Choroid Plexus Papilloma

The choroid plexus is a papillary projection of the ventricular ependyma that is lined by neuroepithelium. Although benign cystic lesions of the choroid plexus are not uncommon, neoplasms are rare. Most choroid plexus neoplasms are benign; however, they can become symptomatic by obstructing CSF flow, eventually leading to generalized increased intracranial pressure or mass effect.

Although patients may be cured by total resection, CPP poses significant surgical risks and challenges related to intraoperative hemostasis. Transcollation devices appear to be an effective and safe addition to the armamentarium of neurosurgical hemostasis options for intracranial tumor resection in which there is high risk of intraoperative hemorrhage.[4]

Choroid plexus papillomas are rare, accounting for about 1% of all brain tumors, 2-6% of pediatric brain tumors, and 0.5% of adult brain tumors.[11, 12]  They most often occur in children, with a predilection for younger ages.[7] CPPs make up 4-6% of 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.[17]  The frequency of CPPs in children is similar in China (1.5%)[18] and in France (2.3%).[19]

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

Choroid plexus papillomas 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. Typical locations of the normal choroid plexus correspond to the most common sites for occurrence of CPP.

One 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]

Choroid plexus papillomas 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. Genomic hybridization data show that choroid plexus papilloma and choroid plexus carcinoma have characteristic chromosomal additions and deletions, which suggests that the genetic basis for these tumors is distinct.[20]

The polyoma viruses SV40, JC, and BK have been implicated in the development of choroid plexus tumors. Choroid plexus tumors have been induced experimentally in transgenic mice by using the polyomavirus common gene product, T antigen. The mechanism is thought to involve binding of T antigen with both pRb and p53 tumor suppressor proteins, as these complexes have been identified in humans with choroid plexus tumors.[21] Research is ongoing to further elucidate the relationship between polyoma viruses and human CNS tumors.

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.[22]

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 the cerebellopontine angle (CPA) in adults. Bilateral CPA choroid plexus papillomas have been reported in the setting of neurofibromatosis type 2.[23] Rarely, CPPs can be found in the third ventricle. Other unusual or rare sites include the sella and primary intraparenchymal sites.[24, 25] Occasionally, CPPs may show extensive calcification or even ossification or may lack their usual radiographic contrast enhancement.[26, 27]

In some instances, the 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.

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

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 generally are not a feature of CPP but may be seen in choroid plexus carcinoma. Typically, 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 choroid plexus papilloma (CPP).

For older children and adults, MRI is indicated. The appearance of a CPP on MRI (with and without contrast) is similar to that on 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.[28]

Although 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 puncture and in the older patient by ventricular shunt.

Histologically, well-differentiated CPP is 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 World Health Organization (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 papilloma (CPP) stained with hematoxylin and eosin.

Atypical choroid plexus papilloma is now recognized as a grade II lesion by the WHO Classification of Tumours of the Central Nervous System.[29] It is defined as a choroid plexus papilloma with increased mitotic activity. The study cited by the WHO states that a mitotic index of 2 or more mitoses per 10 randomly selected high-power microscopic fields can establish the diagnosis.[30] These 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 carcinoma, WHO grade III, is characterized by frank signs of malignancy such as nuclear pleomorphism and hyperchromasia, increased mitotic activity (usually more 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.

The histologic 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 immunohistologic markers and with careful attention to clinical and imaging features.[5]

Adjuvant chemotherapy and radiotherapy in the treatment of choroid plexus carcinoma have been demonstrated to improve survival 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 before a second resection in patients whose initial surgery resulted in subtotal resection.[31] However, radiation therapy is not appropriate for younger children and may be helpful only for older individuals. The use of chemotherapy or radiation therapy is considered on an individual basis.[32, 9]

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

The usual preoperative studies of complete blood cell count, electrolytes, and 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.

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

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

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 presenting symptoms in nearly all patients. Even in choroid plexus carcinoma, total resection (if feasible) leads to the best possible outcome.[11, 14] The use of neuroendoscopic surgery and radiosurgery has been tested with some success, but these remain alternative methods. Successful endoscopic coagulation of choroid plexus hyperplasia resulting in correction of hydrocephalus without recourse to a shunt has been reported.[9, 33, 32, 34]

Obtaining a biopsy of the lesion at the time of surgery, or even before a definitive surgical procedure is performed, 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. Treatment of hydrocephalus, when present, must be considered both before and after any surgical procedures are performed. An acute increase in intracranial pressure is best managed with a shunt. However, shunting alone without resection of the mass is not sufficient therapy.[35] Hydrocephalus may occur or may persist postoperatively; intracranial pressure should be assessed both preoperatively and postoperatively. Hydrocephalus often is resolved upon removal of the mass.

Although patients may be cured by total resection, CPP poses significant surgical risks and challenges related to intraoperative hemostasis. Transcollation devices appear to be an effective and safe addition to the armamentarium of neurosurgical hemostasis options for intracranial tumor resection in which there is high risk of intraoperative hemorrhage.[4]

In a study conducted to determine the benefit of gross total resection (GTR), the authors concluded that CPPs are not necessarily as indolent as was thought and noted that, although GTR is preferred, this 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), and 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.[36]

Histologically benign CPP has a high incidence of surgical cure if totally resected and if preoperative symptoms are resolved. Such results require less frequent follow-up care. Papilloma with atypical features and choroid plexus carcinoma have a greater rate of recurrence. Appropriate follow-up care is necessary.

Examples of rare complications have been described and generally involve neurologic deficits from the surgical procedure. For cerebellopontine angle papilloma, facial nerve palsy is the most common complication. Hydrocephalus may continue and is managed by CSF shunting. Cavernous vascular malformation has been reported following surgery or radiation therapy. Diffuse metastasis and subarachnoid spread of occasional benign CPP have been reported.

The prognosis for both CPP and carcinoma is determined by the completeness of lesion removal at surgery. Gross total resection of intraventricular CPP 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.[30]

Analysis of 75 pediatric cases of choroid plexus carcinoma by Fitzpatrick and colleagues (2002) also revealed the benefits of gross total tumor resection: 84% of patients with gross total resection were alive compared with 18% of patients with subtotal resection at approximately 2 years.[37] Subtotally resected papilloma or carcinoma requires adjuvant therapy such as chemotherapy or craniospinal irradiation. Meta-analysis data suggest that patients with incompletely resected choroid plexus carcinoma have a better prognosis with a second resection than without.[38] Patients with a subtotal resection alone or with extensive parenchymal invasion have the worst prognosis.

Tabori and colleagues found that alterations of tumor suppressor gene TP53 define clinical subgroups of patients with choroid plexus carcinoma.[39] In a study of 64 patients, tumors that were immunopositive for TP53 conferred 5-year survival of 0% compared to 82% for those that were immunonegative. These researchers believed that patients who lack TP53 dysfunction could be treated successfully without radiotherapy.

As noted above, numerous chromosomal imbalances in choroid plexus tumors have been discovered. Although most of these genetic aberrations did not affect survival, significantly longer survival times were noted in patients with choroid plexus carcinoma associated with +9p and -10q.[40]

Gamma knife radiosurgery (GKR) can be considered for patients for whom surgical excision and re-excision have failed, or for those with surgically inaccessible tumor or with recurrence.[41]

Complications resulting in neurological or psychological problems may also influence outcomes. In some series, this number may be as high as 50%.[42]

Increasingly widespread use of endoscopic surgery may alter future therapy for 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.[43] Hallaert et al reported successful treatment of hydrocephalus due to choroid plexus hyperplasia in a young child using endoscopic coagulation.[34]

Evaluation of choroid plexus tumors, including choroid plexus papilloma, atypical papilloma, and choroid plexus carcinoma, 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 validated the separation of choroid plexus tumors into papillomas, atypical papillomas, and carcinomas based on MIB-1 labeling and p53 status, as confirmed by clinical outcomes in 92 patients at 5 years.[44]

Two groups 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).[45, 46] This may represent a rationale for using treatments targeting PDGFR signaling, such as imatinib.

The recent emergence of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy has increased treatment options for patients with residual disease following initial surgery.[31] Future studies will clarify whether this regimen will be useful for recurrence or for metastatic disease.

A difficult decision centers on the recommended degree of therapy, especially for 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 CPP.[42] Because 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 CPP should be the goal, regardless of tumor size or location, or the clinical condition of the infant.[34]