (Y.K. Lim). 2211-338X/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.gynor.2013.01.004

revealed a mature cystic teratoma comprising skin, adipose, gastrointestinal tract, respiratory tract, cartilage, lamellar bone, hematopoietic and neural tissue (Fig. 2). However, the mural nodule from the largest locule showed an area of malignant transformation, comprising a nodular focus of PNET measuring 7 mm in greatest dimension (Fig. 3A). The PNET was composed of sheets of primitive round cells with high nuclear-cytoplasmic ratio, frequent mitoses and focal necrosis, set in a finely fibrillary background (Fig. 3B and C). At its edges, the PNET showed infiltration into surrounding mature teratomatous neural tissue (Fig. 3D). Several adjacent foci of lymphovascular invasion were also seen (Fig. 3E). Immunohistochemical studies demonstrated within the PNET expression of neural markers chromogranin A and synaptophysin, and a Ki67 labeling index of 90% (Fig. 3B). There was absence of immunoreactivity for CD99, indicating that the tumor was a central-type PNET. Chest X-ray (abdominal shielding) and MRI of the abdomen and pelvis did not reveal any distant metastases. She had at least a FIGO Stage IC cPNET of the ovary (T1c NX M0). Subsequently, she was managed by a multidisciplinary team comprising of a gynecologic oncologist, a medical oncologist, as well as a maternal fetal medicine specialist. In view of the lymphovascular space invasion and high risk of metastases, coupled with the highly aggressive nature of cPNET, the patient was counseled for staging surgery and the pros and cons of chemotherapy were also discussed. However, she declined further surgery and chemotherapy during pregnancy. She was followed up closely throughout pregnancy, which remained largely uneventful. She delivered a healthy baby boy at 37 weeks of gestation via an elective lower segment cesarean section (LSCS), with a birth weight of 2925 g. At the same time, she underwent a left salpingo-oophorectomy, left pelvic lymph node sampling, omentectomy and peritoneal washing for staging. She had opted for a fertility sparing surgery instead of a full staging surgery. Intra-operatively, the left ovary was slightly nodular, but the right ovary appeared normal. There was no enlarged retroperitoneal lymphadenopathy or peritoneal disease. Histological examination of the remnant left ovary did not show any residual disease, and the left pelvic lymph nodes, omentum and peritoneal washing were all negative for malignancy. The patient was then counseled for adjuvant chemotherapy after her delivery in view of the aggressive nature of cPNET and evidence of lymphovascular invasion on histology. However, she declined any further treatment, and was given regular follow-up in the gynecologic oncology clinic.

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Discussion

Fig. 1. Gross specimen of resected ovarian cyst.

Half a year later, the patient became pregnant with her second child in July 2010. She was well antenatally. She delivered her second child by elective LSCS, with a birth weight of 3438 g. She continued to be on regular follow up in our hospital, with no cancer relapse 2.5 years after her diagnosis.

Fig. 2. Histological diagnosis of mature cystic teratoma. The main tumor was a mature cystic teratoma, with skin and adipose tissue elements shown here (H&E, low power).

The incidence of ovarian cysts during pregnancy varies from 1 in 100 to 1 in 2000 pregnancies and malignant ovarian tumors are relatively uncommon. The primary diagnostic challenge in this case involved distinguishing between an immature teratoma with only a minor focus of immature neuroepithelial elements, versus a mature teratoma with focal secondary malignant (PNET) transformation. The risk of malignant transformation develops in about 0.17 to 2% of mature cystic teratomas, and occurs most often in postmenopausal women (Hinshaw et al., 2012). Malignant neural tumors arising in mature cystic teratomas are rare, and those reported in young women usually but not always represent immature teratomas that characteristically contain immature neuroepithelial elements. Nonetheless, in this case, the following features indicated the diagnosis of mature cystic teratoma with secondary malignant (PNET) transformation, i.e. the nodular focus of primitive round cells arising from the cystic teratoma did not resemble normal embryonal neural tissue, but instead displayed anaplastic features consistent with PNET, such as nuclear atypia, a high mitotic rate and Ki67 labeling index, necrosis, infiltrative edges and lymphovascular invasion. Having established the diagnosis of PNET arising in a mature teratoma, we further performed immunohistochemistry for CD99 to distinguish between cPNET and pPNET. Though histologically similar, cPNET and pPNET are different clinical entities, with different localizations, immunohistochemical profiles and genetics (Morovic and Damjanov, 2008b), and are often confused or not differentiated by authors. cPNET is an embryonal tumor deriving from the central nervous system (CNS), whereas pPNET arises outside the CNS and is grouped under the Ewing sarcoma family of tumors. pPNET expresses MIC2 glycoprotein (CD99) and shows the specific chimeric gene EWS-FLI1, which can be detected by immunohistochemical staining for CD99 (Ishii et al., 2001). Often, distinguishing between cPNET and pPNET is uncomplicated due to the location of the tumor. However, in this case, the origin of the PNET within the ovarian teratoma necessitated the performance of CD99 immunohistochemistry, and the negative staining result confirmed a cPNET. This is consistent with findings from previous studies that demonstrate that the majority of PNET transformed from testicular or ovarian germ cell tumors exhibit morphological features of central rather than peripheral PNETs (Ulbright et al., 2010). The rarity of cPNET of the ovary precludes randomized clinical study to guide the management of this disease hence the optimal treatment strategies have not been established. In general, ovarian PNET malignancies are highly aggressive and the prognosis is poor especially in the presence of extra-ovarian spread. One of the largest studies by Morovic and Damjanov (2008a) identified that disease stage appears to be the most important prognostic factor in PNET of the ovary. The majority of patients with Stage I disease (nine out of eleven cases) were alive and free of disease at a follow-up period of between three to five years. Many of the patients with Stage IA disease were treated with staging laparotomy, total hysterectomy bilateral salpingo-ophorectomy, omentectomy and pelvic/para-aortic lymphadenectomy only, whereas the Stage IC patients received chemotherapy in addition to surgery. On the other hand, women with Stage III or IV disease were often treated with surgery in combination with chemotherapy and or radiotherapy. Despite treatments, the prognoses of these women with advanced disease remained poor, the diseases were highly aggressive and rapidly gave rise to metastases and death. Fertility-preserving surgery followed by chemotherapy for early stage PNET of the ovary with successful pregnancies has been reported recently by Demirtas et al. (2004). He reported a young patient with Stage IC PNET of the ovary who was treated with unilateral salpingooophorectomy, wedge resection of the right ovary and complete pelvic and para-aortic lymphadenectomy. She received adjuvant chemotherapy consisting of bleomycin, etoposide and cisplatin (BEP protocol). Her

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Fig. 3. (A) Nodular focus of PNET arising in the mature cystic teratoma (H&E, low power). (B) Immunohistochemistry showed a very high Ki67 labeling index of approximately 90%. (C) Anaplasia and necrosis, indicative of PNET (H&E, medium power). (D) At its edges, the PNET infiltrated adjacent mature teratomatous neural tissue (H&E, medium power). (E) The PNET showed peritumoral lymphovascular invasion (H&E, medium power).

disease recurred shortly after and salvage chemotherapy with VIP protocol was administered. Seven months later, the patient was pregnant and delivered a healthy baby girl at term. Sixteen months later, the patient again delivered a healthy infant. However, the two studies by Morovic and Damjanov (2008a), and Demirtas et al. (2004) described patients with primary PNET of the ovary and not patients with malignant transformation to PNET within a mature cystic teratoma, which is the case here. The optimal chemotherapy regimen for the treatment of cPNET transformed from germ cell tumors of ovary remains unknown. Management of these cases is based on case reports and largely extrapolated from our knowledge of the transformed male germ cell testicular tumors. For PNETs that are transformed from germ cell tumors, some authors advocate the use of cisplatin-based chemotherapy, such as BEP (Bleomycin, Etoposide and Cisplatin), directed at the germ cell tumors (Demirtas et al., 2004); many other authors however felt that despite arising within germ cell tumors, PNETs are usually resistant to cisplatin-based treatment (Ganjoo et al., 2001) and therefore advocate chemotherapy regimens comprising of doxorubicin, ifosfamide and cyclophosphamide, directed at the transformed PNET component (Kleinman et al., 1993; Ehrlich et al., 2010). In one of the largest series by Ehrlich Y and colleagues, CAV/IE (Cyclophosphamide/Doxorubicin/

Vincristine alternating with Ifosfamide/Etoposide), was the treatment of choice for PNETs transformed from testicular teratoma (Ehrlich et al., 2010). Yet other authors had used integrated chemotherapy regimens that target both PNET and germ cell tumor (Al-Jumaily et al., 2012). In our case, the patient was diagnosed after an ovarian cystectomy at 14 weeks of gestation. Conventionally, a staging laparotomy followed by adjuvant chemotherapy would have been performed during pregnancy. However, the patient declined and in spite of her reluctance to undergo any form of adjuvant treatment during pregnancy or even after delivery, she has remained free of disease 2.5 years after her initial diagnosis of her cancer. Conclusion PNET of the ovary during pregnancy is a rare entity which requires a multidisciplinary team approach to optimize both maternal oncologic outcomes and fetal well-being. Pros and cons of the treatment options should be discussed with the patient in detail so as to allow her to make an informed decision about the treatment plans. In a select group of young women with early stage cPNET of the ovary, fertility-sparing treatment may be considered.

Y.K. Lim et al. / Gynecologic Oncology Reports 4 (2013) 56–59 Conflict of interest statement The authors declare that they have no competing interests.

References Al-Jumaily, Usama, Al-Hussaini, Maysa, Ajlouni, Fatenah, Abulruz, Abdulrahman, Sultan, Iyad, 2012. Ovarian germ cell tumors with rhabdomyosarcomatous components and later development of growing teratoma syndrome: a case report. J. Med. Case Rep. 6, 13. Demirtas, E., Guven, S., Guven, E.S., Baykal, C., Ayhan, A., 2004. Two successful spontaneous pregnancies in a patient with a primary primitive neuroectodermal tumor of the ovary. Fertil. Steril. 81 (3), 679–681 (Mar). Ehrlich, Y., Beck, S.D., Ulbright, T.M., Cheng, L., Brames, M.J., Andreoiu, M., Foster, R.S., Einhorn, L.H., 2010. Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor. Ann. Oncol. 21 (9), 1846–1850. Ganjoo, K.N., Foster, R.S., Michael, H., Donohue, J.P., Einhorn, L.H., 2001. Germ cell tumor associated primitive neuroectodermal tumors. J. Urol. 165, 1514–1516.

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Hinshaw, H.D., Smith, A.L., Desouki, M.M., Olawaiye, A.B., 2012. Malignant transformation of a mature cystic ovarian teratoma into thyroid carcinoma, mucinous adenocarcinoma, and strumal carcinoid: a case report and literature review. Case Rep. Obstet. Gynecol. 2012, 269489. Ishii, N., Hiraga, H., Sawamura, Y., Shinohe, Y., Nagashima, K., 2001. Alternative EWSFLI1 fusion gene and MIC2 expression in peripheral and central primitive neuroectodermal tumors. Neuropathology 21 (1), 40–44 (Mar). Kleinman, G.M., Young, R.H., Scully, R.E., 1993. Primary neuroectodermal tumors of the ovary. A report of 25 cases. Am. J. Surg. Pathol. 17 (8), 764–778 (Aug). Kovar, H., 1998. Ewing's sarcoma and peripheral primitive neuroectodermal tumors after their genetic union. Curr. Opin. Oncol. 10 (4), 334–342 (Jul). Morovic, A., Damjanov, I., 2008a. Neuroectodermal ovarian tumors: a brief overview. Histol. Histopathol. 23 (6), 765–771 (Jun). Morovic, A., Damjanov, I., 2008b. Ovarian neuroectodermal tumors — a brief overview. Histol. Histopathol. 23 (6), 765–771. Ulbright, Thomas M., Hattab, Eyas M., Zhang, Shaobo, Ehrlich, Yaron, Foster, Richard S., Einhorn, Lawrence H., Cheng, Liang, 2010. Primitive neuroectodermal tumors in patients with testicular germ cell tumors usually resemble pediatric-type central nervous system embryonal neoplasms and lack chromosome 22 rearrangements. Mod. Pathol. 23, 972–980.

Central primary primitive neuroectodermal tumor (cPNET) arising from an ovarian mature cystic teratoma in pregnancy: A case report and review of medical literature.

► This is a case of central PNET arising from a mature teratoma in the ovary in pregnancy. ► Fertility sparing surgery can be considered for early sta...
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