Pathology of Choroid Plexus Neoplasms

Choroid plexus neoplasms are rare, intraventricular, primary central nervous system (CNS) tumors derived from choroid plexus epithelium that are seen predominantly in children. Choroid plexus tumors are graded based on the World Health Organization (WHO) classification scheme and include choroid plexus papilloma (CPP) (WHO grade I) (see the following image), atypical choroid plexus papilloma (WHO grade II), and choroid plexus carcinoma (CPC) (WHO grade III). ^[1]

The overall annual incidence of choroid plexus neoplasms for all ages is 0.3 cases per million. Although these tumors arise in all age groups, their peak incidence is within the mid-teenage years. ^{[2, 3]} In adults, they account for less than 1% of primary intracranial neoplasms, whereas choroid plexus tumors represent up to 5% of pediatric brain tumors, and up to 20% of those arising in children aged 1 year and younger. ^{[4, 5]} Occasional fetal and congenital examples have been presented.

Irrespective of patient age, choroid plexus papillomas outnumber choroid plexus carcinomas by a 5:1 ratio. Up to 90% of choroid plexus tumors in children are papillomas, and up to 70% of all choroid plexus papillomas occur in children younger than 2 years. Choroid plexus carcinomas are also far more common in the pediatric population, with approximately 80% of choroid plexus carcinomas occurring in children. There is no significant sex predilection. ^[1]

Although the vast majority of choroid plexus tumors are sporadic, hereditary factors appear to play a role in the development of some choroid plexus papillomas and carcinomas. Choroid plexus papillomas are a component of Aicardi syndrome, ^[6] and they may also arise in the context of Down syndrome, ^[7]  von Hippel-Lindau disease, ^[8]  and neurofibromatosis type 2. Choroid plexus carcinomas occasionally arise in association with hereditary cancer predisposition syndromes, including the Li-Fraumeni and rhabdoid predisposition syndromes, with germline mutations of TP53 and hSNF5/INI1/SMARCB1, respectively. ^{[9, 10, 11, 12]}

The vast majority of choroid plexus neoplasms arise within the ventricles. In children, the lateral ventricles are the most common location of involvement, followed by the fourth ventricle. In adults, this pattern of localization is reversed, with the fourth ventricle being the most common location, and the lateral ventricles second in frequency. The third ventricle is the least common intraventricular location for choroid plexus neoplasms, irrespective of patient age. ^[1]  Primary extraventricular papillomas are rare and most often occur at the cerebellopontine angle. ^{[13, 14]}  Occasionally, involvement of both lateral or multiple ventricles is encountered. ^[15]

Choroid plexus neoplasms can produce hydrocephalus and increased intracranial pressure by a number of mechanisms, including obstruction of normal cerebrospinal fluid (CSF) flow, overproduction of CSF by the tumor itself, local expansion of the ventricles, or spontaneous hemorrhage. From a clinical standpoint, signs and symptoms related to the above abnormalities would include headache, vomiting, papilledema, ataxia, strabismus, increased head circumference and bulging fontanelles (in infants), developmental delay, and altered mental status. ^[3]

Tumor spread

The most frequent route of choroid plexus tumor spread is via seeding of the CSF. Drop metastases may occur throughout the neuroaxis as a result, particularly in the region of the cauda equina. Seeding of the CSF may be seen even in benign choroid plexus papillomas, but leptomeningeal dissemination is much more common in choroid plexus carcinomas. Shunt-related metastases have been reported at abdominal sites, with extracranial metastases to the lung and bone reported in rare cases. ^{[16, 17, 18]}

Typical radioimaging of a choroid plexus papilloma shows a lobulated, solid, well-demarcated intraventricular mass that is isodense to mildly hyperdense on computer tomography (CT) scans; these lesions enhance homogeneously following contrast administration. Choroid plexus papillomas appear homogeneous and isointense to gray matter on T1-weighted magnetic resonance images (MRIs), hyperintense on T2 images, and exhibit intense contrast enhancement (see the image below). More aggressive atypical choroid plexus papillomas may have an irregular margin with adjacent white matter edema. ^[19] (See also the Medscape Reference article Imaging in Choroid Plexus Papilloma.)

In contrast, choroid plexus carcinomas are usually larger than papillomas and display heterogeneous signal patterns on both CT scans and MRIs. Their enhancement characteristics are likewise more variable, and intratumoral calcifications, necrosis, and hemorrhage may be present. Cystic change and flow voids are features shared with choroid plexus papillomas. Unlike choroid plexus papillomas, however, carcinomas frequently invade the adjacent/periventricular brain parenchyma with associated vasogenic edema. Leptomeningeal enhancement correlates with cerebrospinal fluid (CSF) dissemination of the tumor (see the following image). ^{[16, 20]}

Gross inspection of choroid plexus neoplasms is available through autopsy or surgical retrieval of tumor material. Choroid plexus papillomas are generally well-circumscribed, globular, cauliflowerlike masses that frequently adhere to the ventricular wall but which do not invade into the brain parenchyma proper. Often, there is surface stippling that correlates with a papillary microscopic architecture. Their pink to red-brown coloration is due to extensive vascularity. Calcifications, cysts, and hemorrhages may be seen. ^[21] Choroid plexus carcinomas consist of a solid tissue mass with invasion into the periventricular brain parenchyma. Hemorrhage and necrosis are common.

The three World Health Organization (WHO) grades of choroid plexus neoplasms are discussed in this section. Cytopathology and ultrastructural studies of choroid plexus neoplasms are discussed below.

Choroid plexus papillomas (WHO grade I)

The fibrovascular papillary projections of choroid plexus papilloma are lined by cuboidal to columnar epithelium with significantly more cell crowding, elongation, and stratification in comparison to the orderly cobblestone appearance of normal choroid plexus tissue. They likewise often display a mildly elevated nuclear-to-cytoplasmic ratio, nuclear hyperchromasia and/or irregular nuclear profiles, and occasional mitoses. Nonetheless, the epithelial cells of choroid plexus papillomas are typically cytologically bland, and they may have eosinophilic or clear cytoplasm. ^[22]

On occasion, papillomas may show oncocytic change, melanization, cytoplasmic vacuolization reminiscent of signet ring cells, tubular-glandular architecture, focal ependymal differentiation, or neuropil-like islands. ^{[23, 24, 25]} Degenerative features may be quite prominent, including an angiomalike increase in blood vessels; hyalinization or calcification; xanthomatous or mucinous change; or formation of metaplastic bone, cartilage, or adipose tissue. ^{[25, 26, 27]}  Features such as brain invasion, hypercellularity, necrosis, overt nuclear pleomorphism, and loss of papillary architecture are generally absent. See examples in the following images.

Atypical choroid plexus papillomas (WHO grade II)

Although they closely resemble grade I choroid plexus papillomas, the hallmark of atypical choroid plexus papillomas (WHO grade II) is their increased mitotic activity (defined as ≥2 mitoses per 10 high-power fields [HPF]) ^[1] (see the first image below). Cribriforming, anastomosing papillary formations, and focal solid growth patterns (see the second image below) may be encountered. Additional histologic features often present in atypical choroid plexus papillomas include hypercellularity, nuclear pleomorphism, and necrosis. ^{[1, 28]}

Choroid plexus carcinomas (WHO grade III)

Although choroid plexus papillomas typically look similar, one to another, choroid plexus carcinomas (WHO grade III) are notable for their significant histologic heterogeneity and ability to mimic a wide variety of both primary brain tumors and metastatic lesions. Choroid plexus carcinomas show frank features of malignancy. According to the 2016 WHO criteria, they must harbor at least four of the five following characteristics: elevated mitotic activity (generally >5 mitoses per 10 HPF), hypercellularity, nuclear pleomorphism, solid growth with sheets of tumor cells, and necrosis. ^{[1, 29]} Papillary architecture may be retained focally in some choroid plexus carcinomas, although it may be completely absent in others. Extensive invasion into the surrounding brain parenchyma is a frequent finding.

Choroid plexus carcinomas may contain cells with a rhabdoid morphology similar to that seen in atypical teratoid/rhabdoid tumors, or small primitive-appearing cells resembling those in medulloblastomas and other central nervous system (CNS) embryonal tumors. ^{[22, 30, 31]} Unusual and degenerative histologic features akin to those noted above for choroid plexus papillomas (especially melanin pigment) may be encountered in occasional choroid plexus carcinomas. ^[32]

The following images illustrate different examples of choroid plexus carcinomas.

Choroid plexus papillomas may closely resemble normal choroid plexus or villous hypertrophy on cytology, except choroid plexus papillomas usually have more papillary clusters, sheets, and isolated single cells. The tumor cells tend to be cuboidal to columnar with a moderate amount of cytoplasm and bland nuclei with fine chromatin. Choroid plexus papillomas may also be difficult to distinguish from papillary ependymoma; papillary ependymomas have multilayered cell clusters with glial processes approaching a central blood vessel. ^[33]

In contrast, the cytologic features of choroid plexus carcinoma include tight three-dimensional clusters and isolated anaplastic cells, variably sized nuclei, a high nuclear-to-cytoplasmic ratio, nuclear indentations and lobulations, single or multiple micronucleoli, and scant, pale, granular cytoplasm. Papillary architecture tends to be minimal or absent, mitotic activity and hypercellularity are obvious, and necrosis is often present. ^[34] (see the following image).

When examined under electron microscopy, choroid plexus tumors are seen to be composed of epithelial cells with interdigitating cell membranes, apical tight junctions, bulbous microvilli, coated vesicles, and cytoplasmic intermediate filaments. A continuous basement membrane separates these cells from the nearby capillaries with their fenestrated endothelial cells. ^[35] Cilia are consistently present in choroid plexus papillomas, but they may have an abnormal arrangement; these are less frequent and more difficult to identify in choroid plexus carcinomas. ^[36]

Pigmented choroid plexus tumors may demonstrate either melanosomes in various stages of development or accumulation of neuromelanin on electron microscopy. ^[32]

Expression of pancytokeratin and vimentin is a consistent feature of choroid plexus papillomas, whereas staining for S100 protein, glial fibrillary acidic protein (GFAP), transthyretin, and synaptophysin is more variable (see the image below). ^{[22, 37, 38, 39, 40]} Ethidium monoazide (EMA) is usually negative, as is carcinoembryonic antigen (CEA). ^{[37, 38]}

Interestingly, expression patterns may vary by tumor location, patient age, and tumor grade. For example, S-100, transthyretin, and GFAP are all less likely to be positive in choroid plexus carcinomas compared with choroid plexus papillomas. S-100 expression tends to be greater in choroid plexus tumors arising in the fourth ventricle, whereas transthyretin expression by these tumors may be higher in patients older than 20 years. ^[37] Although any combination of positivity for CK7 and CK20 may be encountered, it is the limited focal staining of choroid plexus tumors with these markers that is useful in discriminating them from metastatic carcinomas. ^{[25, 41]}

Similar to choroid plexus papillomas, choroid plexus carcinomas are generally immunopositive for cytokeratin; however, s100 and transthyretin are less consistently positive. ^{[22, 37, 38, 40, 42]} Synaptophysin, GFAP, CA19-9, and EMA may all be focally expressed, whereas CEA staining is quite unusual. ^{[39, 43, 44]} MIB-1 (Ki67) proliferative index is typically brisk in choroid plexus carcinomas, ^[45] and the majority show nuclear positivity for p53. ^[46]

Several markers may be helpful in distinguishing choroid plexus neoplasms from other primary central nervous system and metastatic tumors. For example, membranous positivity for excitatory amino acid transporter-1 (EAAT-1) is present in a significant proportion of choroid plexus tumors, whereas EAAT-1 is typically negative in metastatic adenocarcinoma, urothelial and small cell carcinomas, and endolymphatic sac tumors (which may quite closely mimic choroid plexus tumors). ^{[47, 48]}

HEA-125 and Ber-EP4 are negative in most choroid plexus neoplasms, whereas these markers are positive in most metastatic carcinomas. ^[49]

Synaptophysin may also be useful in distinguishing choroid plexus neoplasms from metastatic papillary carcinomas, as synaptophysin is frequently demonstrable in choroid plexus neoplasms but lacking in the later. ^[39]

CA19-9 and CEA, which are positive in some metastatic carcinomas, are also occasionally positive in choroid plexus carcinomas. Although not useful in distinguishing choroid plexus neoplasms from metastatic carcinoma, both of these markers can be detected in peripheral blood and may be efficacious as follow-up tumor markers after treatment. ^{[42, 43, 50]}

The inwardly rectifying potassium channel Kir7.1 and stanniocalcin-1 have been found to be both sensitive and specific markers for choroid plexus neoplasms when compared to other primary brain tumors and metastases. ^{[40, 48]}

Laminin and collagen IV, however, highlight the basement membrane in almost all choroid plexus papillomas and can therefore effectively separate these lesions from papillary ependymomas, which lack such basement membranes. Basement membrane stains may not be quite as useful in choroid plexus carcinomas in which fragmentation of the basement membrane is quite common. ^[51]

E-cadherin is positive in many choroid plexus tumors and may be useful in distinguishing them from ependymomas, as ependymomas are typically negative. ^[52] Podoplanin is positive in almost all choroid plexus tumors, but it is also frequently positive in ependymomas and some other primary brain tumors. ^[53] Lastly, nuclear INI-1 (BAF-47) reactivity is retained in choroid plexus carcinomas, but this finding is absent in atypical teratoid/rhabdoid tumors (AT/RTs), aiding in differentiation between these two neoplasms. ^[54]

See the image below.

Choroid plexus papillomas and atypical papillomas are frequently hyperdiploid, whereas choroid plexus carcinomas tend to mainly harbor chromosomal losses. ^[55]  Comparative genomic hybridization and more recent high-resolution genomic and methylation profiling studies not only confirm genetic differences between choroid plexus papillomas and choroid plexus carcinomas, but they likewise suggest that there are genetic distinctions between adult and pediatric choroid plexus tumors. ^{[55, 56, 57]}  In addition to recurrent gains common to all choroid plexus neoplasms (including gains in regions harboring OTX2, LAMB1, and TRPM3), focal alterations shared by papillomas and atypical papillomas have been detected, as well as separate and distinct carcinoma-specific alterations. ^{[55, 57]}  

With regard to specific genetic alterations, VHL allele loss may be seen in those choroid plexus papillomas arising in the context of von Hippel-Lindau disease. ^[8]  Activation of the Notch signaling pathway may also play a role in the formation of choroid plexus papillomas, with nuclear translocation or overexpression of one or more Notch receptors (Notch 1, 2, and 3) identified in some choroid plexus papillomas. ^[57] Chromosome 22q loss and INI1 alterations have been described for some choroid plexus carcinomas; nonetheless, immunohistochemical studies have indicated that INI1 protein expression remains intact in choroid plexus carcinomas, including those with a "rhabdoid morphology." ^[54] Lastly, platelet-derived growth factor (PDGF) receptors may be overexpressed or amplified in some choroid plexus carcinomas. PDGF receptor signaling has been suggested as a potential therapeutic target. ^[58]

Choroid plexus tumors need to be distinguished from a wide variety of lesions, both neoplastic and non-neoplastic. In the realm of non-neoplastic lesions, choroid plexus papillomas must be distinguished from both normal choroid plexus and villous hypertrophy of the choroid plexus; as discussed earlier, mild epithelial cell cytomorphologic abnormalities in conjunction with cellular crowding and stratification are reliable features in favor of choroid plexus papillomas. ^[59]

In addition to choroid plexus papillomas, a number of other primary central nervous system (CNS) tumors may exhibit a papillary architecture; papillary ependymoma and astroblastoma would be the most likely to cause diagnostic confusion. Choroid plexus papillomas have a cytokeratin-positive epithelium with an underlying demonstrable basement membrane, and they lack the perivascular pseudorosettes and diffuse positivity for glial fibrillary acidic protein (GFAP) of these other tumors.

On a similar note, anaplastic ependymoma may mimic choroid plexus carcinoma; choroid plexus carcinoma is distinguished by virtue of strong cytokeratin positivity, lack of significant GFAP staining, lack of true or perivascular pseudorosettes, and a present (although often fragmented) basement membrane. Choroid plexus tumors are also typically E-cadherin positive and neural cell adhesion molecule (NCAM) negative, whereas ependymomas exhibit an inverse staining pattern for these markers. ^[52]

Choroid plexus tumors arising in the adult population need to be differentiated from a host of metastatic carcinomas (papillary or otherwise). This workup often necessitates a battery of immunohistochemical studies. Transthyretin and/or S100 expression is supportive evidence for a choroid plexus neoplasm—unfortunately these stains are not 100% reliable. Whereas CK7 and CK20 may not be especially helpful, demonstration of GFAP and/or synaptophysin positivity would not be expected in metastatic carcinomas, and would therefore favor choroid plexus tumor. Additional immunostains may be needed in some cases, choroid plexus carcinomas being positive for EAAT1, Ki17.1, and stanniocalcin-1, whereas positivity for HEA-125 and BerEP4 are indicative of a metastatic carcinoma. ^[49]

As noted previously, choroid plexus carcinomas may contain cells with rhabdoid morphology and immunohistochemical polyphenotypia, thus raising consideration of atypical teratoid/rhabdoid tumor (AT/RT) as a possible diagnosis. To complicate matters somewhat, choroid plexus carcinomas (similar to AT/RT) frequently show chromosome 22q deletions; therefore, fluorescence in situ hybridization (FISH) assays for INI1 (22q11.2) copy number alterations are of minimal utility in this differential diagnosis. In contrast, positive nuclear staining with anti-INI1 (BAF-47) by immunohistochemistry reliably differentiates choroid plexus carcinoma from AT/RT, the latter consistently lacking nuclear positivity with this marker indicative of INI1 protein loss. ^[54]

Other conditions that should be considered when evaluating suspected choroid plexus neoplasms include metastatic cancer with unknown primary site, endolymphatic sac tumor, ^[48]  CNS embryonal tumor or medulloblastoma, and papillary thyroid carcinoma.

The extent of resection and histologic grade are the most important prognostic factors determining recurrence-free and overall survival in patients with choroid plexus tumors, and surgical resection remains the first-line therapy for these patients. ^[60] Choroid plexus papillomas may be cured by gross total resection alone, and even in cases with recurrent disease, the outcome is often still favorable (5-year survival rates of 80-100% following gross total resection and approximately 68% following subtotal resection). ^{[3, 61, 62]} A small percentage of choroid plexus papillomas undergo malignant progression, but this is an extremely rare occurrence. ^[63]

Choroid plexus carcinomas are significantly more aggressive, with a greater tendency for leptomeningeal dissemination and/or recurrence as well as a survival rate around half of that seen with choroid plexus papillomas. ^{[2, 3, 4, 61]}  Choroid plexus carcinomas may have a favorable outcome when gross total resection is combined with adjuvant chemotherapy and/or local radiotherapy. ^{[2, 5, 64, 65, 66]}  One study found that carcinomas with two copies of mutated TP53 were significantly more aggressive and resulted in poorer survival outcomes then carcinomas with only one mutated TP53. ^[57]  Relatively recent evidence suggests that methylation profling may potentially provide useful prognostic information for choroid plexus tumor, in addition to histopathology. ^[56]  Craniospinal irradiation may be helpful in those cases of choroid plexus carcinoma that undergo subtotal resection and/or have disseminated leptomeningeal disease at presentation. ^{[16, 67, 68]}

Not surprisingly, atypical choroid plexus papillomas fall somewhere between these two extremes in terms of their biologic behavior; in general, atypical choroid plexus papillomas have a good prognosis but with a greater risk of local recurrence than conventional choroid plexus papillomas. ^{[1, 69]} In fact, increased mitotic activity is the only histologic feature identified to be independently associated with recurrence: choroid plexus papillomas with increased mitoses carry nearly five times the risk of recurrence compared with less proliferative papillomas. Additional histologic features suggesting a poor prognosis include decreased S-100 protein expression (<50% of cells strongly positive for S-100), lack of immunoreactivity for transthyretin, brain invasion, lack of marked stromal edema, and the presence of necrosis. ^[28]

For more detailed information regarding choroid plexus neoplasms, the authors suggest the following resources:

• Louis DN, Ohgaki H, Wiestler OD, et al, eds. WHO Classification of Tumours of the Central Nervous System. Lyon, France: IARC Press; 2016. ^[1]

• Mallick S, Benson R, Melgandi W, Rath GK. Effect of surgery, adjuvant therapy, and other prognostic factors on choroid plexus carcinoma: a systematic review and individual patient data analysis. Int J Radiat Oncol Biol Phys. 2017 Dec 1. 99 (5):1199-206. [QxMD MEDLINE Link]. ^[5]

• Wrede B, Hasselblatt M, Peters O, et al. Atypical choroid plexus papilloma: clinical experience in the CPT-SIOP-2000 study. J Neurooncol. Dec 2009;95(3):383-92. [QxMD MEDLINE Link]. ^[69]

• Ogiwara H, Dipatri AJ Jr, Alden TD, Bowman RM, Tomita T. Choroid plexus tumors in pediatric patients. Br J Neurosurg. Feb 2012;26(1):32-7. [QxMD MEDLINE Link]. ^[61]

• Bettegowda C, Adogwa O, Mehta V, et al. Treatment of choroid plexus tumors: a 20-year single institutional experience. J Neurosurg Pediatr. Nov 2012;10(5):398-405. [QxMD MEDLINE Link]. ^[3]

• Wrede B, Liu P, Wolff JE. Chemotherapy improves the survival of patients with choroid plexus carcinoma: a meta-analysis of individual cases with choroid plexus tumors. J Neurooncol. Dec 2007;85(3):345-51. [QxMD MEDLINE Link]. ^[68]

• Passariello A, Tufano M, Spennato P, et al. The role of chemotherapy and surgical removal in the treatment of choroid plexus carcinomas and atypical papillomas. Childs Nerv Syst. 2015 Jul. 31 (7):1079-88. [QxMD MEDLINE Link]. ^[67]

• Merino DM, Shlien A, Villani A, et al. Molecular characterization of choroid plexus tumors reveals novel clinically relevant subgroups. Clin Cancer Res. 2015 Jan 1. 21 (1):184-92. [QxMD MEDLINE Link]. ^[57]