Choroid Plexus Papilloma


Background

Choroid plexus papillomas (CPPs) are benign neoplasms of the choroid plexus, a structure made from tufts of villi within the ventricular system that produces cerebrospinal fluid (CSF). [123CPPs are commonly observed in the lateral ventricles of children, but they can be encountered in adults. While the vast majority of these neoplasms are benign, a small percentage can be malignant. [456789]

CPPs comprise about 1% of intracranial neoplasms but 2-4% in children. The most common location is the atrium of the lateral ventricle in children and the fourth ventricle in adults. Rare locations include the third ventricle, cerebellopontine (CP) angle, and cerebral parenchyma. [7]

An image depicting a choroid plexus papilloma can be seen below.

Imaging appearance of a fourth ventricular choroidImaging appearance of a fourth ventricular choroid plexus papilloma (CPP).

SEER data

The Surveillance and End Results (SEER) database was reviewed for population-based outcomes of choroid plexus tumors (CPTs), including choroid plexus papillomas (CPP), atypical CPPs (aCPP), and choroid plexus carcinomas (CPC). A total of 349 patients with CPTs were identified (120 CPCs, 26 aCPPs, and 203 CPPs). Patients with CPC presented at a younger age (median, 3 yr; mean, 14.8 yr) relative to CPP (median, 25 yr; mean, 28.4 yr). Histology was a significant predictor of overall survival (OS), with 5-year OS rates of 90% for CPP, 77% for aCPP, and 58% for CPC. Older age and male sex were prognostic for worse OS and cause-specific survival for CPP. Only extent of surgery had a significant impact on survival for CPC. [10]

In another review of SEER data, of 107 CPPs and 95 CPCs, more than 75% of CPCs were diagnosed in patients younger than 5 years, versus 48% for CPPs; and 65% of CPCs and 57% of CPPs occurred in males. In both groups, at least 90% of children underwent surgical resection, and gross total resection (GTR) was achieved in 67% of CPCs and 63.6% of CPPs. Almost 17% of CPCs were treated with radiation, versus only 0.9% of CPPs. More than 98% of patients with CPP were alive at the last follow-up, whereas only 62% of CPC patients were. [1112]

Problem

The choroid plexus is a neuroepithelial-lined papillary projection of the ventricular ependyma. The papillae consist of cores of fibrovascular tissue lined by low-cuboidal neuroepithelial cells. While benign cystic lesions of the choroid plexus are not uncommon, neoplasms are rare. Although most choroid plexus neoplasms are benign, they can become symptomatic by obstructing CSF flow, eventually leading to generalized increased intracranial pressure or mass effect.

Epidemiology

Frequency

CPPs are rare, comprising less than 1% of brain tumors in patients of all ages. However, CPPs most often occur in children and constitute 2-4% of childhood intracranial neoplasms with a predilection for younger ages. [6CPPs comprise 4-6% of the intracranial neoplasms in children younger than 2 years and 12-13% of intracranial neoplasms in children younger than 1 year.

CPPs have been associated with von Hippel-Lindau syndrome and Li-Fraumeni syndrome. [13]

The frequency of CPPs in children is similar in China (1.5%) [14and France (2.3%) [15.

The male-to-female incidence ratio of CPP is 2.8:1.

No distribution by race has been described.

Etiology

CPPs arise from the single layer of cuboidal epithelial cells lining the papillae of the choroid plexus. The choroid plexus is associated with the ventricular lining of the body, trigone, and inferior horn of the lateral ventricles; the foramen of Monro; the roof of the third ventricle; and the posterior portion of the roof of the fourth ventricle. The typical locations of normal choroid plexus correspond to the most common locations for a CPP to occur.

A recent study points to the role of a transmembrane receptor protein (Notch3) in the pathogenesis of human choroid plexus tumors. The Notch pathway helps regulate development of the mammalian nervous system, and activation of the Notch pathway has been increasingly recognized in human cancers. Notch3 is expressed in ventricular zone progenitor cells in the fetal brain and, when activated, can function as an oncogene. [16]

CPPs are associated with the Li-Fraumeni cancer syndrome (an autosomal dominant syndrome characterized by a germline mutation in the TP53 gene) and the Aicardi syndrome (a rare X-linked dominant condition observed in females, characterized by visual impairment, developmental delay, and seizures).

Both somatic and germline abnormalities that involve multiple genetic loci have been associated with the development of choroid plexus tumors. Recent genomic hybridization data shows that choroid plexus papillomas and choroid plexus carcinomas have characteristic chromosomal additions and deletions, which suggests that the genetic basis for these tumors is distinct. [17]

The polyoma viruses SV40, JC, and BK have also been implicated in the development of choroid plexus tumors. Choroid plexus tumors have been induced experimentally in transgenic mice using the polyomavirus common gene product, T antigen. The mechanism is thought to involve the binding of T antigen with both pRb and p53 tumor suppressor proteins, as these complexes have been identified in humans with choroid plexus tumors. [18Research is ongoing to further elucidate the relationship between polyoma viruses and human CNS tumors.

Recent research has also demonstrated differential expression of several genes in choroid papilloma tumor cells using DNA microarray techniques on cells from 7 choroid plexus papillomas. Among the abnormalities identified was up-regulation of the TWIST-1 transcription factor, which was shown to promote proliferation and in vitro invasion. TWIST-1 is involved in the p53 tumor suppressor pathway as an inhibitor. [19]

Pathophysiology

Symptoms from choroid plexus tumors generally result from secretion of CSF by tumor cells, leading to an increased amount of fluid and, eventually, to hydrocephalus. Not infrequently, the tumor itself can cause mass effect, with symptoms depending on tumor location. In either case, eventual progression and increased intracranial pressure can occur. Cases of hydrocephalus occasionally do not resolve with surgery, possibly because of derangement of reabsorption mechanisms or blockage at other sites in the ventricular system.

Presentation

Patients usually present with the following signs of increased intracranial pressure: headache, nausea and vomiting, drowsiness, ocular or gaze palsies (cranial nerves [CN] III and VI), papilledema, visual disturbances, and, eventually, blindness.

Infants, especially those with a tumor located in the third ventricle, can present with hydrocephalus or macrocephalus, as well as with associated increased intracranial pressure.

Unusual presentations include trochlear palsies (CN IV), psychosis, or occasionally, seizures.

Indications

As CPPs grow, they eventually obstruct the flow of CSF. Once the intracranial space can no longer compensate for the increase in pressure, a tension-obstruction type of hydrocephalus develops. Persistently increased intracranial pressure is not compatible with life. The pressure is alleviated by resection of the tumor or a ventricular shunting procedure.

Relevant Anatomy

Because the choroid plexus is located within the ventricles, the CPP can expand into a space-occupying lesion that may not cause symptoms until either the flow of CSF is blocked or the papilloma becomes large enough to press against the ventricular walls and, subsequently, the brain parenchyma.

These tumors most often occur in the lateral ventricles in children and in the fourth ventricle or cerebellopontine angle (CPA) of adults. Bilateral CPA choroid plexus papillomas have also been reported in the setting of neurofibromatosis Type 2. [20Rarely, CPPs can also be found in the third ventricle. Other unusual or rare sites include the sella and primary intraparenchymal sites. [2122Occasionally, CPPs show extensive calcification or even ossification or may lack their usual radiographic contrast enhancement. [2324]

In some instances, choroid plexus can be found in the cerebellopontine angle, where it has escaped the ventricle via the lateral foramen of Luschka. From this unusual placement of the choroid, or from exophytic growth of the papilloma through the foramen of Luschka, CPPs sometimes manifest in the cerebellopontine angle.

The appearance of CPPs in unusual sites most frequently occurs in the setting of von Hippel-Lindau syndrome.

Grossly, these tumors are tan and lobulated. They fill the ventricles and compress the walls; when they are benign, they do not generally invade brain parenchyma.

Contraindications

Contraindications to surgical correction of CPP are based on the patient's comorbidities and his or her ability to tolerate surgery. However, watchful waiting is inappropriate in most cases. As choroid plexus tumors grow, the resulting hydrocephalus and other complications usually result in greater morbidity than occurs if tumors are removed when they are first discovered and smaller.



Laboratory Studies

No particular laboratory studies are required for the evaluation of choroid plexus tumors. Any preoperative lab study needed to prepare the patient for surgery is indicated.

Imaging Studies

Imaging studies are required in patients presenting with presumed mass effect.

In very young children, CT scanning is the procedure of choice. CT scan demonstrates a homogeneously hypodense to slightly hyperdense enhancing mass with cystic areas. This mass may be sizable and may be associated with hydrocephalus. Punctate calcifications, observed in 20% of tumors, are more indicative of a papilloma, whereas global calcification throughout the mass is more indicative of carcinoma. A choroid plexus carcinoma is generally associated with edema or invasion into the surrounding parenchyma, which may be observed as an area of enhancement. Areas suggestive of necrosis by imaging studies are generally not a feature of CPP but may be seen in choroid plexus carcinomas. Typically, the changes on CT scan are observed in the lateral ventricles of children and in the fourth ventricle of adults, as depicted in the image below, corresponding to the typical location of this tumor.

Imaging appearance of a fourth ventricular choroidImaging appearance of a fourth ventricular choroid plexus papilloma (CPP).

In older children and adults, MRI is indicated. The appearance of a CPP on MRI (with and without contrast) is similar to that of a CT scan and shows intermediate-to-strong intensity on both T1- and T2-weighted images. The malignant choroid plexus carcinoma appears more heterogeneous than the papilloma and often shows adjacent parenchymal invasion or surrounding edema.

Prenatal ultrasound and prenatal/antenatal MRI have also been used for diagnosis. [25]

Diagnostic Procedures

While intraventricular lesions are readily identified on imaging studies, tumor biopsy is still warranted. Biopsy may facilitate differentiation of a papilloma from an aggressive carcinoma that may require a different surgical approach. Biopsy also helps diagnose tumors not of choroid plexus origin. Biopsy is most practically accomplished intraoperatively with the help of frozen section neuropathology consultation. However, differentiating normal choroid plexus from CPP can be very difficult.

Monitoring and normalizing excessive CSF pressure in young children is suggested prior to surgery. This is generally accomplished in the very young patient by repeated lumbar punctures and in the older patient by ventricular shunt.

Histologic Findings

Histologically, well-differentiated CPPs are difficult to distinguish from normal choroid plexus. Both have papillae with fibrovascular cores and are lined by a single layer of cuboidal-to-columnar epithelium. Normal choroid plexus epithelial cells tend to have a hobnail shape on the ventricular side, whereas the epithelium of CPPs is more flattened, as depicted in the image below. Well-differentiated choroid plexus papillomas are designated as WHO Grade I lesions. Occasional examples of brain invasion in otherwise benign CPPs have been described, but parenchymal invasion more often heralds anaplasia.

Histologic appearance of a choroid plexus papillomHistologic appearance of a choroid plexus papilloma (CPP) stained with hematoxylin and eosin.

Atypical choroid plexus papillomas are now recognized as Grade II lesions by the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (2007). [26They are defined as choroid plexus papillomas with increased mitotic activity. The study cited by the WHO states that a mitotic index of two or more mitoses per 10 randomly selected high power microscopic fields can establish the diagnosis. [27These tumors often have a more solid appearance with blurring of papillary architecture, increased cellularity, nuclear pleomorphism and tumor necrosis, but these criteria are not required for the diagnosis.

Choroid plexus carcinomas, WHO Grade III, as depicted in the image below, are characterized by frank signs of malignancy such as nuclear pleomorphism and hyperchromasia, increased mitotic activity (usually greater than 5 mitoses per 10 high power fields), the occurrence of tumor giant cells and tumor necrosis. Frank invasion of the underlying brain parenchyma is also seen in high-grade lesions, however, the significance of brain invasion in an otherwise low-grade lesion is unclear.

Histologic appearance of a choroid plexus carcinomHistologic appearance of a choroid plexus carcinoma stained with hematoxylin and eosin.

The histological differential diagnosis includes choroid plexus hyperplasia, papillary ependymoma, metastatic carcinoma (in older patients), and rare entities such as medulloepithelioma or germ cell tumor, in which a papillary pattern may predominate. Distinction of these entities can be successfully accomplished with the judicious use of immunohistological markers and careful attention to the clinical and imaging features. [4]

Staging

As with most CNS neoplasms, confinement to the intracranial cavity is usual. If myelopathic symptoms are present, consideration of dissemination into the spinal canal should warrant spinal cord neuroimaging studies.



Medical Therapy

Adjuvant chemotherapy and radiotherapy have been demonstrated to increase survival in the treatment of choroid plexus carcinoma and may be indicated for aggressive disease. The ifosfamide, carboplatin, and etoposide (ICE) regimen has been successfully used for choroid plexus carcinoma in young children, including neoadjuvant use prior to a second resection in patients whose initial surgery resulted in subtotal resection. [28However, radiation therapy is not appropriate in younger children and may be helpful only in older individuals. The use of chemotherapy or radiation therapy is considered on an individual basis. [298]

Hydrocephalus is frequently associated with CPP. The treatment for this secondary problem is surgical.

Surgical Therapy

The primary treatment of CPP is surgical, and total surgical resection is the goal. Complete removal of the tumor is generally curative and leads to resolution of the presenting symptoms in nearly all patients. Even in choroid plexus carcinoma, total resection (if feasible) leads to the best possible outcome. The use of neuroendoscopic surgery and radiosurgery has been tested with some success, but these remain alternate methodologies to date. However, successful endoscopic coagulation of choroid plexus hyperplasia has been recently reported and resulted in correction of hydrocephalus without recourse to a shunt. [3029128]

Obtaining a biopsy of the lesion at the time of surgery, or even prior to a definitive surgical procedure, can be of great help in evaluation of a tumor, particularly when the diagnosis remains uncertain after other diagnostic procedures are complete.

A significant secondary problem of CPP is hydrocephalus. The treatment of hydrocephalus when present, must be considered both before and after any surgical procedures. An acute increase in intracranial pressure is best managed with a shunt. However, shunting alone without resection of the mass is not sufficient therapy. [31Hydrocephalus may occur or persist postoperatively as well; intracranial pressure should be assessed both preoperatively and postoperatively. However, hydrocephalus often resolves following removal of the mass.

In a study to determine the benefit of gross total resection (GTR), the authors concluded that CPPs are not necessarily as indolent as thought and noted that although GTR is preferred, it is not always curative. In the study, 193 patients were identified with a mean age of 39.9 ± 1.1 years. GTR was achieved in 72% of patients, with subtotal resection (STR) in 28%. GTR was associated with a significant increase in both progression-free survival (PFS) (P = 0.015) and overall survival (OS) (P = 0.004), as compared to STR. The authors found that only GTR was associated with recurrence (hazard ratio [HR] = 0.47, 95% confidence interval [CI] 0.25-0.90), while both age (HR = 1.03, 95% CI 1.00-1.05) and GTR (HR = 0.36, 95% CI 0.17-0.78) were associated with OS. [32]

Preoperative Details

The usual preoperative studies of complete blood cell count, electrolytes, blood type and match, as well as measurement of intracranial pressure and imaging studies of the tumor are required. During imaging of the lesion, determination of the location of the tumor stalk is crucial because stalk location dictates the surgical approach.

Intraoperative Details

Gross total surgical resection remains the criterion standard treatment for CPP, and all efforts should be aimed towards this goal.

Postoperative Details

Upon removal of choroid plexus or other intraventricular neoplasms, assessment of intracranial pressure is necessary. Resolution of hydrocephalus must be accomplished and requires treatment if not resolved.

Follow-up

Histologically benign CPPs have a high incidence of surgical cure if totally resected and the preoperative symptoms resolve. Such results require less frequent follow-up care.

Papillomas with atypical features and choroid plexus carcinomas have a greater rate of recurrence. Appropriate follow-up care is necessary.

Complications

Examples of rare complications have been described and generally involve neurologic deficits from the surgical procedure. For cerebellopontine angle papillomas, facial nerve palsy is the most common complication. Hydrocephalus may continue and is managed by CSF shunting.

Cavernous vascular malformations have been reported following surgery or radiation therapy. Diffuse metastasis and subarachnoid spread of occasional benign CPPs have been reported.

Outcome and Prognosis

The prognosis for both CPPs and carcinomas is determined by the completeness of lesion removal at surgery. Gross total resection of intraventricular CPPs nearly always effects a cure. Multivariate analysis of 124 patients showed increased mitotic activity (2 or more per 10 high-power fields) to be the sole histologic feature associated with recurrence, increasing the likelihood of recurrence at 5 years to almost 5 fold. [27]

Analysis of 75 pediatric cases of choroid plexus carcinomas by Fitzpatrick and colleagues (2002) also reveals the benefit of gross total tumor resection: 84% of patients with gross total resections were alive compared with 18% of patients with subtotal resections at approximately 2 years. [33Subtotally resected papillomas or carcinomas require adjuvant therapy such as chemotherapy or craniospinal irradiation. Meta-analysis data suggests that patients with incompletely resected choroid plexus carcinomas have a better prognosis with a second resection than without. [34Patients with either a subtotal resection alone or with extensive parenchymal invasion have the worst prognosis.

Recent work by Tabori and colleagues indicates that alterations of tumor suppressor gene TP53 define clinical subgroups of patients with choroid plexus carcinoma. [35In a study of 64 patients, tumors that were immunopositive for TP53 conferred a 5-year survival of 0% compared to 82% for those that were immunonegative. These researchers felt that patients who lack TP53 dysfunction could be treated successfully without radiotherapy.

As noted above, numerous chromosomal imbalances have been discovered in choroid plexus tumors. Although most of these genetic aberrations did not affect survival, significantly longer survival times were noted in patients with choroid plexus carcinomas associated with +9p and -10q. [36]

Gamma knife radiosurgery (GKR) can be considered for those patients for whom surgical excision and re-excision have failed or for surgically inaccessible tumors and recurrences. [37]

Complications resulting in neurological or psychological problems may also influence outcome. In some series, this number may be as high as 50%. [38]

Future and Controversies

Increasingly widespread use of endoscopic surgery may alter the future therapy of choroid plexus neoplasms. In Gaab and Schroeder's 1998 series, many types of intraventricular lesions could be totally resected through the endoscope, with fewer and less severe complications. [39Hallaert et al have recently reported the successful treatment of hydrocephalus due to choroid plexus hyperplasia in a young child using endoscopic coagulation. [30]

The evaluation of choroid plexus tumors, including choroid plexus papillomas, atypical papillomas, and choroid plexus carcinomas may be aided by such markers as the proliferation index (MIB-1 labeling index) and tumor-suppressor protein p53. The CPT-SIOP-2000 chemotherapy study reported by Wrede and colleagues has validated the separation of choroid plexus tumors into papilloma, atypical papilloma, and carcinoma based on MIB-1 labeling and p53 status, as confirmed by clinical outcomes in 92 patients at 5 years. [40]

Two groups have recently found that many choroid plexus tumors express platelet-derived growth factor receptor B (PDGFRB) and, to a lesser extent, platelet-derived growth factor A (PDGFRA). [4142This may, therefore, represent a rationale for using treatments targeting PDGFR signaling, such as imatinib.

The recent emergence of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy increases treatment options for those patients with residual disease following initial surgery. [28Future studies will clarify whether this regimen will be useful for recurrences or metastatic disease.

A difficult decision centers on the degree of therapy, especially in very young children. Tumor surgery adjacent to functionally important areas in the brain requires caution. Nevertheless, the infant brain is able to accommodate insults to functional areas, often without permanent deficits. Malignant transformation has been reported in pediatric patients with subtotal resection of choroid plexus papilloma (CPP). [38Because of the poor prognosis associated with malignant transformation and the ability of the infant brain to compensate, most clinicians agree that complete surgical resection of CPPs should be the goal, regardless of tumor size, location, or clinical condition of the infant.