Case 4 -

Primitive Neuroectodermal Tumor of the Ovary. Jaime Prat Professor and Chairman of Pathology Hospital de la Santa Creu i Sant Pau Autonomous University of Barcelona, Spain

Clinical History: A 22 year-old woman was admitted to the hospital emergency room because of abdominal pain and swelling. Two months prior to admission she underwent a D&C for retained POC of about 9 weeks of gestational age. At that time pelvic examination was unremarkable. Subsequently, she developed massive abdominal enlargement and pain over a two months period. Abdominal examination revealed a large mobile mass in the left lower quadrant that extended up to 2 cm below the umbilicus. A CT scan showed a cystic and solid heterogeneous tumor (18 x 17 x 14 cm). Serum levels, CA19.9: 100 KU/l (normal range <37); CA125:192 KU/l (normal range <35); b-hCG: 2.2 UI/l; CEA and a-FP were normal. At laparotomy there was a large cystic and solid left ovarian tumor with ruptured capsule (3.5 cm). A left salpingooophorectomy, biopsy of the contralateral ovary and appendectomy were performed. Case 4 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis: Primitive neuroectodermal tumor of the ovary. Gross features: Unilateral ovarian tumor, 21 cm in greatest diameter (1,280 g). Cystic and solid. Solid component with hemorrhage and necrosis (malignant appearance). Capsular rupture, 3.5 cm. Unremarkable Fallopian tube. Microscopic features: Hypercellularity (high grade malignant tumor). Extensive necrosis. Patternless sheets or lobules separated by fibrous septa. Closely packed small cells with hyperchromatic round to oval nuclei. Occasional rhabdoid cells. Vesicular nuclei with prominent nucleoli. Scanty/abundant, clear/eosinophilic cytoplasms. High mitotic rate (> 10/10 HPF). Homer Wright rosettes and ribbons (resembling medulloblastoma or neuroblastoma). Follicle-like spaces (resembling small cell carcinoma or juvenile granulosa cell tumor). Microscopic foci of endodermal-like ciliated mucosecretory glands (teratomatous nature). Ascitic fluid negative for malignant cells (Stage Ic). NB. The microscopic features were reminiscent of those of PNET found in the CNS of children. Immunohistochemical findings: The following immunostains were positive: neuron-specific enolase (NSE), synaptophysin, neurofilament protein, and CD99. The following stains were negative: Cytokeratin CAM 5.2, EMA, S100 protein, and chromogranin. Alpha-inhibin was only positive in the luteinized stromal cells. Follow-up: Postoperatively the patient was given four cycles of chemotherapy (platinum and etoposide). Five months later a CT scan revealed recurrent tumor (3.0 cm) in the anterior abdominal wall, above the bladder, and retroperitoneal lymph node metastases (3.0 cm). Discussion Primitive neuroectodermal tumors (PNET) of the ovary are rare. Following the original 1982 description by Aguirre and Scully, less than 50 cases have been reported. These tumors are considered monodermal teratomas composed exclusively or almost exclusively of neuroectodermal tissue resembling CNS neoplasms of children. The average age of the patients was 23 years and the presenting symptoms were similar to those of other cancers of the ovary. Like almost all immature teratomas of the ovary all tumors were unilateral. On gross examination they ranged from 4 to 20 (average 14) cm in diameter and appeared cystic and solid. On microscopic examination all tumors contained masses of poorly differentiated small cells exhibiting slight to marked nuclear pleomorphism. Necrosis was common and peripheral pseudopalisading of the tumor cells similar to that of glioblastoma multiforme was seen. Most tumors contained areas of medulloepithelioma, neuroblastoma, ependymoblastoma, and medulloblastoma. The tumors may be associated with mature cystic teratomas (dermoid cysts) or teratomatous elements may be encountered in small amounts such as in the case under discussion. Although clearly of germ cell origin, PNETs should be classified according to Aguirre and Scully separately from immature teratomas with predominant immature neuroectodermal components (Grade III teratomas) and for two main reasons: a) Ovarian PNETs represent a distinctive form of monodermal teratoma in which the neoplastic tissues do not resemble stages of embryonic development of the CNS. b) Whereas the immature teratoma with predominant neuroectodermal differentiation is easily recognized because of the presence of many other teratomatous elements, the pure or almost pure neuroectodermal tumor is frequently confused with other types of ovarian tumors such as granulosa cell tumor, small cell carcinoma of the hypercalcemic type, and endometrioid carcinoma. When one considers the frequency with which tissue of neural type is encountered within teratomas it is not surprising that occasionally pure neural tumors similar to those found in the central nervous system occur in the ovary. Several cases of pure ependymoma arising in the ovary have also been reported. The presence of the Homer Wright rosettes are helpful in the diagnosis of PNET. In the absence of rosettes and ribbons, PNETs may be erroneously taken for small cell malignant tumors of other type, including malignant lymphoma and leukemia, rhabdomyosarcoma, small cell carcinoma associated with hypercalcemia, desmoplastic small round cell tumor, granulosa cell tumor, endometrial stromal sarcoma, and metastatic melanoma and small cell carcinoma of lung. In the case under discussion, the presence of follicle-like spaces initially suggested the diagnosis of small cell carcinoma or juvenile granulosa cell tumor. Immunohistochemistry may be helpful in the differential diagnosis: PNETs are positive for GFAP, synaptophysin, neurofilament protein, vimentin, NSE, and CD99. Cytokeratin and desmin are negative. Alpha-inhibin is helpful in the differential diagnosis with granulosa cell and sex cord-stromal tumors. In the current case only the luteinized stromal cells were decorated by the immunoreaction but the tumor cells appeared negative. Neuroblastoma of adrenal or extra-adrenal origin metastasizes to the ovary in about 25% of the autopsy cases. The tumors are usually bilateral and are not associated with teratomatous elements. Some of the reported neuroblastomas of the ovary are grade 3 immature teratomas. The tumor under discussion was interpreted as a PNET of the CNS associated with teratoma; in other words, a monodermal teratoma of germ cell origin. Recently, an ovarian PNET of the peripheral type (PNET/Ewing's sarcoma family) has been reported. In contrast to the CNS type, pPNET exhibits the characteristic translocation t(11;22)(q24;q12) and expresses EWS/FLI-1 chimeric mRNA which could not be detected in the current case. However, CD99, stated to be negative in PNET of the CNS, resulted positive in the seminar case. The pathologist dealing with difficult problems in the differential diagnosis of malignant ovarian tumors, particularly in young patients, should be aware of the existence of malignant neuroectodermal tumors of various types. An identical tumor has been described in the testis. Although these tumors are rare and the largest reported series was mainly composed of consultation cases (and different treatments were administered to these patients) it appears that these neoplasms do not respond to the chemotherapy used for non seminomatous germ cell tumors (vinblastine, bleomycin and platinum). In the current case, para-aortic and pelvic recurrence occurred only 5 months after administration of chemotherapy. References Aguirre P, Scully R.E. Malignant neuroectodermal tumor of the ovary, a distinctive form of monodermal teratoma. Report of five cases. Am J Surg Pathol 1982; 6:283-292. Kanbour-Shakir A, Sawady J, Kanbour AI, et al. Primitive neuroectodermal tumor arising in an ovarian mature cystic teratoma: immunohistochemical and electron microscopic studies. Int J Gynecol Pathol 1993; 12:270-275. Kawauchi S, Fukuda T, Miyamoto S, et al. Peripheral primitive neuroectodermal tumor of the ovary confirmed by CD99 immunostaining, karyotypic analysis, and RT-PCR for EWS/FLI-1 chimeric mRNA. Am J Surg Pathol 1998; 22:1417-1422. Kleinman GM, Young RH, Scully RE. Primary neuroectodermal tumors of the ovary. A report of 25 cases. Am J Surg Pathol 1993; 17:764-778. Scully RE, Young RH and Clement PB. Tumors of the ovary, maldeveloped gonads, fallopian tube, and broad ligament. In Atlas of Tumor Pathology, third series. Fascicle 23. Washington, D.C. Armed Forces Institute of Pathology, 1998; pp300-303.