Epidemiology:
CPTs are rare CNS tumors and account for 0.5%–0.6% of all intracranial neoplasms in all ages (2, 3). About 5% of all CPTs are located in third ventricle(16). According to multiple reports, third ventricle CPP comprise a very rare entity (11, 17, 18). 14% of choroid plexus tumors occur during infancy although there are reports of third ventricle choroid plexus papilloma during 5th decade of life (19, 20). In majority of reports there is no reported sex predilection in CPTs (21, 22). CPCs are almost 4 fold more common in children than adults(12). In literature there are 55 cases of reported CPPs and just three cases of CPC located in third ventricle which elicits extreme rarity of third ventricle CPC.
Clinical features:
According to anatomic specifications of third ventricle, CPTs in this location tend to be symptomatic earlier in life than tumors located in other common locations(23). Common presentation in pediatric population is hydrocephalus manifested as macrocephaly, splaying of cranial sutures, fontanel widening/bulging and forced downward gaze, also known as sunset eyes. Older patients suffer from headache, nausea, vomiting and visual disturbances (24). These tumors can infrequently manifest as bobbing head doll syndrome or endocrine abnormalities (24, 25). In our case, ICP rising manifestations such as sunset eyes and sutural splaying was dominant regarding patient’s age.
Imaging characteristics:
In CT and MR imaging, CPTs present as well-defined large lobulated masses. They appear as hyperdense structures in CT images as a result of micro-hemorrhages and micro-calcifications(26). On MR imaging, tumor signal usually seems to be isointense on T1 and isointense to moderately hyperintense on T2 sequences. Due to high vascularity of structures derived from choroid plexus, these tumors enhance brightly and homogenously after administration of contrast agent on both CT and MRI. Calcifications are rare in children but may be seen in 14–25% of cases in all ages (25, 27). There is no specific imaging criteria for CPCs, but parenchymal invasion or heterogeneous enhancement as a result of necrotic areas, calcifications or micro-hemorrhages may be a clue(28). As can be seen, there was no such imaging characteristics of carcinomas in our case which emphasize on the fact that CPCs can’t be diagnosed solely on radiological grounds. CPTs are often accompanied by significant hydrocephalus. Pathophysiology of hydrocephalus can be related to CSF overproduction, obstruction of CSF pathways, hemorrhage from tumor leading to arachnoid villi dysfunction and high CSF protein content (7, 11, 25). Despite all these imaging specifications, diagnosis may be challenging in uncommon locations.
Histopathology:
Microscopically, CPPs are composed of well-structured fibrovascular papillary formations lined by single layer of columnar or cuboidal epithelium without malignant features. In contrast, CPCs are recognized with presence of at least four of five malignant features such as increased cellularity, high mitotic activity (more than 5 in 10 HPF), multiple areas of necrosis, highly pleomorphic nuclei and blurring of papillary architecture(4). Occasionally, CPTs show one or few of aforementioned malignant parameters but not enough to classify them as CPC. So, aCPP is recognized as an intermediate entity regarding mitotic activity since 2007 WHO classification. Clear diagnostic criteria have not been established but high mitotic figures (more than 2 in 10 HPF) without other malignant features can lead to diagnosis of aCPP(12). There is a direct relationship between Ki–67/MIB–1 staining and tumor grade. Mean values of MIB–1 index in CPP, aCPP and CPC are reported as 1.3–4.5, 5.8–9.1 and 13.4–20.3 percent respectively (29–31). In histological examination of tumor specimen in our case, diffuse blurring of papillary structures, increased cellularity, multiple areas of necrosis and significant pleomorphism was evident leading to diagnosis of CPC. Measured MIB–1 index was 20% which is also in favor of CPC.
Management:
Surgical resection is first line treatment in all CPTs. Because of small diameters and complex neuroanatomy of third ventricle, resection of tumors in this area are challenging and highly demands expertise(32). Due to high vascularity of these tumors significant blood loss during resection should be anticipated and effectively managed specially in pediatric population(7, 11, 21, 25). Blood loss can be limited by initial finding and securing of arterial feeders which are branches of adjacent choroidal arteries and subsequent coagulation and en-bloc or piecemeal removal of tumor bulk (7, 10, 24). There are some reports of pre-operative embolization of feeder artery, however this approach is challenging and have potential risks of vessel injury or stroke (25, 32, 33). Neoadjuvant chemotherapy can be considered as an alternative approach which reduces tumor size and vascularity and facilitates total resection (34).
Optimal management of hydrocephalus in these patients is a matter of debate. Majority of reports suggest emergent ventriculoperitoneal shunting (VPS) procedure in cases of neurological deterioration and definite resection of tumor a few days later after patient stabilization, when facilities for emergent total tumor resection is not accessible. In patients with stable neurological situation, semi-urgent external ventricular drainage (EVD) placement and tumor resection in one session will be feasible. In these circumstances, EVD tapering and removal or change to VPS should be considered as soon as possible given the high risk of meningitis with EVD in place (11, 35). Pre-operative endoscopic third ventriculostomy (ETV) is another option in patients with non-communicating hydrocephalus with different reported success rates(7). In our case, patient showed significant neurological deterioration as drowsiness and lack of response to stimuli upon admission and severe hydrocephalus on imaging. So, because facilities for emergent resection of tumor were not available, we decided to emergently place a VPS which resulted in dramatic clinical response.
Although we resected tumor through transcortical-transforaminal approach, there are different surgical approaches for different locations of CPTs. Specifically for third ventricle CPTs, transcallosal, transcortical-transforaminal and endoscopic approaches can be used for resection of tumors located in anterior third ventricle and infratentorial-supracerebellar, occipital-transtentorial and transcallosal approaches are among the described approaches to posterior third ventricle tumors(10, 11, 36). The choice of surgical approach varies based on location, anatomy, size, and blood supply of tumor. The transcortical-transforaminal approach is ideal for patients with larger tumors and larger ventricles as in our case. Most frequent complication of this approach is seizure and subdural collection, the latter occurred in our case (37). Although the aim of surgery is gross total resection, it may be not possible as a result of significant bleeding (especially in children) or invasion to critical structures. In former situation, reoperation at a later time is suggested but adjuvant therapy can be used in later (11, 35). Neuroendoscopic biopsy followed by chemoradiotherapy is the best treatment option in cases where the tumor is not resectable (38).
Role of adjuvant therapies in management of CPTs is controversial. As a consensus, completely removed CPP can be followed without any adjuvant therapy. There are some reports of radiotherapy or radiosurgery in CPTs but they all suggest that these modalities be reserved for patients with unresectable residual tumor or aggressive subtypes (35, 39, 40). Chemotherapy is suggested in cases of higher grade tumors or recurrences, although it showed mixed results. The most debate in this regard is about role of adjuvant therapy in aCPPs which is relatively newer entity with few cases reported in literature (41, 42). Role of adjuvant therapy in CPC is more obvious with some reports of significant increase in overall survival following adjuvant chemoradiotherapy or chemotherapy alone (28, 42–44).
Outcome:
Main prognostic factors in CPTs are extent of resection and tumor grade. Best outcome is expected in totally removed CPPs with10 year survival of about 100% in different reports (6, 24, 45). Whereas, 5-year survival rate of CPC patients are approximately 58 % and 20 % after complete or partial resection respectively(28). Natural history and outcome of aCPPs fall somewhere in between, but is not well recognized and needs to be elucidated.