Choroid Plexus Anomalies: Cysts and Papillomas

Definition

Choroid plexus cysts (CPCs) are most frequently transient and benign, often round and sonolucent spaces within the developing choroid plexus of the lateral ventricles. They were first described by Chudleigh et al. and were found to be associated with aneuploidy, especially trisomy 18.

Choroid plexus papilloma (CPP) is a very rare, usually benign, fetal intracranial tumor. According to the World Health Organization classification of tumors of the nervous system, this more differentiated tumor is classified as a primary tumor of the choroid plexus grade I, as distinguished from atypical choroid plexus papilloma (grade II) and choroid plexus carcinoma (grade III).

Prevalence and Epidemiology

CPCs are frequently detected during the second-trimester US screening examination. The reported prevalence of fetal CPC ranges from 0.18% to 3.6%, independent of fetal sex.

CPPs represent 0.5% to 3% of intracranial tumors in children and 5% to 20% of all perinatal brain tumors. They are the most common brain tumors in the first year of life (up to 20%). Postnatally there is a male predilection, but a higher incidence in girls with Aicardi syndrome.

Etiology and Pathophysiology

CPCs are thought to originate from neuroepithelial folds of the choroid plexus filling with CSF and debris. The collection of fluid is surrounded by choroid plexus tissue. At 6 weeks' gestation, the onset of the development of choroid plexus, a bulge from the medial wall of the lateral ventricle, becomes covered with pseudostratified epithelium, and then lobulated with villi. The cells change from cuboid to columnar epithelium. The choroid plexus produces CSF beginning from ninth week of gestation, leading to expansion of the ventricular system. As the villi grow and become entangled, a cystic space is formed, which traps CSF. Most villi form at 13 to 18 weeks' gestation. Fluid accumulates and results in the formation of CPCs, which can be detected by prenatal US. Usually, the CSF is released and the cysts resolve as the stroma decreases with increasing gestational age, mostly between 26 to 28 weeks' gestation.

Choroid plexus and CPCs differ in vascularity. Kraus and Jirasek showed typical wavy longitudinal nonbranching capillary loops under the surface epithelium of the choroid plexus. In contrast, there is a net of interconnecting angiomatous irregular capillaries (capillary plexus) with variable volumes in the walls of CPCs.

CPCs are typically transient and benign findings. Without associated anomalies they should be considered normal variants. CPCs in low-risk populations confer a 1% aneuploidy risk, mostly for trisomy 18, but occasionally also for trisomy 21 and triploidy. CPCs are found in 30% to 53% of fetuses with trisomy 18 in the second trimester. In trisomy 18, CPCs are associated with other sonographic anomalies in the majority (80%–90%) of these cases, but in 11% of pregnancies with trisomy 18 CPCs, they were the only detected sign. They have no known association with other adverse outcomes when the karyotype is normal. Long-term outcome studies have shown that the prenatal finding of isolated CPC, in the absence of aneuploidy, was not associated with altered fetal growth and development, delayed infant and early childhood development, or significant neurocognitive or neurobehavioral delays. Even in a case series of fetal ventriculomegaly secondary to large CPCs, in all cases the lateral ventricles became normal or decreased in size during pregnancy, resulting in normal growth and development on long-term follow-up (4–6 years).

No other known fetal anomalies are linked to CPCs. All studies so far have shown that the presence of associated anomalies, but not of CPCs per se, are the most important predictor of a fetal chromosomal defect, followed by increased maternal age.

When isolated CPCs are found in a low-risk population, the likelihood of trisomy 18 increases 3.5-fold to 9-fold when assessing only this single marker. In a metaanalysis of 13 prospective studies involving 1346 second-trimester fetuses with isolated CPC, Yoder et al. found a significant association between isolated CPC and trisomy 18, with a likelihood ratio of 13.8. In association with a structural abnormality, the risk increase above baseline was almost 1800-fold. The risk of chromosomal abnormalities in the presence of isolated CPCs depends on the a priori risk. For example, based on maternal age alone, the risk changes from less than 1 : 2500 if the mother is 20 years old to about 1 : 50 if the maternal age is 45 years ( Table 33.1 ).

Other factors, such as serum analyte screening, can alter the calculated a priori risk. Gupta used data from 200,000 US examinations to calculate aneuploidy risk in pregnancies with fetal CPC. In women who had multiple-marker screening tests indicating no increased risk, who had otherwise normal-appearing fetuses, and who were younger than 32 years, isolated CPCs did not increase the risk of trisomy 18 sufficiently to indicate fetal karyotyping. From a metaanalysis of eight prospective trials published between 1990 and 2000, Demasio et al. concluded that there is no evidence that detection of isolated CPC in women younger than 35 years increases the risk of trisomy 18. CPCs were suggested as a possible minor marker of trisomy 21, but the prevalence of CPCs in fetuses with trisomy 21 and in the general population is the same (1.4%), so they should not be considered to increase the risk of trisomy 21.

CPP is a polygenetic disorder. Different genetic loci have been implicated, and chromosomal alterations such as +7q (65%), +5q (62%), +7p (59%), and +5p (56%) have been reported. Different pathways in tumorigenesis of CPPs are active, such as platelet-derived growth factor receptor (PDGFR), the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) pathways (CASP8, TFRSF10C, and TFRSF10D), Notch3 signaling, and the transcription factor TWIST1.

CPP is usually a benign tumor of ependymal origin, arising from the neuroepithelial cells of the choroid plexus, most commonly at the level of the atria of the lateral ventricles (70%–80%) but also from the third ventricle (14%), fourth ventricle (7%), and interventricular foramen.

CPP histologically resembles the nonneoplastic choroid plexus, with highly differentiated cuboidal epithelial cells based on papillary fibrovascular tissue, without signs of increased mitotic activity, nuclear atypia, or altered vascularization, but higher cellular density. These tumors are classified as choroid plexus papilloma World Health Organization grade I. The noninvasive and slow-growing tumor blocks the physiologic drainage of the CSF in the subarachnoid cisterns and secretes additional CSF, causing ventriculomergaly.

Malignant transformation of CPPs is rare (5%–10%). The 5-year survival rate after surgery of CPP has improved from 50% in early studies to approximately 100% in more recent reports, due to advances in imaging, surgical approaches, and quality of intensive care. There is no established association between fetal and neonatal tumors and chromosomal aberrations, other than in two syndromes, Aicardi-Goutières syndrome and hypomelanosis of Ito.

Manifestations of Disease