Human Pathology (2011) 42, 403–408
www.elsevier.com/locate/humpath
Original contribution
Ovarian ependymomas of extra-axial type or central immunophenotypes Simona Stolnicu MD, PhD a , Antonia Furtado MD b , Agostinho Sanches MD c , Alina Nicolae MD c , Ovidiu Preda MD c , Monica Hincu MD d , Francisco F. Nogales MD, PhD c,⁎ a
Department of Pathology of Universities of Targu Mures, Targu Mures, Romania Hospital de Vila Nova de Gaia, Vila Nova de Gaia, Portugal c Departamento de Anatomía Patológica, Av. de Madrid s/n, 18012 Granada, Spain d Gynecologic Hospital, Brasov, Romania b
Received 30 March 2010; revised 17 June 2010; accepted 6 July 2010
Keywords: Ovary; Ependymoma; Ectopic; Immunohistochemistry
Summary We report the differential clinicopathologic and immunophenotypical features of 2 pure ovarian ependymomas of extra-axial type with a predominant microcystic, anaplastic pattern occurring in patients aged 22 and 32 years and a unique myxopapillary pigmented ependymoma that originated within an ovarian mature cystic teratoma in a 35-year-old woman. The latter had a central nervous system phenotype different from that previously reported in ovarian ependymomas of extra-axial types, being negative for estrogen and progesterone receptors, epithelial membrane antigen and cytokeratin 34βE12, cell adhesion molecule 5.2, and cytokeratin 7. Furthermore, its benign behavior contrasted with the aggressive course of the other 2 ependymomas of extra-axial types, in which peritoneal invasion was present at the time of diagnosis. These findings illustrate that both central and extra-axial types of ependymoma show phenotypic variations that may point to either a derivation from different precursors or differentiation along diverse pathways. Thus, whereas ependymomas of extra-axial types would represent neometaplastic phenomena, those originated from the nervous tissue of teratomas resemble central nervous system ependymomas. Moreover, the dissimilarities between central and peripheral types of ependymoma would parallel the phenotypic differences present in primitive neural tumors of the female genital tract. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Ependymomas usually arise in the central nervous system, but they can also occur in various extra-axial locations [1]. They are found rarely only in the female ⁎ Corresponding author. E-mail address:
[email protected] (F. F. Nogales). 0046-8177/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2010.07.017
genital tract; to date, only 16 cases have been reported in the ovary [1-17] and 3 [18,19] in the broad ligament, and none of these cases originated unequivocally from a preexistent mature teratoma. Because of their highly variable histology, ovarian ependymomas may often cause diagnostic errors because they may have papillary areas with psammoma bodies, pseudofollicles, trabeculae, microcysts, and other that may resemble unrelated ovarian tumors such as struma ovarii,
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granulosa cell, Sertoli-Leydig cell, serous, and wolffian tumors. In this article, we report the differential clinicopathologic and immunophenotypical features of 2 pure ovarian ependymomas of extra-axial type (EEATs) and, for the first time, a unique myxopapillary pigmented ependymoma that developed within an ovarian cystic teratoma. The latter had a central nervous system phenotype different from that previously reported in ovarian EEATs. These findings would confirm that both central and extra-axial types of ependymoma show differences that may point to either a derivation from different precursors or differentiation along different pathways [1]. The dissimilarities between central and peripheral types of ependymoma would parallel the phenotypic differences present in primitive neural tumors of the female genital tract.
2. Materials and methods Three cases of ovarian ependymoma sent for consultation to one of the authors (F.F.N.) were reviewed together with the clinical and follow-up data of the patients. The number of available samples ranged from 8 blocks in case 3 to 20 blocks in case 1. Immunohistochemistry, using Dako Envision system, Dako, Denmark, was performed in routine formalinfixed material with antibodies directed against the following antigens (Table 1): glial fibrillary acidic protein (GFAP), estrogen receptor (ER), progesterone receptor (PR), CD99, cytokeratin 34βE12 (CK34βE12), cytokeratin 18 (CK18), cell adhesion molecule (CAM) 5.2, cytokeratin 7 (CK7), epithelial membrane antigen (EMA), neuron-specific enolase (NSE), S-100 protein (S-100), vimentin, Ki-67, chromogranin, cytokeratin 20, α-inhibin, cancer antigen 125 (CA125), thyroglobulin and thyroid transcription factor 1 (TTF-1), and HMB-45, all provided by Dako, Spain.
Table 1
Immunohistochemical analysis
Antibody
Clone
Case 1
Case 2
Case 3
GFAP ER PR CD99 CK34βE12 CK18 CAM5.2 CK7 EMA NSE S-100 Vimentin Ki-67
6F2 SP1 SP2 HO36-1.1 34βE12 DC10 CAM5.2 Ovtl 12/30 E29 E27 4C4.9 V9 Polyclonal
+++ +++ +++ + + ++ + + + ++ + +++ Index 20%
+++ +++ +++ − + ++ + ++ + ++ + +++ Index 50%
++ − − − − + − − − ++ + +++ Index 20%
3. Results 3.1. Clinical data 3.1.1. Case 1 A 32-year-old nulliparous patient was admitted with pelvic pain and elevated (94.3U/mL) serum CA125. Ultrasound revealed a massive solid pelvic tumor, and laparotomy exposed a right 15-cm International Federation of Gynecology and Obstetrics (FIGO) stage IIIB ovarian tumor. A left salpingooophorectomy was performed, and multiple pelvic nodules were sampled. Postoperatively, she was treated with 6 cycles of combination chemotherapy containing cisplatin and etoposide. Eight months later, second-look surgery showed large residual pelvic masses that involved the remaining left ovary, uterus, urinary bladder, and sigmoid colon. The patient underwent a total abdominal hysterectomy with left salpingo-oophorectomy, omentectomy, urinary bladder and distal large bowel resection, and regional lymphadenectomy. After further chemotherapy, the patient is alive and well without recurrence 3 years after the initial diagnosis. 3.1.2. Case 2 A 22-year-old woman presented with a painful pelvic mass. Laparotomy revealed a right 14-cm FIGO stage IIIA ovarian mass with a ruptured capsule. Right salpingooophorectomy, omental resection, and appendectomy were performed, and postoperatively, she underwent chemotherapy with carboplatin and etoposide. One year later, she had a pelvic recurrence that was treated with tumor resection and further chemotherapy. Two and a half years after the initial diagnosis, the patient is alive, but the tumor is still present. 3.1.3. Case 3 A 35-year-old woman presented with menometrorrhagia. Ultrasound revealed bilateral 5- and 7-cm ovarian tumors consistent with benign cystic teratomas. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, and adjuvant chemotherapy. She remained well without evidence of disease for 14 years until a stage III colonic carcinoma was diagnosed, and she died 2 years later because of complications of her intestinal cancer.
3.2. Pathology 3.2.1. Macroscopy Cases 1 and 2 were bulky tumors measuring 15 and 14 cm in diameter. They were white-yellow and solid with minor cystic areas and had multiple foci of necrosis and hemorrhage. Peritoneal metastatic deposits had a similar appearance. In case 3, cystic teratomas were found in both ovaries, and on the left, a 4-cm white uniform, translucent mural nodule without necrosis or hemorrhage occurred next to the sebum-filled cavity of the teratoma (Fig. 1).
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Fig. 1 Case 3. Mature cystic teratoma of left ovary (right) is separated by a septum (arrows) harboring a solid, translucent mural nodule (left).
3.2.2. Microscopy These cases had a heterogeneous histology. Cases 1 and 2 exhibited a predominantly cystic growth with spaces filled with an eosinophilic proteinaceous fluid (Fig. 2A). Cysts of varying sizes (Fig. 2B) were lined with cuboidal cells that merged with solid sheets of predominantly clear, oligodendroglial-like cells with occasional lipidization, moderate to marked atypicality, and frequent mitoses. Neoplastic cells had evident nuclear grooves. Some areas showed characteristic perivascular pseudorossettes, “balloons” (Fig. 2C), and a gliovascular arrangement (Fig. 2D). Ependymal rosettes
were rarely seen. As a secondary pattern, cases 1 and 2 revealed well-formed papillae with fibrovascular cores and a ciliated columnar lining with prominent fibrillary cytoplasm. Papillae projected into cystic spaces (Fig. 2E) that resembled the fronds of the fallopian tube in case 1, but in contrast, in case 2, they were short, branching, and hyalinized with many psammoma bodies (Fig. 2F). Vessels had endothelial and adventitial proliferation often associated with focal necrosis and hemorrhage. The peritoneal and omental metastases in cases 1 and 2 had lost their cystic and papillary components and were composed of clear, anaplastic-type cells. Case 3 had a substantially different histology, similar to that of ependymomas of the cauda equina. A mature cystic teratoma, with the usual cutaneous and nervous tissue structures, merged (Fig. 3A) with a distinct, predominant myxopapillary, growth that showed papillae and a mucoid perivascular matrix (Fig. 3B) as well as some trabecular areas. Melanin pigmentation was prominent throughout and was present in the cytoplasm of tumor cells (Fig. 3C). Clinicopathologic findings are summarized in Table 2. 3.2.3. Immunohistochemistry A common feature in all 3 cases was a strong positivity to GFAP, NSE, S-100, and vimentin. However, case 3 had a substantially different immunophenotype from cases 1 and 2. Although the latter 2 cases had diffused nuclear positivity for ER and PR and cytoplasmic positivity in the lining of microcysts for CK34βE12, CK18, CAM5.2, CK7, and EMA, case 3 was consistently negative for these antibodies. CD99
A
B
C
D
E
F
Fig. 2 Histologic patterns of extra-axial ependymomas. Microcystic areas with proteinaceous fluid (case 1) (A) simulate thyroid tissue and wolffian adnexal tumor (case 2) (B). Characteristic balloons (C) and gliovascular arrangements (D) from case 1. Complex papillary growth (E) resembles the fimbriae of the fallopian tube, whereas fine papillae with psammoma bodies (F) mimic an ovarian serous neoplasm.
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A
B
C
Fig. 3 Case 3. A, Interface between fat and sebaceous glands of mature teratoma (left) and ependymoma (right) showing a myxopapillary growth (B) and marked intracellular melanin pigmentation (C).
was only focally positive in case 1, and NSE was strongly positive in the clear cells of the primary and metastases of cases 1 and 2. Case 3 was also positive for HMB-45 in melanin-producing cells. All cases were negative for chromogranin, cytokeratin 20, α-inhibin, CA125, thyroglobulin, and TTF-1. Ki-67 index ranged from 10% to 50%, being higher in solid areas and metastases. Immunopathologic findings are summarized in Table 1. Table 2
Clinicopathologic features Age (y)
Association
Initial diagnoses
Treatment
Histologic patterns
Stage
Follow-up
1
32
Pure
Malignant struma ovarii Juvenile granulosa cell tumor
LSO and omentectomy Chemotherapy
IIIB
3 y, alive and recurrence free
2
22
Pure
Papillary serous carcinoma Wolffian adnexal tumor
RSO and omentectomy Chemotherapy
IIIA
2 1/2 y, alive with disease
3
35
Bilateral mature cystic teratoma
Pigmented neuroectodermal tumor
TAH-BSO and lymphadenectomy Chemotherapy
Predominant: macrocystic and microcystic Secondary: solid and papillary Predominant: microcystic and macrocystic Secondary: solid and papillary with psammoma bodies Predominant: myxopapillary Secondary: microcystic and trabecular
IA
No recurrence in 14 y
Abbreviations: LSO, left salpingo-oophorectomy; RSO, right salpingo-oophorectomy; BSO, bilateral salpingo-oophorectomy.
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4. Discussion The 19 cases previously reported in the literature were all pure ependymomas and were found in patients ranging from ages 13 to 76 years, with an average of 34 years [1-19]. Tumors were large and solid and often appeared as nodular masses within a cystic cavity. All described histologic patterns of central nervous system ependymoma were found, although only 1 case [19] had a myxopapillary pattern. Although ovarian and broad ligament ependymomas are histologically indistinguishable from central nervous system ones [2], they display a wider spectrum of admixtures of morphologic patterns including macrocystic, microcystic, papillary, follicular, solid, cribriform, glandular, and trabecular ones. This variability leads to differential diagnoses with various ovarian and adnexal tumors such as serous papillary, juvenile granulosa cell, adnexal wolffian tumors, and even, as in 2 of our cases, with malignant struma ovarii and pigmented neuroectodermal tumor. However, the characteristics of ependymoma, such as rossettes, fibrillary cytoplasm, and gliovascular arrangement as well as a strong GFAP positivity and negativity for specific markers such as TTF-1, thyroglobulin, and α-inhibin, were present in all cases and led to the correct diagnosis. A recent comparative immmunohistochemical study between central nervous system ependymomas and EEATs [1] revealed marked phenotypic differences among them. EEATs were positive for ER and PR and showed a complex pattern of expression of CAM5.2, CK7, CK34βE12, and EMA that is absent or minimally represented in central nervous system ependymomas. We present 3 further cases of ependymomas of the ovary and broad ligament in which evident morphologic differences were found between the 2 cases corresponding to EEATs and the 1 arising in a mature cystic teratoma. No cases of ependymomas of the female genital tract arising from the tissues of mature teratoma have previously been reported. Two cases were associated only with contralateral teratomas [5,10], and although areas of cartilage were present in 2 further tumors [16,18], no complex admixture of tissues that characterize teratoma was found. The presence of cartilage alone is not proof of an origin from a teratoma because it is known that central nervous system ependymomas can also show foci of heterologous cartilage and bone [20]. Our case of teratoma-associated ependymoma presented a myxopapillary pattern of the type usually found in the cauda equina, conus medullaris, and filum terminale areas as well as in ependymomas originated from sacrococcigeal or sacral teratomas [19] and, in addition, had extensive melanotic pigmentation, which is a feature, albeit an unusual one, of central ependymomas, but never described in EEAT [20,21]. These findings suggest the existence of 2 distinct types of ependymoma, each with a different histogenesis, indicating perhaps either a derivation from distinct precursors or a
407 differentiation along different pathways [1]. Ovarian ependymomas have been considered either to have a germ cell origin or to result from neometaplastic differentiation [9]. Only case 3 would support an unequivocal germ cell origin because it was derived from teratoid tissues, whereas our other 2 cases may have occurred de novo and, consequently, would probably represent examples of neometaplasia. In support of this hypothesis, it is known that various patterns of nonteratoid central nervous system tumors such as astrocytoma, glioblastoma, and other also occur in the female genital tract and are considered examples of neometaplasia [22,23]. The different behavior of EEATs and teratoma-derived tumors would be a further manifestation of their distinct origins. In the present cases, the putative neometaplastic tumors were clearly malignant, whereas that originating from teratoma behaved in a nonaggressive fashion [1,20]. These 2 different origins are also considered in primitive neural tumors of the female genital tract, based on the different expression of the Ewing's sarcoma (EWS) translocation. The cases where the translocation is absent would represent a central type of tumor, whereas the cases in which it is present would correspond to the peripheral type [21]. In summary, we believe that female genital ependymomas can have different origins and histogenesis that would be reflected in varying morphologies, immunophenotypes, and behaviors. Although rare, their presence must be borne in mind when considering the differential diagnoses of ovarian tumors.
Acknowledgments The authors thank Dr Aurelio Ariza, neuropathologist from Hospital Germans Trias, Badalona, Spain, for his help.
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