Choroid Plexus Tumors

Main Text

Preamble

The 5th edition WHO separates choroid plexus tumors from gliomas, glioneuronal tumors, and neuronal tumors. Choroid plexus neoplasms are now considered as their own distinct category of tumors.

Choroid Plexus Tumors

Preamble

The 5th edition WHO recognizes three histologic subtypes of choroid plexus tumors (CPTs): Choroid plexus papilloma (CPP), atypical CPP (APP), and choroid plexus carcinoma (CPC).

Recent DNA methylation profiling studies suggest further segregating CPTs into three clinically/molecularly relevant subclasses: (1) Pediatric low-risk CPT (CPP/APP) = “pediatric A” CPT; (2) infratentorial adult low-risk CPT (CPP/APP) = “adult” CPT; and (3) supratentorial pediatric high-risk CPT (all CPCs, very few APP/CPPs) = “pediatric B.”

In this section, we discuss each of the three histopathologic types of choroid plexus neoplasms with the major focus on CPP—the most common primary CPT.

Choroid Plexus Papilloma

Terminology

CPP is, by far, the most common, as well as the most benign, of the choroid plexus neoplasms. Both pediatric A and most adult low-risk infratentorial CPTs are CPPs.

Etiology

Genetics

Genomic analysis of CPPs suggests a role of genes involved in the development and biology of plexus epithelium (i.e., OTX2 and TRPM3).

SMARCB1 mutations with INI1 protein alterations and CPPs have been described in the rhabdoid predisposition syndrome. Both mutations are very rarely identified in sporadic CPPs.

CPPs also occur as part of Aicardi syndrome, an X-linked dominant syndrome that occurs almost exclusively in female patients. Aicardi syndrome is defined by the triad of infantile spasms, corpus callosum agenesis, and pathognomonic chorioretinal abnormalities (lacunae). Since it was first described in 1965, new features, such as cortical malformations, gray matter heterotopias, CPPs, and choroid plexus cysts, have been identified and added to the Aicardi spectrum. The prevalence of CPPs in Aicardi syndrome is estimated at 3-5%. Bilateral and triventricular CPPs occur in 1% of cases.

Pathology

Location

CPPs can arise wherever choroid plexus is normally found, in proportion to the amount of choroid plexus normally present in each location. Therefore, the vast majority arise in the lateral (50%) and fourth (40%) ventricles. The trigone is the most common overall site in the lateral ventricles (23-1)followed by the temporal horn. The body of the fourth ventricle is its most common site (23-17). Tufts of normal choroid plexus extrude through the foramina of Luschka into the adjacent cerebellopontine angle (CPA) cisterns so CPPs within the lateral recesses or CPA also sometimes occur (23-13).

Only 5-10% of all CPPs occur in locations other than the lateral and fourth ventricles. Just 5% are found in the third ventricle (23-19) (23-20). Extraventricular CPPs are extremely rare. They have been reported in the brainstem, cerebellum, pituitary fossa, and septi pellucidi.

A few large CPPs involve multiple locations. Triventricular CPP is seen in 5% of cases and originates in the third ventricle, extending cephalad through the foramen of Monro into both lateral ventricles.

There is a strong effect of age on CPP location. More than 80% of all CPPs in infants arise in the atrium of the lateral ventricle. The fourth ventricle and CPA cisterns are more typical locations in adults. The lateral ventricles are an exceptionally rare site of CPP in older patients (23-15).

Size and Number

CPPs are usually solitary tumors, varying in size from small to huge masses. Occasionally, multiple noncontiguous lesions are seen, but most represent CSF dissemination from the primary tumor site. Multiple CPPs arise independently as synchronous tumors are rarely seen.

Gross Pathology

CPPs are well-circumscribed papillary or cauliflower-like masses that may adhere to—but usually do not invade through—the ventricular wall (23-2). Cysts and hemorrhage are common.

Microscopic Features

Histologically, the architecture of CPPs closely resembles that of normal nonneoplastic choroid plexus. A core of fibrovascular connective tissue covered by a single layer of uniform benign-appearing epithelial cells is typical. Cells tend to be more crowded and elongated or stratified. Cytokeratins, vimentin, and podoplanin are expressed by virtually all CPPs.

Mitotic activity is very low with MIB-1 < 1%. High cellularity, necrosis, nuclear pleomorphism, and focal blurring of the papillary pattern are unusual but may occur. CPPs are generally confined to the ventricle of origin and rarely exhibit an infiltrative growth pattern.

Staging, Grading, and Classification

CPPs are CNS WHO grade 1 neoplasms.

Clinical Issues

Epidemiology

CPPs are rare lesions, accounting for < 1% of all primary intracranial neoplasms. However, CPPs represent 10-20% of brain tumors occurring in the first year of life.

Demographics

Median age at presentation is 1.5 years for lateral and third ventricular CPPs, 22.5 years for fourth ventricle CPPs, and 35.5 years for CPA CPPs. There is a very slight male predominance. About 80% of all lateral ventricle CPPs occur in patients < 20 years while fourth ventricle tumors are evenly distributed across all age groups.

Presentation

CPPs tend to obstruct normal CSF pathways. Infants present with increased head size and raised intracranial pressure. Children and adults may experience headache, nausea, and vomiting.

CPP can also present as a fetal brain tumor and is the fifth most common congenital brain neoplasm (after teratoma, astrocytoma, craniopharyngioma, and primitive neuroectodermal tumor). Macrocephaly with a large intracranial mass and hydrocephalus is the most common presentation.

Natural History

Surgical resection is often curative. The recurrence rate following gross total resection is low, only about 5-6%. Malignant progression of CPP to CPC has been reported but is very rare.

Imaging

General Features

A well-delineated, lobulated intraventricular mass with frond-like papillary excrescences is typical (23-3). Diffuse leptomeningeal dissemination is uncommon but does occur with histologically benign CPP s , so preoperative imaging of the entire neuraxis is recommended!

CT Findings

The majority of CPPs are iso- to hyperdense compared with brain on NECT scans (23-3). Calcification is seen in 25% of cases (23-16A). Hydrocephalus—either obstructive or caused by CSF overproduction—is common (23-3). CECT scans show intense homogeneous enhancement (23-10B).

MR Findings

A sharply marginated lobular mass that is iso- to slightly hypointense relative to brain is seen on T1WI. CPPs are iso- to hyperintense on T2WI and FLAIR (23-4). Linear and branching internal “flow voids” reflect the increased vascularity common in CPPs. T2/T2* (GRE, SWI) may show hypointense foci secondary to calcification or intratumoral hemorrhage (23-11).

Intense homogeneous enhancement is seen following contrast administration (23-7) (23-10C) (23-18). CPPs generally do not restrict on DWI. MRS may show elevated myoinositol (mI).

Rare CPP variants include cystic extraaxial metastases from an intraventricular CPP. Cystic extraaxial metastases from CPP are seen as nonenhancing cisternal CSF-like cysts that resemble multiple parasitic cysts, such as neurocysticercosis (23-31).

Ultrasound

CPPs appear as well-defined, lobular, hyperechoic intraventricular masses on transcranial US.

Differential Diagnosis

The major differential diagnoses of CPP are atypical CPP (APP) and choroid plexus carcinoma (CPC). Both share similar imaging features on standard MR sequences. CPC is also far more likely to invade brain parenchyma than CPP. CSF dissemination occurs with all three histologic types of CPTs and is therefore neither a distinguishing feature nor a reliable predictor of malignancy.

Choroid plexus hyperplasia, also called villous hypertrophy of the choroid plexus, is a very rare cause of CSF overproduction and shunt-resistant hydrocephalus. Diffuse villous hyperplasia may result in CSF production exceeding three liters per day. Unlike CPP, most cases of choroid plexus hyperplasia are bilateral and diffusely enlarge the entire length of the choroid plexus.

Choroid plexus xanthogranulomas are benign incidental lesions that occur commonly in the lateral ventricular choroid plexus. They consist of desquamated epithelial cells with accumulated lipid together with macrophages and multinucleated foreign body giant cells. In contrast to most CPPs, they are found primarily in middle-aged and older patients. On imaging, they appear as bilateral multiloculated cysts within the enhancing choroid plexus glomus. Choroid plexus metastasis occurs in middle-aged and older adults and is not in the differential diagnosis of a pediatric CPP. Subependymoma is in the differential diagnosis of an adult fourth ventricular CPP.

Atypical Choroid Plexus Papilloma

Atypical CPP (APP) has intermediate pathologic features, prognosis, and outcomes between CPP (a WHO grade 1 neoplasm) and CPC (a WHO grade 3 neoplasm). APPs represent ~ 15% of all CPTs. Although they can occur at all ages, APPs are more common in children compared with adults and are usually located in the lateral ventricles.

The main distinguishing histopathologic feature of APP is increased mitotic activity (≥ 2 mitoses/10 HPF) with elevated MIB-1 labeling (23-23). One or two of the following four features may be present: Increased cellularity, nuclear pleomorphism, solid (not papillary) growth, and areas of necrosis.

Only a few imaging cases of APP have been reported. Most have the lobulated papillary appearance with strong uniform enhancement that also characterizes CPPs (23-21). Cysts, necrosis, peritumoral edema, larger tumor volume, blurred borders, and CSF dissemination are more common in APPs compared to CPPs (23-25). However, imaging findings do not reliably discriminate between APP and CPP, so the definitive diagnosis depends on histopathology.

Choroid Plexus Carcinoma

Terminology

CPC is a rare malignant tumor that occurs almost exclusively in young children.

Etiology

Genetics

Nearly 1/2 of all CPCs harbor TP53 mutations. The TP53-mutated tumor genome is associated with significant risk of progression and poor outcome. CPCs also occur in patients with Li-Fraumeni syndrome, a cancer predisposition syndrome caused by TP53 germline mutation.

Recent data suggest that abnormalities in regulation of ventricular ependymal cell multiciliogenesis directed by the GMNC-MCIDAS transcriptional network may also be involved in the development of CPCs.

All CPCs fall into the supratentorial pediatric B, high-risk group and are associated with a mean progression-free survival of 55 months.

Pathology

Gross Pathology

The vast majority of CPCs in children arise in the lateral ventricle. This heterogeneous, bulky intraventricular tumor often displays gross hemorrhage and necrotic foci. Invasion into adjacent brain parenchyma is common (23-26). Adult CPCs are rare; when they occur, the fourth ventricle is the most common location.

Microscopic Features

Frank cytologic features of malignancy are seen. CPCs demonstrate at least four of five histologic features: Increased cellular density, nuclear pleomorphism, loss of papillary architecture with poorly structured sheets of tumor cells, foci of necrosis, and frequent mitoses (> 2.5/mm³ equating to > 5 mitoses/10 HPF). MIB-1 is elevated, ranging from 15% to 20%.

The presence of TP53 mutation and a methylation profile of CPC also support the diagnosis.

Staging, Grading, and Classification

CPC is a CNS WHO grade 3 neoplasm. Malignant progression from CPPs to CPCs is exceedingly rare with only a handful of reported cases, mostly occurring with germline TP53 mutation.

Clinical Issues

Epidemiology

Although CPC is uncommon, representing < 1% of all pediatric brain tumors, it accounts for 5% of supratentorial neoplasms. CPC represents 20-40% of all primary choroid plexus neoplasms.

Demographics

Between 70-80% of CPCs arise in children younger than three years. Median age at diagnosis is 18 months. CPCs in adults have been reported but are very rare.

Natural History

Prognosis in patients with these aggressive tumors is generally dismal, especially those with incomplete resection of a TP53-mutated genotype. Approximately 20% of patients with CPCs have metastases at initial diagnosis. Five-year overall survival is ~ 65%.

Imaging

CPC often invades through the ventricular ependyma into adjacent brain. Edema, necrosis, intratumoral cysts, and hemorrhage are common (23-29). Enhancement is typically strong but heterogeneous. CSF dissemination is common (23-27).

Differential Diagnosis

The major differential diagnoses are CPP and APP. Imaging features of all three tumors overlap. CSF spread can occur with both benign and malignant CPTs. The presence of frank parenchymal invasion and accompanying edema suggests CPC.

OTHER CHOROID PLEXUS NEOPLASMS

Atypical Choroid Plexus Papilloma

• WHO grade 2

• Imaging findings similar to those of choroid plexus papilloma

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