In our study we report a large single institution series of patients undergoing microsurgical resection of IVT. In a majority of cases, complete resection without neurological deficit could be achieved. A meticulous surgical planning and detailed anatomic knowledge is crucial for successful treatment. One has to separate approaches to the lateral and third ventricle from approaches to infratentorial lesions and the fourth ventricle.
4.1 Surgical approach
4.1.1 Approaches to the lateral and third ventricle
To enter the lateral and third ventricle a variety of approaches have been described including the frontal-transcortical, the anterior/posterior interhemispheric-transcallosal and the contralateral interhemispheric-transfalcine-transprecuneal approach (17-22). They allow excellent visualization of important anatomical structures like the thalamostriatal, anterior-septal and caudate veins, foramen of Monro and choroid plexus (23). The transcortical approach is supposed to be associated with higher incidence of postoperative seizures and possible neurological deficits due to frontal lobe corticotomy and retraction of the supplemental motor or premotor area, but offers greater access and overview, especially in larger intraventricular lesions. The transcallosal approach is technical more demanding for proper dissection but is supposed to leave more cortical structures intact. However, transcallosal approach is also associated with higher morbidity and, in case of e.g. permanent damage of corpus callosum, with postoperative severe neurological deficits like well known “disconnection syndrome” (22, 23). Taking these circumstances into consideration, the transcortical approach is preferred as workhorse approach in our institute. Historically, high morbidity ratio in the literature initially led to disqualify the transcortical approach to the lateral and third ventricle at the beginning, but closer review of above-mentioned publications display that extended craniotomies and cortical exposure with rough retraction were transacted. Keyhole exposures are pushing minimal invasive philosophy of modern neurosurgery forward and are associated with less brain damage, comparable to injury caused by ventricle puncture, and offers a much more comfortable approach to the ventricle system (24). Special attention has to be given to the head positioning to ensure optimal conditions. We perform surgery in supine position with ~ 30° anteroflection to elevate the preconorary part of the frontal lobe to the highest point and therefore minimize outflow of cerebrospinal fluid. This avoids collapsing ventricles and tearing of bridging veins. The craniotomy is usually centered on the coronary suture, a diameter of ~ 3cm is regularly sufficient to guarantee an adequate working canal. Figure 4 summarizes and reflects most prominent approaches.
4.1.2 Approaches to the fourth ventricle
To access the fourth ventricle, historically the trans-vermian approach was very popular. Still, this approach harbors the risk of cerebellar mutism and disequilibrium (15, 16) leading to the development of the less invasive median suboccipital telovelar approach (25, 26).
Nevertheless, surgical morbidity of tumors of the fourth ventricle, mostly ependymomas, remains high with up to 30% adverse events. This is probably due to adhesive nature of the lesion and proximity of cranial nerves and their nuclei (15, 27, 28). To reduce the risk for cranial nerve lesions, monitoring of cranial nerves and electrical intraoperative mapping of the floor of the fourth ventricle can be performed (29).
In the present series 44.4% (20/45) received resection via the microscopic frontal-keyhole approach and 48.9% (22/45) a median suboccipital telovelar approach. Both approaches offer satisfying anatomical overview and thus facilitate possibility for safe complete tumor removal. Our postoperative complication rate of 20.0% with a shunt-dependency rate of 13.3% highlights the advantages of the keyhole as well as the median suboccipital telovelar approach. 10.0% (2/22) of median suboccipital telovelar approaches and three frontal approaches led to secondary shunt-implantation. 10.0% (1/10) of resected central neurocytoma by a frontal approach led to postoperative ventricle entrapment with secondary cisternostomy. During resection of 4th ventricle lesions intraoperative neuromonitoring was performed to ensure safe functional resection and to reduce cranial nerve lesions. No secondary surgical intervention requiring wound healing disorders was observed, one case of CSF leakage was successfully treated conservatively.
4.2 Histopathological considerations
IVTs share their predominantly intraventricular location as a result from specific peri- and intraventricular structures from which they arise. The ventricle system raises from telencephalic vesicles from the cranial end of the neural tube as ependymal-lined outpouchings. Into these vesicles the choroid plexus develops from an invagination of primitive pia, creating the choroidal fissure. The epithelium is composed of ependymal cells, origin of ependymomas. Subjacent to the ependymal lining is a subependymal plate of glial cells, from which subependymomas upraise. Residual neuronal precursor cells are found, inter alia, at the septum pellucidum, from which the central neurocytoma may arise (30).
Ependymomas account for 1%–5% of intracranial central nervous neoplasms (31).
Arising from the ependymal cells of the ventricular wall, they can be found anywhere along the ventricular system and/or the spinal cord. Intracranially they show predominant occurrence in the posterior fossa e.g. the fourth ventricle (60%) compared to supratentorial location (40%) (2, 15, 32, 33). The majority (>50%) of supratentorial ependymomas are intra-axial lesions, only few reports on extra-axial ependymomas exist (34).
Ependymomas can be found at any age (figure 1), with a higher proportion of infratentorial lesions in pediatric patients (mean age 6y), compared to supratentorial tumor location (mean age 18–24y) (30, 31). If this is because infratentorial lesions become symptomatic at an earlier stage due to the special anatomy of the fourth ventricle or specific pathological patterns represent distinct age-related subgroups remains unclear to date.
The treatment of choice is surgical removal of the tumor, gross total resection shows a prognostic role in recurrence-free and overall outcome. Nevertheless, regarding the mostly benign character of the lesion, avoidance of neurological deficits is of utmost importance and special attention has to be paid to the floor of the fourth ventricle – origin of multiple cranial nerve nuclei and/or ascending/descending tracts (15, 35-37).
In the present series, we achieved complete resection in 84,6% (11/13) and 83,3% (10/12) regarding 4th ventricle ependymomas (figure 1), which coincides with the results of previous case series (15, 27, 28, 38-42), recent major case series are displayed in table 4. Rates of gross total resection (91-82% of patients), cranial nerve deficits or shunt dependency differ among the reports of fourth ventricle ependymomas highlighting the complex anatomy of the fourth ventricle and its floor, institutional experience may play a major role (40) (15). Higher rates of gross total resection (~ 86-93%) have been reported about forth ventricle tumors of other pathology (40, 41). In our series, 15,4% (2/13) developed a postoperative shunt-dependent hydrocephalus and 7.7% (1/13) a deterioration of functional outcome (KPSS from 90 to 40%) due to hemorrhagic infarction. One patient developed postoperative new cranial nerve deficits (8,3%), representing a satisfying rate compared to previous reports (15, 27, 28, 38-42). Our findings coincide with prior studies highlighting good response to operative treatment of ependymomas, also in the fourth ventricle (15, 42). Our higher rate of complete surgical removal was not associated to higher neurological morbidity or mortality (15, 27, 28, 38-42).
According to the recent 2018 EANO guidelines for diagnosis and treatment of ependymal tumors (43), the role of postoperative radiotherapy in patients with WHO grade II ependymoma undergoing complete removal is still controversial (44, 45). Two larger retrospective analyses could not find any significant association between radiotherapy and survival outcome (43, 46, 47).
Regarding patients with anaplastic WHO° III ependymoma or incomplete resection of WHO°II ependymomas, adjuvant radiotherapy is recommended (48). In 2006, Combs et al. described non-inferiority regarding recurrence free survival of fractionated stereotactic radiotherapy (FSRT) compared to conventional radiotherapy, especially at the field borders (49), opposing earlier paradigms in radiotherapy (50).
In our series, two patients underwent postoperative radiotherapy after complete removal. One of them was an anaplastic WHO° III ependymoma, following the actual guidelines of adjuvant therapy. The second case, in 2011, was a tanycytic ependymoma WHO°II, in which the decision for adjuvant radiotherapy was based on ambiguous histopathological findings.
Subependymomas account for 0.2%–0.7% of intracranial neoplasms (51). About 82% of subependymomas occur in patients older than 15 years and they show a male predominance (figure 2). Subependymomas are generally asymptomatic, incidental findings, located in the walls of the fourth (66–70%) and lateral ventricles (30-40%) (52-54). The foramen of Monro and spinal cord may also be affected (55).
Tumor location and extend of resection are the most important prognostic factors as recurrence has only been reported in case of subtotal resection (52, 56). Their growth rate tends to be slow (30, 52). Rarely, aggressive tumors invading brain parenchyma or showing CSF dissemination are described as well (57). As MRI findings of subependymomas are very heterogenous. Histological confirmation of the diagnosis is mandatory due to several differential diagnosis including inter-alia ependymomas and central neurocytomas. Therefore a “watch and wait” strategy with regular MRI follow-ups can lead to undertreatment in case of more aggressive entities mistaken for a subependymoma.
Most reports on subependymomas published represent smaller and retrospective cohorts (3, 56-64). The largest report of Elisabeth Rushing et al. comprised 83 cases, but focused on histopathological findings and does not consider surgical aspects (3).
We report on 21 patients, representing the second largest “surgical” series published to date (table 5) (3, 56-64). As radiation or systemic treatment do not apply for subependymomas, surgery remains the only viable option in this entity. The surgical strategy focusses on maximal but safe resection, resulting in permanent absence of the tumor. In the majority of reports, gross total resection could be achieved in >70% of patients, with low rates of mortality and morbidity after surgery (3, 56-64). In our cohort, we were able to achieve gross total resection in all cases (21/21) with a surgery-related mortality rate of 4,8%.
4.2.3 Central Neurocytoma
The central neurocytoma is a rare brain tumor with a frequency of 0.1-0.5% of all intracranial central nervous tumors. It is a benign WHO grade II tumor with a 5-year survival of 89% (2, 65, 66).
The origin of these tumors remains unclear, but cell-culture investigations proclaim origin from bipotential progenitor cells that are capable of both neuronal and glial differentiation (5, 67).
They are typically located in lateral ventricles and/or the third ventricle (figure 3). The anterior portion of one lateral ventricle is the most frequent site (50%), followed by combined involvement of the lateral and third ventricles (15%) and the involvement of both lateral ventricles (13%). Surgical resection is primary treatment for central neurocytomas but may also include radiation or systemic therapy. Extend of resection correlates with the rate of recurrence. Patients undergoing subtotal resection are commonly treated with adjuvant stereotactic radiation therapy, resulting in improved outcome compared to surgery alone (68).
Extraventricular neurocytomas are also described and occur in the brain parenchyma, cerebellum or spinal cord (69). The term central neurocytoma is related to the ventricular system.
The tumor's rarity makes it challenging to define treatment standards. Most institutions, including our center, regrade surgical gross total resection as gold standard for treatment of central neurocytomas with complete removal rates of 30–50% (69-72). In this cohort, we achieved gross total resection in 90.0% (9/10), table 6 summarize recent major case series reports and their findings since 2000 (71, 73-75).
After total resection a five-year survival rate of 99% is reported (69, 76-79), compared to 86% in cases of subtotal resection (78). Nevertheless, they do not emphasize on adjuvant therapy strategies. This is backed by a pooled analysis by Rades including over 400 cases, that demonstrates superiority of gross total resection regarding overall survival (70).
However, this is in contrast to a series of 45 central neurocytomas showing no significant difference in local tumor control or survival comparing complete and incomplete resection including adjuvant therapy (74). A systematic review by Garcia et al. displayed that extent of resection was not predictive regarding improved local control (80), while a prospective multi-center study reported that in 71 patients, those with subtotal resection had a 3,8 times higher risk of recurrence (81). The role of gross total resection remains ambiguous, with several treatment pathways including external beam radiation therapy, stereotactic radiosurgery, re-operation and/or chemotherapy (71). Whether pathological subtypes or molecular patterns of central neurocytomas play a role in the course of disease and should guide therapy strategies remains unclear to date. Table 6 highlights the multimodal treatment options of different institutions and their different outcomes taking above mentioned results and recommendations into consideration (71, 73-75). Hallock et al. confirmed, e.g., that gross total resection can be associated with durable long-term outcome and should be first line therapy, but also reported that subtotal resection with no further adjuvant treatment can be seen as salvage treatment with surgery or radiation at the time of clinical and radiographic progression. Nevertheless, he also reported a recurrence rate of about 33% with majority of recurrences within 2.5 years of surgery (75).
Other studies advocated postoperative adjuvant radiotherapy for improved local control of central neurocytomas, but given the overall long-term survival and radiation related adverse events of > 60% should be taken into careful consideration (82, 83).
Nevertheless, stereotactic radiosurgery, shows promising results in a report of recurrent or residual neurocytomas(84).
Based on our findings and outcome, we recommend safe, gross total resection to be the first line therapy as initial treatment. For recurrent disease individual decisions according to overall patient status, tumor location, age and patient preference should guide the mode of therapy.
4.2.4 Glioependymal cyst (GEC)
The etiology of GECs remains controversial as actual theories on its natural history fail to demonstrate why those cysts occur in different anatomical locations and also do not explain the histological variability in the cyst wall (85). They are counted to congenital benign lesions with a neuroectodermal origin that share many radiological characteristics with other neuroepithelial lesions. Diagnosis of GECs is confirmed by histological examination (86). Yasaragil et al. proclaimed that GECs could originate from the tela choroidea migrated somehow during embryogenesis towards brain parenchyma or subarachnoid place (87), resulting in various tumor locations. A systemic review highlighted the difficulties of grouping GECs as few case reports and series are published. Treatment of GECs is indicated if they become symptomatic and therefore surgical resection is favored.
4.2.5 Study Limitations
Our study harbors several flaws and limitations. As it is a retrospective case series, causalities are not possible to draw with respect to clinical outcome. Nevertheless, detailed clinical examination including scores on functional performance as well as a standardized follow up protocol based on a certified neurooncological board are implemented in our clinical workflow. Given the rarity of these lesions prospective inclusion and follow up is hard to achieve within a reasonable time period. Having this in mind, even though we report a relatively large single center series, the absolute amount of cases does not allow for proper statistical analysis. We recommend that, multi-center studies should be conducted to address this problem. In our study we do not focus on long term outcome of different tumor entities, but more on the surgical approach and perioperative outcome. If one wants to address therapy strategies in a whole of these rare lesions, further histopathological, molecular and gene markers have to be taken into account to guide individual therapy strategies. Another problem in rare surgical entities is reflected by the changing therapy modalities, that may bias the therapy outcome, reflected by a learning curve of treating surgeons, various surgeons involved in the treatment or changes in surgical technique. Therefore, in our cohort we limit the report on classic microsurgical approaches. The role of intraventricular endoscopy is not reflected in our series. Even more, local tumor treating strategies like local drug perfusion catheters or laser interstitial thermal therapy might become more important in the future treatment of deep located lesions.