Gynecologic Oncology Reports 4 (2013) 56–59

Contents lists available at SciVerse ScienceDirect

Gynecologic Oncology Reports

j ourna l homepage: www.e lsev ie r .com/ locate /gynor

Case Report

Central primary primitive neuroectodermal tumor (cPNET) arisingfrom an ovarian mature cystic teratoma in pregnancy: A case reportand 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, Singaporeb Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singaporec KK Women's and Children's Hospital, Department of Pathology and Laboratory Medicine, 100 Bukit Timah Road, Singapore 229899, Singapored KK Women's and Children's Hospital, Division of Obstetrics and Gynaecology, 100 Bukit Timah Road, Singapore 229899, Singapore

a r t i c l e i n f o

Article history:Received 21 November 2012Accepted 11 January 2013Available online 23 January 2013

Keywords:Primitive neuroectodermal tumorOvaryChemotherapyPregnancy

Introduction

Primary primitive neuroectodermal tumor (PNET) of the ovary isa rare entity. PNETs may be classified under 2 broad categories withdiffering clinical characteristics, immunohistochemical profiles andgenetics: (i) central PNET (cPNET) and (ii) peripheral PNET (pPNET).PNETs in general are aggressive cancers associatedwith a highmortality(Kovar, 1998). We present a case of a patient diagnosed with cPNETarising from a mature cystic teratoma during pregnancy, managedwith fertility-preserving surgery.

Case report

A 27 year old nulliparous Chinesewoman presented to her obstetri-cian at 12 weeks of gestation. Ultrasound showed a left triloculated cystmeasuring 8.9×7 cmand serum tumormarkers (CA-125, CEA and AFP)were normal. She underwent an open ovarian cystectomy at 14 weeksof gestation in June 2009. Therewas an iatrogenic capsular rupture dur-ing the cystectomy.

Gross examination of the resected ovarian cyst revealed loculescontaining sebaceous material and hairs (Fig. 1). The largest loculeshowed a mural nodule measuring 8×5×3 cm, with adipose, cartilagi-nous and bony areas. Histological examination of the ovarian cyst

⁎ Corresponding author.E-mail address: Timothy.lim.yk@kkh.com.sg (Y.K. Lim).

2211-338X © 2013 Elsevier Inc.http://dx.doi.org/10.1016/j.gynor.2013.01.004

Open access under CC BY-NC-ND license.

revealed a mature cystic teratoma comprising skin, adipose, gastroin-testinal tract, respiratory tract, cartilage, lamellar bone, hematopoieticand neural tissue (Fig. 2). However, the mural nodule from the largestlocule showed an area of malignant transformation, comprising a nod-ular focus of PNET measuring 7 mm in greatest dimension (Fig. 3A).The PNET was composed of sheets of primitive round cells with highnuclear-cytoplasmic ratio, frequent mitoses and focal necrosis, set in afinely fibrillary background (Fig. 3B and C). At its edges, the PNETshowed infiltration into surroundingmature teratomatousneural tissue(Fig. 3D). Several adjacent foci of lymphovascular invasionwere also seen(Fig. 3E). Immunohistochemical studies demonstrated within the PNETexpression of neural markers chromogranin A and synaptophysin, and aKi67 labeling index of 90% (Fig. 3B). There was absence of immunoreac-tivity for CD99, indicating that the tumor was a central-type PNET.

Chest X-ray (abdominal shielding) andMRI of the abdomen and pel-vis did not reveal any distantmetastases. She had at least a FIGOStage ICcPNET of the ovary (T1c NX M0). Subsequently, she was managed by amultidisciplinary team comprising of a gynecologic oncologist, a medi-cal oncologist, as well as a maternal fetal medicine specialist.

In viewof the lymphovascular space invasion andhigh risk ofmetas-tases, coupled with the highly aggressive nature of cPNET, the patientwas counseled for staging surgery and the pros and cons of chemother-apy were also discussed. However, she declined further surgery andchemotherapy during pregnancy. Shewas followed up closely through-out pregnancy, which remained largely uneventful. She delivered ahealthy baby boy at 37 weeks of gestation via an elective lower seg-ment cesarean section (LSCS), with a birth weight of 2925 g. At thesame time, she underwent a left salpingo-oophorectomy, left pelviclymph node sampling, omentectomy and peritoneal washing for stag-ing. She had opted for a fertility sparing surgery instead of a full stagingsurgery. Intra-operatively, the left ovary was slightly nodular, but theright ovary appeared normal. There was no enlarged retroperitoneallymphadenopathy or peritoneal disease. Histological examination ofthe remnant left ovary did not show any residual disease, and the leftpelvic lymph nodes, omentum and peritoneal washing were all nega-tive for malignancy. The patient was then counseled for adjuvant che-motherapy after her delivery in view of the aggressive nature ofcPNET and evidence of lymphovascular invasion on histology. However,she declined any further treatment, and was given regular follow-up inthe gynecologic oncology clinic.

Fig. 1. Gross specimen of resected ovarian cyst.

57Y.K. Lim et al. / Gynecologic Oncology Reports 4 (2013) 56–59

Half a year later, the patient became pregnant with her secondchild in July 2010. She was well antenatally. She delivered her secondchild by elective LSCS, with a birth weight of 3438 g. She continuedto be on regular follow up in our hospital, with no cancer relapse2.5 years after her diagnosis.

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

Discussion

The incidence of ovarian cysts during pregnancy varies from 1 in100 to 1 in 2000 pregnancies and malignant ovarian tumors are rela-tively uncommon.

The primary diagnostic challenge in this case involved dis-tinguishing between an immature teratoma with only a minor focusof immature neuroepithelial elements, versus a mature teratomawith focal secondary malignant (PNET) transformation. The risk ofmalignant transformation develops in about 0.17 to 2% of maturecystic teratomas, and occurs most often in postmenopausal women(Hinshaw et al., 2012). Malignant neural tumors arising in maturecystic teratomas are rare, and those reported in young women usuallybut not always represent immature teratomas that characteristicallycontain immature neuroepithelial elements. Nonetheless, in thiscase, the following features indicated the diagnosis of mature cysticteratoma with secondary malignant (PNET) transformation, i.e. thenodular focus of primitive round cells arising from the cystic teratomadid not resemble normal embryonal neural tissue, but instead displayedanaplastic features consistent with PNET, such as nuclear atypia, a highmitotic rate and Ki67 labeling index, necrosis, infiltrative edges andlymphovascular invasion. Having established the diagnosis of PNETarising in amature teratoma,we further performed immunohistochem-istry for CD99 to distinguish between cPNET and pPNET. Though histo-logically similar, cPNET and pPNET are different clinical entities, withdifferent localizations, immunohistochemical profiles and genetics(Morovic and Damjanov, 2008b), and are often confused or not differ-entiated by authors. cPNET is an embryonal tumor deriving from thecentral nervous system (CNS), whereas pPNET arises outside the CNSand is grouped under the Ewing sarcoma family of tumors. pPNET ex-presses MIC2 glycoprotein (CD99) and shows the specific chimericgene EWS-FLI1, which can be detected by immunohistochemicalstaining for CD99 (Ishii et al., 2001). Often, distinguishing betweencPNET and pPNET is uncomplicated due to the location of the tumor.However, in this case, the origin of the PNETwithin the ovarian teratomanecessitated the performance of CD99 immunohistochemistry, and thenegative staining result confirmed a cPNET. This is consistent with find-ings from previous studies that demonstrate that the majority of PNETtransformed from testicular or ovarian germ cell tumors exhibit mor-phological features of central rather than peripheral PNETs (Ulbright etal., 2010).

The rarity of cPNET of the ovary precludes randomized clinical studyto guide the management of this disease hence the optimal treatmentstrategies have not been established. In general, ovarian PNET malig-nancies are highly aggressive and the prognosis is poor especially inthe presence of extra-ovarian spread. One of the largest studies byMorovic and Damjanov (2008a) identified that disease stage appearsto be themost important prognostic factor in PNET of the ovary. Thema-jority of patients with Stage I disease (nine out of eleven cases) werealive and free of disease at a follow-up period of between three to fiveyears.Many of the patientswith Stage IA diseasewere treatedwith stag-ing laparotomy, total hysterectomy bilateral salpingo-ophorectomy,omentectomy and pelvic/para-aortic lymphadenectomy only, whereasthe Stage IC patients received chemotherapy in addition to surgery. Onthe other hand, women with Stage III or IV disease were often treatedwith surgery in combination with chemotherapy and or radiotherapy.Despite treatments, the prognoses of these women with advanced dis-ease remained poor, the diseases were highly aggressive and rapidlygave rise to metastases and death.

Fertility-preserving surgery followed by chemotherapy for earlystage PNET of the ovary with successful pregnancies has been reportedrecently by Demirtas et al. (2004). He reported a young patient withStage IC PNET of the ovary who was treated with unilateral salpingo-oophorectomy, wedge resection of the right ovary and complete pelvicand para-aortic lymphadenectomy. She received adjuvant chemothera-py consisting of bleomycin, etoposide and cisplatin (BEP protocol). Her

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) ThePNET showed peritumoral lymphovascular invasion (H&E, medium power).

58 Y.K. Lim et al. / Gynecologic Oncology Reports 4 (2013) 56–59

disease recurred shortly after and salvage chemotherapy with VIP pro-tocol was administered. Seven months later, the patient was pregnantand delivered a healthy baby girl at term. Sixteen months later, thepatient again delivered a healthy infant. However, the two studies byMorovic and Damjanov (2008a), and Demirtas et al. (2004) describedpatients with primary PNET of the ovary and not patients with malig-nant transformation to PNET within a mature cystic teratoma, whichis the case here.

The optimal chemotherapy regimen for the treatment of cPNETtransformed from germ cell tumors of ovary remains unknown. Man-agement of these cases is based on case reports and largely extrapolatedfrom our knowledge of the transformed male germ cell testiculartumors. For PNETs that are transformed from germ cell tumors, someauthors advocate the use of cisplatin-based chemotherapy, such asBEP (Bleomycin, Etoposide and Cisplatin), directed at the germ celltumors (Demirtas et al., 2004); many other authors however felt thatdespite arising within germ cell tumors, PNETs are usually resistant tocisplatin-based treatment (Ganjoo et al., 2001) and therefore advocatechemotherapy regimens comprising of doxorubicin, ifosfamide andcyclophosphamide, directed at the transformed PNET component(Kleinman et al., 1993; Ehrlich et al., 2010). In one of the largest seriesby Ehrlich Y and colleagues, CAV/IE (Cyclophosphamide/Doxorubicin/

Vincristine alternating with Ifosfamide/Etoposide), was the treatmentof choice for PNETs transformed from testicular teratoma (Ehrlich etal., 2010). Yet other authors had used integrated chemotherapy regi-mens that target both PNET and germ cell tumor (Al-Jumaily et al.,2012).

In our case, the patientwas diagnosed after an ovarian cystectomy at14 weeks of gestation. Conventionally, a staging laparotomy followedby adjuvant chemotherapy would have been performed during preg-nancy. However, the patient declined and in spite of her reluctance toundergo any form of adjuvant treatment during pregnancy or evenafter delivery, she has remained free of disease 2.5 years after her initialdiagnosis of her cancer.

Conclusion

PNET of the ovary during pregnancy is a rare entity which requiresa multidisciplinary team approach to optimize both maternal onco-logic outcomes and fetal well-being. Pros and cons of the treatmentoptions should be discussed with the patient in detail so as to allowher to make an informed decision about the treatment plans. In a se-lect group of young women with early stage cPNET of the ovary,fertility-sparing treatment may be considered.

59Y.K. Lim et al. / Gynecologic Oncology Reports 4 (2013) 56–59

Conflict of interest statementThe 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 componentsand later development of growing teratoma syndrome: a case report. J. Med. CaseRep. 6, 13.

Demirtas, E., Guven, S., Guven, E.S., Baykal, C., Ayhan, A., 2004. Two successful sponta-neous pregnancies in a patient with a primary primitive neuroectodermal tumor ofthe 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 toprimitive neuroectodermal tumor. Ann. Oncol. 21 (9), 1846–1850.

Ganjoo, K.N., Foster, R.S., Michael, H., Donohue, J.P., Einhorn, L.H., 2001. Germ celltumor associated primitive neuroectodermal tumors. J. Urol. 165, 1514–1516.

Hinshaw, H.D., Smith, A.L., Desouki, M.M., Olawaiye, A.B., 2012. Malignant transformationof a mature cystic ovarian teratoma into thyroid carcinoma, mucinous adenocarcino-ma, 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 EWS-FLI1 fusion gene and MIC2 expression in peripheral and central primitiveneuroectodermal tumors. Neuropathology 21 (1), 40–44 (Mar).

Kleinman, G.M., Young, R.H., Scully, R.E., 1993. Primary neuroectodermal tumors of theovary. A report of 25 cases. Am. J. Surg. Pathol. 17 (8), 764–778 (Aug).

Kovar, H., 1998. Ewing's sarcoma and peripheral primitive neuroectodermal tumorsafter 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 inpatients with testicular germ cell tumors usually resemble pediatric-type centralnervous system embryonal neoplasms and lack chromosome 22 rearrangements.Mod. Pathol. 23, 972–980.