Abstract
Introduction: Ependymomas are glial neoplasms that arise at or close to the inner ependymal surface of the ventricular system. They are most frequently located intraventricularly, but they may also occur in the spinal cord or, very seldom, at extraneural sites. Here we report a case of an ectopic ependymoma, arising in the pelvic cavity. Case Report: A 35 year-old female patient was diagnosed with a suspect tumor mass in the rectovaginal space, infiltrating the perirectal adipose tissue and the vagina. Three years later, liver and peritoneal metastases of the same tumor were diagnosed. Two years after that, the patient experienced a recidive in the left adnexa. Histological analysis revealed an anaplastic tumor of dual nature, comprising of mesenchymal and epithelial features. There were ependymoma-like rosettes and pseudorosettes, indicating an ependymal differentiation. Immunohistochemically, the tumor was positive for epithelial membrane antigen (EMA) and glial fibrillary acidic protein (GFAP). Accordingly, the diagnosis “grade 3 ependymoma, i.e. ependymoblastoma” was made. Review: Ependymomas are most frequently located in the ventricular system, but may also occur in the spinal cord or rarely at extraneural sites. Extraneural ependymomas represent a diagnostic challenge, since they can mimic other tumor types and the immunohistochemical profile may be non-specific. The most important features of ependymal differentiation are rosette- or pseudorosette formation. Extraneural ependymomas can be located in the ovary or elsewhere in the pelvic cavity. Locations in the lung, liver and the small bowel have also been described. In the present article we review several reported cases of ectopic, extraneural ependymomas. Discussion: The origin of extraneural ependymomas is not completely clarified. They probably arise from glial tissue that is a residue from the embryonic development, pinched-off from the neural tube during its closure. We propose, that extraneural ependymoma should be considered in differential diagnosis for anaplastic tumors of the pelvic cavity.
Ependymomas are glial neoplasms that arise at or close to the inner ependymal surface of the ventricular system. They are most frequently located intraventricularly with the fourth ventricle being the most common localization, but they may also occur in the spinal cord or, very seldom, at extraneural sites (1). They can also occur at an intradural, extramedullary location in the spine, which is also very rare (2). There have been case reports about ependymomas occurring at extraneural sites, namely in the lung, ovary and mesoovarium, in the broad ligament and in the subcutaneous tissue in the sacrococcygeal region (3-5).
Presently we report a case of an ectopic ependymoma, arising in the pelvic cavity.
Case Report
A 35 year-old female patient was diagnosed with a suspect tumor mass close to the left adnexa measuring 10×7×9 cm. The diagnosis was made by computer tomography (CT). A laparotomy was performed and the tumor was removed. The tumor mass infiltrated the whole rectovaginal space, but was not directly linked to the rectum, vagina, uterus or adnexa. Since the tumor infiltrated nearly the entire rectovaginal space, excision of the rectum was performed. Local metastases were found in the peri-rectal adipose tissue, but without direct infiltration of the rectum. Furthermore, the vagina was infiltrated by tumor tissue. The histological analysis was very difficult, and therefore the tumor was primarily termed “unclassified malignant neoplasm”. Three years later, liver metastases of the same cancer were observed, and the peritoneum was also focally infiltrated. After a further two years, a new tumor mass in the left adnexa was detected and consequently, left-side adnexectomy followed. At that time it was uncertain whether the tumor was a relapse of the unclassified primary tumor or if it was primary cancer of the ovary or tube. The histological analysis clarified, however, that this tumor was actually a relapse of the primary tumor. Figure 1 illustrates the macroscopic appearance of the recidive tumor.
Macroscopic appearance of the recidive tumor in the adnexa. A: Tumor as a whole. B: Cut surface.
Hematoxylin & eosin (H&E) staining of the ependymoblastoma in the ovary, featuring rosettes and pseudorosettes. Magnifications: A: 10×; B: 20×; C: 40×; D: 60×.
Currently, the patient is alive and in close meshed follow-up investigations at a gynecology clinic. The patient is undergoing further chemotherapy cycles to prolong the time interval to the next relapse, and to delay tumor progression. Since the patient already suffers from metastatic disease, the intention of treatment is, of course, palliative.
Microscopic analysis. Initially, the histological type of the adnexal tumor could not be clearly classified. It was assumed that the tumor had evolved from the rectal mucosa. Histological examination indicated a dual tumor growth pattern with mesenchymal and epithelial components (Figure 2). The neoplasm was proposed as synovial sarcoma intermixed with several other tissue elements. The tumor tissue was partly of papillary/pseudopapillary structure and partly solid. Tumor cells were aggregated in tubular structures, and local rosette formation and gland-like structures were observed. The cytoplasm of the tumor cells was eosinophilic and featured no periodic acid-Schiff (PAS) positivity. Cytoplasmic vacuolation dominated, and some intra-cytoplasmic hyaline globuli were present. The nuclear/cytoplasmic ratio was high, but in contrast, atypia and pleomorphism remained moderate, and only few mitoses were seen. Because of the mixture of the described features, the diagnosis “unclassified malignant neoplasm” was chosen.
Immunohistochemical staining of the ependymoblastoma in the ovary. There is striking positivity for GFAP (A, B) and focal positivity for EMA (C, D) and CD99 (E, F), respecitvely. Magnifications: A, C, E: 40×; B, D, F: 60×.
After further microscopic examination, components of the tumor were evaluated as being derived from either a sertoli cell or a yolk sac tumor, probably evolving from the ovary, or a neuroendocrine tumor or a type of a primitive neuroectodermal tumor (PNET) as differential diagnosis.
The liver tumor that was found three years after the primary tumor in the rectovaginal space, exhibited the same microscopic features as the primary and thus, it was diagnosed as “metastasis of an unclassified malignant neoplasm”.
Immunohistochemistry. The immunohistochemical profiling of the primary tumor revealed focal positivity for EMA, pan-keratin and keratin-7 (CK7). CK5 and -6, Forkhead Box K1 (MNF) and high molecular weight-cytokeratin (HMW-CK) were positive on the surface of the papillary tumor areas. Most tumor cells displayed diffuse nuclear positivity for Wilm's tumor protein 1 (WT-1), striking cytoplasmic positivity for glial fibrillary acidic protein (GFAP) and focal nuclear positivity for p53. Additionally, diffuse positivity for vimentin and neural cell adhesion molecule 1 and strong positivity for estrogen receptors were observed. There was only weak and questionable positivity for calponin and p63. Diffuse and moderate positivity for b-cell lymphoma-2 (BCL-2) and cluster of differentiation 99 (CD99) was observed. Stains for calretinin, inhibin, cluster of differentiation 31 and 117 (CD31 and CD117) and S-100 protein were all negative. Negativity for α-fetoprotein led to the exclusion of a yolk sac tumor, which had initially been included in differential diagnosis.
The liver tumor that occurred later on featured an almost identical immune profile and was, therefore, diagnosed as metastasis of the previously described neoplasm. Figure 3 demonstrates the immunohistochemical results.
Diagnosis. Histologically, the rosette formation of the tumor cells pointed to the tumor most likely being of neuroectodermal origin. There were ependyma-like rosettes and perivascular pseudorosettes that suggested an ependymal differentiation of the tumor. The immunohistochemical profile assured this diagnosis. Positive staining for EMA and GFAP are typical for ependymomas, but the rest of the immunohistochemical profile was rather confusing and non-specific, indicating poor differentiation and anaplasia.
Accordingly, the final diagnosis was “anaplastic/grade 3 ependymoma” (ependymoblastoma) or rather “primitive neuroectodermal tumor with ependymal differentiation”.
Ependymomas
Central nervous system (CNS) ependymomas are normally located in the supratentorial brain area or around the brain stem and the cerebellum, so they mostly occur at intramedullary sites and represent 60% of all intramedullary tumors (2, 6-8). When ependymomas metastasize outside the CNS, the lung, pleura, liver and lymph nodes are predominantly affected (9-13). Ependymomas account for 5% of all intracranial neoplasms in adults and for 10% in children (14, 15). They are predominantly found in children, but also in adults, mostly around 50 years of age (1). Ependymomas are the third most common brain tumors in children and, since brain tumors are responsible for the majority of cancer deaths in children, ependymomas pose a significant clinical burden (16). More than 50% of all ependymomas arise in children below the age of five years (17, 18). Unfortunately, no chemotherapy regimen yet prolongs overall survival in children suffering from ependymoma (19-24). Nevertheless, today's treatment modalities for ependymomas are resection, radio- and chemotherapy (2, 25, 26). The primary treatment should comprise of resection and radiotherapy, with total surgical resection being the most important prognostic factor (16, 21, 23, 27-30). Myelo-ablative chemotherapy followed by autologous hematopoietic cell rescue, and hyperthermotherapy are further therapeutic options (25, 31). In a case study by Gerber et al., where 11 cases of children with epedymoblastomas were described, ifosfamide, metotrexate, etoposide, cis-diaminodichloroplatine, cytarabine, lomustine, carboplatine, cyclophosphamide and vincristine were used as chemotherapeutic agents (31).
Corresponding to the degree of malignancy, ependymomas are divided into grade 1, i.e. subependymoma and myxopapillary ependymoma; grade 2, the conventional ependymoma and grade 3, anaplastic ependymoma/ependymoblastoma (1). In the World Health Organization (WHO) classification of brain tumors of 2007, ependymoblastomas are classified in PNETs as “a heterogeneous group of tumors occurring predominantly in children and adolescents” (32, 33). However, the borderline between grade 2 ependymoma and the anaplastic, grade 3 type is ill-defined (1). Oritz et al. have reported a case of a divergent ependymal tumor of the posterior fossa in an 8-year-old boy. In this case, the tumor featured parts of ependymal differentiation, but next to these well-differentiated parts there were areas with anaplastic features, typical for an ependymoblastoma (34). This case illustrates the difficulty of discrimination between a grade 2 ependymoma and a grade 3 ependymoblastoma.
According to Rubinstein, who defined “ependymoblastoma” in 1972, it is a malignant, primitive glioma with ependymoma-like features (35, 36, 36). There are certain characteristics that differentiate ependymoblastomas from grade 2 ependymomas, namely poikilokaryosis, i.e. round, oval and long nuclei, the small size of the tumor cells and their rather uniform appearance and a higher mitotic count (37, 38). Furthermore, ependymoblastomas form primitive ependymal rosettes and canals, resembling structures that are observed in the later phase of development of the neural tube (37, 39). Bailey and Cushing, who first described ependymoblastomas as a distinct subtype, later recognized that ependymomas cannot be distinguished accurately from ependymoblastomas, so that the histological differentiation poorly-correlated with the biological behaviour. Therefore, they abandoned the diagnostic entity “ependymoblastoma”, and recommended to generally diagnose ependymal tumors as “ependymomas” (33, 39). Judkins and Ellison studied 14 cases of undifferentiated ependymal tumors to determine, whether “ependymoblastomas” are a distinct and recognizable entity, with ependymoblastic rosettes as a key diagnostic feature. In this study, however, it was found that ependymoblastic rosettes are not exclusively found in ependymoblastomas. Evidently, non-ependymal embryonal tumors such as atypical or teratoid tumors or medulloblastomas can mimic ependymoblastic rosettes, and so the authors also suggest completely retiring the diagnosis “ependymoblastoma” (33).
In the magnetic resonance imaging (MRI) scan of the brain, it is not possible to discriminate ependymoblastomas from other PNETs (35). The CT scan usually shows a dyshomogeneous, hyperdense lesion with either homogeneous or rather diffuse enhancement (40). The tumor mass is commonly large and clearly circumscribed with only little edema. The radiographic features also correspond with other types of brain tumors, such as astrocytoma, choroid plexus papilloma, oligodendroglioma, teratoma and mesenchymal tumors (35, 40).
Histology, immunohistochemistry and cytogenetics. The tumor cells in ependymomas usually form rosettes, surrounding a cell-free lumen, ependymal canals or they are arranged in perivascular pseudorosettes containing a blood vessel (41). Furthermore multi-nucleated giant cells and cytological stratification may occur (34, 42). Like in any neoplasm, high-grade ependymal tumors are recognized by the presence of atypical vessels, high cytological anaplasia and areas of necrosis (43, 44).
A rather uncommon variant of ependymoma is the clear cell ependymoma, consisting of sheets of uniform cells with round nuclei that encircle clear perinuclear halos (29, 45-47). Clear cell ependymomas are diagnostically challenging because their histological appearance resembles various tumors, including oligodendroglioma, neurocytoma or hemangioblastoma (48). In this case, the presence of ependymal rosettes and perivascular pseudorosettes leads to the correct diagnosis (29, 49).
Immunohistochemically, ependymomas are often positive for GFAP, the S-100 protein, vimentin, CD56 and EMA (1, 50, 51). Vimentin is often expressed in grade 3 ependymoblastomas, which could be due to the fact that vimentin is the earliest intermediate filament appearing in developing neuroepithelial cells, indicating the embryonal origin of ependymoblastomas (52-55).
The cytogenetic analysis of ependymomas often reveals copy number abnormalities in chromosomes 1, 6, 7, 9, 10, 13, 17, 19 and 22 (1). Commonly there are deletions such as the loss of chromosome 22, which occurs in more than 50% of adult spinal ependymomas (1, 56-60). The genes that are affected by these chromosomal aberrations are in most cases unknown, except for the loss of both wild-type copies of the neurofibromatosis type-2 (NF2) gene (57, 59, 60). Interestingly, the genes expressed in ependymomas differ with tumor location (supra-, infratentorial or spinal), and so does their biological behavior (17, 19).
Ectopic ependymomas. Ependymomas seldom occur at extraneural sites, i.e. in the lung, liver, in the small bowel, the omentum, in and around the ovary or in the sacrococcygeal soft tissue (5, 61-64). Several cases of ovarian ependymomas have been reported, i.e. monophasic teratomas that consist of neuroectodermal tissue (7, 8, 65). Teratomas of the ovary often feature neuroectodermally-differentiated components, but ovarian ependymomas that histologically resemble primary CNS tumors are extremely rare (42, 66-68). Histologically, the tumor cells of ovarian ependymomas resemble CNS ependymoma cells (69). They are arranged in ependymal rosettes and in perivascular pseudorosettes, as it is characteristic for ependymal tumors (69, 70). In ovarian ependymomas, and also in any other reported cases on extraneural ependymomas, surgical resection is the therapy of choice, and adjuvant radio- and chemotherapy, also in combination with hyperthermotherapy are suggested (5, 41, 42, 70, 71).
Ectopic/extraneural Ependymomas: Review of Clinical Cases
There have been case reports on ovarian ependymomas (41, 42, 72-74). The first three cases of ovarian ependymoma were reported by Kleinman and colleagues in 1984. One of the patients was diagnosed with a stage I tumor and survived relapse-free for five years after resection of the tumor. The other two patients had stage III disease. One of them died six years after the diagnosis while the outcome of the other patient is not known (42). In 1992, Komuro and colleagues published another case of ovarian ependymoma in a 26-year old woman. The patient underwent surgical resection and adjuvant chemotherapy. After six disease-free years, the patient experienced a relapse and was treated with a etoposide- and cisplatin-chemotherapy regimen. At a follow-up two years later, the woman was still alive (41). In 16 ovarian ependymoma cases that were outlined by Kleinman et al. in 1993, treatment consisted of extensive surgery (total abdominal hysterectomy, oophorectomy or salpingo-oophorectomy) and mainly platinum- and taxane-based chemotherapy (74). As in our case, estrogen-receptor positivity was observed in one patient and therefore, tamoxifen was administered to this patient. In these 16 cases, the patients survived between two months and five years, depending on clinical stage and grade of differentiation (74).
Whittemore and colleagues have reported a case about a myxopapillary ependymoma in the broad ligament (5). A 22-year-old, nulliparous woman was diagnosed with a suspect adnexal expansion at routine clinical investigation. The patient had no signs of dysmenorrhea or pelvic pain. The tumor mass was adjacent to a normally-appearing left ovary and was separated from the ovary by adipose tissue. Laparoscopic examination was consecutively performed and revealed a tumor in the broad ligament. The tumor was resected in sano. There was no infiltration of the uterus, adnexa or any other intra-abdominal structures. The intraoperative cryo-section was diagnosed as “stromal proliferation with neural-like features”. Further histological examination showed ependymal differentiation of the tumor, comprising also perivascular rosettes, and distinct myxoid and cystic components. Immunohistochemically, the tumor was positive for vimentin and GFAP and focally for EMA. Correspondingly, the tumor was diagnosed as a myxopapillary ependymoma. The patient did not experience relapse in the postoperative course and at the last follow-up, 18 months postoperatively, the patient was still recurrence-free (5).
Duggan and colleagues reported a case of an ependymoma in the uterosacral ligament (75). A 48-year-old gravida 2 para 2 woman presented to the hospital with a 6-month history of suprapubic pain and a 24-h history of urination difficulties. An abdomino-pelvic mass was found in the physical examination and the urinary bladder was widely dilated. The tumor was resected at laparotomy. In the operation, the uterus and adnexa were investigated and all appeared normal, except for 2.0×1.5 cm black areas on the anterior uterine surface. Furthermore, there was a firm tumor of 2.5 cm in diameter in the sigmoid mesentery, whereby the right ureter was compressed. This tumor was resected, and total abdominal hysterectomy, bilateral salpingo-oophorectomy and omente-ctomy were carried out. Postoperatively, the patient underwent pelvic irradiation and at a follow-up 18 months later she was still disease-free (75). In histological examination, an ependymoma was diagnosed. The diagnosis was supported by rosette and pseudo-rosette formation and immuno-histochemical positivity for GFAP, cytokeratin and vimentin. The authors point out that pelvic ependymomas can easily be confused with serous papillary carcinomas, but should carefully be distinguished from other tumor entities because of the apparently better prognosis and tendency for late recurrence (75).
In another case report, an ependymoma in the ischioanal fossa is described. A 61-year-old male presented to hospital with the symptoms of rectal tenseness and constipation (76). An MRI scan was performed, and revealed a soft-tissue mass in the ischioanal fossa, adjacent to the wall of the anal canal. The lesion was clearly circumscribed and of hypo- to isointense signal intensity on T1-weighted images. Histologically, a papillary growth pattern was seen, with cubic and cylindrical cells dispersed in a loosely textured myxoid stroma, with psammomatous calcifications. Correspondingly, a myxopapillary ependymoma of the ischioanal fossa was diagnosed (76).
In a case study by Santi et al., a one-day-old infant was presented with a 6.4×5.6×3.5 cm ruptured tumor mass in the soft tissue of the sacrococcygeal region (77). The infant an open wound of the buttock. Ultrasound revealed that the tumor was located at the end of the spine, compressing the urinary bladder which resulted in hydronephrosis. An MRI scan was performed and showed that the tumor was surrounding the lower sacrum and partially encircling and deviating the rectum. The infant was immediately operated and all the identifiable tumor mass was excised. Histopathologically, an ependymoblastoma was diagnosed. Immunohistochemically, the tumor tissue was distinctly positive for vimentin and some parts were also positive for synaptophysin, GFAP, neurofilament, neuron-specific enolase (NSE), CD99 and nestin. On the 42nd day of life, the patient underwent chemotherapy, modified according to the suggestions by the Children's Oncology Group (COG), consisting of cyclophosphamide, cisplatin and etoposide. The authors state that ependymoblastomas should be considered as a differential diagnosis of a sacral tumor in the newborn (77).
An ependymoma that was located in the pelvic cavity was reported by Hwang et al. in a 27 year-old Korean woman (78). The patient presented to hospital with the symptom of abdominal fullness. An MRI and a CT scan were performed and revealed a large and heterogeneous nodular tumor in the pelvis and lower abdomen. The tumor was surgically removed and was found to consist of two masses, measuring 20×20 cm and 8×8 cm, respectively. Additionally, there were several small tumor nodules disseminated in the pelvis and abdomen. The two large tumor formations were excised, however, the numerous small nodules were not removed. Histologically it was observed that the tumor cells formed true ependymal rosettes and also perivascular pseudorosettes. The immunohistochemical profile revealed positive staining for GFAP and vimentin and partial positivity for the S100 protein and EMA. Correspondingly, the tumor was diagnosed as an ependymoma (78). Chemotherapy, consisting of topotecan and carboplatin, was administered postoperatively. Partial response was observed in the follow-up imaging studies. A second-look laparotomy was performed later on, where a novel tumor mass was found under the right diaphragm. There were nodular tumor formations in the pelvis and lower abdomen. Right hemi-diaphragmectomy and peritoneal resection were performed and after that, the patient received four additional cycles of chemotherapy, consisting of doxorubicin and gemcitabine. At the last follow-up, the patient was still alive and showed no signs of recurrence (78).
Discussion
The origin of extraneural ependymomas is not yet clarified. Interestingly, most pelvic or sacrococcygeal ependymomas are of the myxopapillary type, which is a characteristic of ependymomas of the filum terminale (78). This supports the hypothesis, that pelvic cavity ependymomas arise from cell rests resulting from an incomplete regression of the caudal cell remnants, i.e. glial tissue that is a residue from the embryonic development, pinched-off from the neural tube during its closure (3, 4, 78, 78, 79). Other explanations for the origin of ectopic ependymomas might be a germ cell origin leading to a teratoma, or a so-called “neometaplasia” of the omentum or of mullerian duct-derived tissue (63, 75, 80, 81). Interestingly, women are predominantly affected by extraneural ependymomas, so it is also likely that hormonal mechanisms play a role in tumorigenesis (4). Ependymomas share clinical characteristics with germ cell neoplasms, particularly when they are located in the sacrococcygeal region, the mediastinum or in the ovary (71, 82). Therefore, it is proposed that aberrant cell migration and alterations in pathways of differentiation lead to ependymoma tumorigenesis (17). It is furthermore suggested that ependymomas may arise at various sites of the body because of deregulation of cell signaling pathways in different precursor cells (16). Thus, the gene expression profiles of ependymomas resemble the profile of the adjacent cells in the tissue where the ependymoma originates (8, 16). Taylor and colleagues demonstrated that certain signature genes which are typical for supratentorial, posterior fossa or spinal ependymomas are expressed in normal cells of the corresponding regions in the developing CNS of embryonic mice (8). It has also been found that many of these signature genes interact with signaling pathways for neural precursor cell proliferation and differentiation (8, 83).
Radial glia cells (RGCs) are probably the precursor cells for ependymomas because cancer stem cells that were isolated from ependymomas featured the same immunophenotype as RGCs, namely positivity for prominin 1 (CD133), nestin and brain lipid binding protein (16). RGCs occur in the developing CNS of all vertebrates and are specific neural stem cells. They are precursor cells for neurons and glia cells and act as guide cells for neuronal migration. We, therefore, propose that ectopic/extraneural ependymomas originate from scattered RGCs that have been left behind in the embryonic development of the neural axis. Future research should be dedicated to gene expression analysis, especially of extraneural ependymomas, so as to demonstrate that extraneural ependymoma stem cells are also descendent from RGCs. Identifying the various steps from normal RGCs to ependymoma cells at the molecular level and comprehension of the key mechanisms for ependymoma tumorigenesis paves the way for the development of targeted therapeutics and of prevention strategies. Our case report illustrates that ectopic ependymoblastoma should be considered as differential diagnosis for anaplastic neural-like tumors in the pelvic cavity.
Footnotes
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Conflicts of Interest
The Authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
- Received December 5, 2013.
- Revision received December 15, 2013.
- Accepted December 17, 2013.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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