Focal ependymal differentiation in choroid plexus papillomas

Summary Choroid plexus papillomas are usually easily distinguishable from papillary ependymomas by their delicate fibrovascular stroma and their cytologic similarity to normal choroid plexus epithelium. Exceptionally, however, examples are met which give rise to diagnostic difficulty. We therefore tested 22 choroid plexus papillomas for the presence of glial fibrillary acidic (GFA) protein using the immunoperoxidase technique. Positivity for the protein was found focally in epithelial tumor cells in nine of the 22 papillomas. All were in adults ranging from 19–66 years of age. Eight of the nine tumors originated in the 4th ventricle or from one of its lateral recesses. In six papillomas showing GFA protein in the cells, intracellular fibrils were found in a small number of elongated epithelial cells with the PTAH and/or Masson trichrome stains; in all these six cases, the GFA protein-positive cells were considerably more numerous than cells containing fibrils. Normal choroid plexus epithelium lacks GFA protein, but pathologically altered ependymal cells are often GFA protein-positive. Our findings therefore suggest that focal divergent glial (presumably ependymal) differentiation may be expressed in neoplastic choroid plexus epithelium, consistent with the origin of this epithelium from primitive neuroepithelial (ventricular) cells.This work was supported in part by Research Grant CA-11689 from the National Cancer Institute, USPHS     

Expression of EAAT-1 distinguishes choroid plexus tumors from normal and reactive choroid plexus epithelium

Microscopic distinction of normal choroid plexus (CP) from choroid plexus tumors (CPT) may be difficult, especially in small samples of well-differentiated CP papillomas. So far, there are no established markers that reliably distinguish normal and neoplastic CP epithelium. Recently, a correlation between expression/function of glial glutamate transporters EAAT-1 (GLAST) and EAAT-2 (Glt-1) and tumor proliferation has been reported. Furthermore, we previously found that CPTs frequently express EAAT-1, but not EAAT-2. We now compared expression of EAAT-1, EAAT-2 and GFAP in non-neoplastic CP (n = 68) and CPT (n = 79) by immunohistochemistry. Tissue of normal CP was obtained from 50 autopsy cases (20 normal and 30 pathologic brains) and 18 neurosurgical specimens that included 17 fetal, 21 pediatric and 30 adult cases. In non-neoplastic postnatal CP (n = 51), focal expression of EAAT-1 was found in only two pediatric cases (4%). In CPT, expression of EAAT-1 was found in 64 of 79 (81%) tumor samples and was significantly age-dependent (P < 0.0001). Hence, EAAT-1 expression distinguishes neoplastic from normal CP, both in children (P = 0.0032) and in adults (P < 0.0001). Immunostaining for EAAT-2 in selected samples from cases of different ages showed that normal CP (n = 15) or CPT (n = 16) lacked EAAT-2 expression. GFAP expression was found in 3 of 32 (10%) normal CP and in 28 of 73 (38%) tumor samples. In conclusion, in contrast to neoplastic CP samples, expression of EAAT-1 is exceptionally rare in non-neoplastic CP. Thus, EAAT-1 is superior to GFAP as a helpful diagnostic tool in CP samples.     

Choroid plexus tumors in infancy and childhood. Focal ependymal differentiation

Summary Rubinstein and Brucher [18] tested 22 choroid plexus papillomas for the presence of glial fibrillary acidic protein (GFAP), using the immunoperoxidase technique and obtained focal positive results in nine cases, all of which were adults (19–66 years of age). They recommended performing a similar study in children with a view to determining the incidence of ependymal differentiation.Here we report an immunoperoxidase study of 32 cases (1 month to 14 years of age) of choroid plexus tumors in infancy and childhood tested for GFAP. Nineteen cases were classified as benign papillomas and 13 as malignant (four of which included benign areas). The most frequent site [15] was the lateral ventricle (22 cases). Next came the fourth ventricle (six cases), then the third ventricle (three cases), and lastly the pontocerebellar angle (one case). We found positive results focally in epithelial tumor cells in 11 of the 32 cases (34.3%). Nine were benign and two were maligant with areas of benign or differentiated papilloma. Positive cells were present in these areas. GFAP-positive cells were classified in two groups according to their location. Type 1 cells were located in the epithelium Some of them were small rounded in contact with the basement membrane, without reaching the surface; others were elongated and columnar, some extending into processes that reached the basement membrane or the vessel walls in the stroma of the papillae.Type 2 cells were observed in the stroma of the papillae; these were elongated and stained strongly.An interesting feature in five positive cases was the observation of nodes formed by Type 2 (stromal) cells and fibrils associated with Type 1 cells in the overlying epithelium. Our finding that glial differentiation in choroid plexus papilloma epithelial cells is as frequent in children as it had been reported to be in adults, does not support the idea of a greater capability of divergent differentiation in infancy and childhood.     

Pathological alterations of ependyma and choroid plexus after experimental cerebral infection of mice with Sendai virus

Summary The effects of intracerebral inoculation of Sendai virus into young adult mice were investigated by immunofluorescence, light, and electron microscopy. Immunofluorescence of virus-specific antigens was maximal on the third day after inoculation, revealing infection of leptomeninges, ependyma, and choroid plexus. Histologically, meningitis, ependymitis, and choroiditis occurred between the second and third days. The choroiditis was associated with formation of vacuoles within the cytoplasm of epithelial cells. The vacuoles reached diameters up to 50 m. The ubiquitous vacuolization of plexus epithelia resulted in a honeycomb-like pattern. Opaque viral inclusions were visible within the cytoplasm of choroidal and ependymal epithelium as well as in mononuclear inflammatory cells. On electron microscopy, they were composed of intracytoplasmic nucleocapsid accumulations. Viria lay free between microvilli of plexus epithelial cells, and budding virus structures were observed at cellular surfaces. Occasionally, complete viria occurred in the cytoplasm of plexus epithelial cells and were surrounded by a unit membrane from which they appeared to arise by budding. The formation of this small cavity can be interpreted as the first stage of vacuole formation.This investigation was supported by Deutsche ForschungsgemeinschaftSupported by Freie und Hansestadt Hamburg and Bundesministerium für Jugend, Familie und Gesundheit     

Focal glial differentiation and oncocytic transformation in choroid plexus papilloma

Summary The histiopathological features of a choroid plexus papilloma in a 27-year-old male are described. The tumor displayed marked oncocytic transformation and glial differentiation of the epithelium in areas in which there was also marked sclerosis of the fibrovascular cores. Non-membrane-bound bodies of intermediate filaments characterized ultrastructurally the cells with glial differentiation.Support was derived from a grant-in-aid, Department of Pathology, University of Alabama at Birmingham     

Immunohistochemical evidence of endothelin-1 in human choroid plexus

Summary An immunohistochemical investigation was carried out on 17 specimens of human choroid plexus obtained post mortem, 1 biopsy of normal choroid plexus including part of the lateral ventricle and 1 papilloma of the choroid plexus removed surgically. The material was fixed in formalin. Paraffin and cryostat sections were used. A polyclonal antiserum to endothelin-1 served as a primary antibody. The avidin-biotin-peroxidase method was applied to demonstrate the immunoreaction. The epithelial cells of the choroid plexuses, the choroid papilloma and most ependymal cells of the lateral ventricle showed a distinct brown reaction product in their cytoplasm indicating antigenic sites to endothelin-1. The reaction was of lesser intensity in the ependymal cells. The connective tissue in choroid plexus was unstained. A positive immunoreaction was present in the walls of some vessels in the choroid plexus in cryostat sections. This is the first report on the presence of antigenic sites to endothelin-1 in the epithelial cells of the human choroid plexus. The role of endothelin in these cells should be investigated to ascertain if the cells synthesize this biologically active peptide or if it is merely bound to receptors in them.Supported by grants from Swedish Medical Research Council, project 03020, 1987 Års stiftelse för strokeforskning, Selanders stiftelse, Åhlen-stiftelsen and Stiftelsen Gamla Tjänarinnor, Stockholm Sweden     

Comprehensive lectin histochemistry of normal and neoplastic human choroid plexus cells: alternation of lectin-binding patterns through neoplastic transformation

Summary Lectin histochemistry of the normal and neoplastic human choroid plexus cells [six choroid plexus papillomas (CPPs) and three choroid plexus carcinomas (CPCs)] was performed using eight representative lectins to study the development of sugar chain structures and also to determine whether lectins were useful for a histopathological diagnosis of choroid plexus neoplasms (CPNs). The normal choroid plexus cells reacted with Ricinus communis (RCA-I), Canavalia ensiformis (Con A), Limax flavus (LFA) and Triticum vulgaris (WGA), while Arachis hypoaea (PNA) stained them only after the removal of sialic acid. Human fetal choroid plexus cells at 8 weeks gestation already showed the same lectin-binding patterns as adult ones. All CPNs were stained by RCA-I and Con A in a similar manner as the normal choroid plexus cells. Although seven CPNs were positive for LFA, two CPCs were not stained by LFA, which bound to sialic acid. Two LFA-positive CPPs were stained by PNA before the removal of sialic acid. Moreover, unlike the normal choroid plexus cells, Ulex europaeus-, Glycine maximus- and Dolichos biflorus- binding sites often appeared, and WGA-binding sites of three CPNs remained even after sialic acid removal. In conclusion, the glycosialylation in normal choroid plexus cells was completed during the early embryonic stage. The lectin-binding patterns of CPNs were heterogenous in each case. The alternation of the glycosialylation and/or acquisition of binding sites for some lectins was sometimes observed through a neoplastic transformation.     

The role of endoscopic choroid plexus coagulation in the surgical management of bilateral choroid plexuses hyperplasia

Background Bilateral choroid plexus hyperplasia is a rare condition often associated with cerebrospinal fluid (CSF) overproduction. CSF overproduction is usually so high that the placement of a CSF ventriculoperitoneal shunt almost always results in progressive ascites leading to the necessity of removing the inserted shunt device. A direct surgical treatment of the hyperplastic choroid plexuses is then mandatory. Endoscopic coagulation of the choroid plexuses has been recently proposed as an alternative to open surgical plexectomy. However, the effectiveness of the procedure in controlling CSF overproduction is still debated.Technique We report a case of bilateral choroid plexus hyperplasia in which an extensive bilateral endoscopic coagulation of the choroid plexuses failed to reduce the CSF formation rate sufficiently. A one-stage bilateral open surgical plexectomy was performed.Results The procedure succeeded to control CSF overproduction. Intraoperative blood loss during the surgical removal of the choroid plexuses was significantly reduced due to the previous coagulation of their surface.Conclusion On these grounds, we suggest that endoscopic choroid plexuses coagulation, even when failing to normalize CSF production, may still be considered as a valid adjuvant procedure in the management of this condition.     

Differential effects of chloroquine and of several other amphiphilic cationic drugs upon rat choroid plexus

Summary Several cationic amphiphilic drugs, each of which is known to induce generalized lipidosis in rats, were compared with respect to their cytological effects on rat choroid plexus epithelium. Chloroquine induced large cytoplasmic vacuoles, whereas the other drugs (quinacrine, 4,4-diethylaminoethoxyhexestrol, chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine) caused formation of lamellated or crystalloid inclusions as usually seen in drug-induced lipidosis. The ultrastructure of the chloroquine-induced vacuoles suggested storage of water-soluble materials (polar lipids and/or non-lipid materials) in addition to non-water-soluble polar lipids.Dedicated to Professor Dr. Helmut Leonhardt on the occasion of his 60th birthdaySupported by the Deutsche Forschungsgemeinschaft (Lu 172/3)     

Differential expression of cell adhesion molecules (CAM), neural CAM and epithelial cadherin in ependymomas and choroid plexus tumors

A series of frozen specimens of 18 ependymomas and 7 choroid plexus tumors were examined for their expression of cell adhesion molecules, such as neural cell adhesion molecule (NCAM), its polysialylated isoforms (PSA NCAM), and epithelial (E-) cadherin, and of intermediate filament proteins, such as glial fibrillary acidic protein (GFAP) and cytokeratin, using various monoclonal and polyclonal antibodies. Normal choroid plexus and ependyma were taken as controls. Anti-E-cadherin immunoreactivity was observed on the basolateral part of most adult choroid plexus and benign choroid plexus papilloma cells. However, a small number of atypical papillomas and carcinoma cells showed anti- E-cadherin immunoreactivity throughout their cell surface membrane. NCAM were not expressed by adult choroid plexus and benign papilloma cells. Only a few cells expressed NCAM and PSA NCAM in developing choroid plexus, atypical papillomas and carcinomas. Cytokeratin expression was always observed in choroid plexus and their tumors; GFAP expression was variable from case to case. In contrast, ependymal cells and their tumors never expressed E-cadherin but strongly expressed NCAM. PSA NCAM was found in ependymomas exhibiting anaplastic features. All ependymomas strongly expressed GFAP and a few demonstrated slight expression of cytokeratin. These data suggest that, besides GFAP and cytokeratin, NCAM and E-cadherin are of potential diagnostic value in distinguishing choroid plexus tumors from ependymomas. E-cadherin and NCAM may play a role in the functional organization of normal choroid plexus and ependyma, respectively. In particular, incomplete or irregular anti-E-cadherin expression in choroid plexus tumors and PSA NCAM immunoreativity in ependymomas and choroid plexus tumors correlates with the emergence of anaplastic histological features.     

First report of occurrence of choroid plexus papilloma and medulloblastoma in the same patient

Introduction Choroid plexus papilloma is a benign epithelial brain tumour showing a striking predilection for infants and occurring most frequently in the lateral and fourth ventricles. Medulloblastoma, on the other hand, is a primitive neuroectodermal tumour and is the most frequent malignant brain tumour of the posterior fossa in children. In this study, we report a metachronous occurrence of choroid plexus papilloma and medulloblastoma in the same patient, which has not been reported before to the best of our knowledge. Case report The authors describe the case of a girl who presented with an atypical choroid plexus papilloma on the posterior wall of the left lateral ventricle at 3 months of age that was resected completely. She was followed up regularly after surgery and made good progress with normal development. At 8 years of age, she presented with right cerebellar medulloblastoma. Discussion The authors review literature for incidence and aetiology of the two tumours.     

Characterization of intracellular amyloid fibrils in the human choroid plexus epithelial cells

Summary Intracellular inclusions with staining properties of amyloid are very common in the aging choroid plexus epithelial cells. In many ways these inclusions show similarities with the neurofibrillary tangles, found in cerebral cortical neurons in patients with Alzheimer's dementia. We have now designed a purification method for choroid plexus amyloid and performed a transmission and scanning electron miscroscopic study. This shows that one form of choroid plexus inclusions, the Biondi ring, is a homogeneous globule covered with a thin layer of amyloid fibrils. Partial immunochemical characterization of the choroid plexus amyloid reveals that it is different from the neurofibrillary tangles although there are similarities.Supported by the Swedish Medical Research Council (Project No. 5941) and the Research Fund of King Gustaf V     

Phosphoinositide hydrolysis linked 5-HT2 receptors in fibroblasts from choroid plexus

A serotonin (5-HT)-mediated phosphoinositide hydrolysis response was characterized in fibroblasts cultured from rabbit choroid plexus. 5-HT elicited a maximum 8-fold increase in [³H]inositol-phosphate ([³H]IP) formation, while the partial agonists, (+)-lysergic acid diethylamide and (−)-1-(4-bromo-2,5-dimethyoxyphenyl)-2-aminopropane caused 2- and 5-fold increases, respectively. Mianserin, ketanserin, and spiperone were equipotent at blocking the 5-HT-mediated response. Thus, agonist and antagonist profiles indicate interactions with 5-HT₂ receptors.     

Changes in the choroid plexus,responses by intrinsic epiplexus cells and recruitment from monocytes after experimental head acceleration injury in the non-human primate

Summary We have examined, by scanning and transmission electron microscopy, morphological changes in the choroid plexus of the lateral ventricles of the non-human primate brain after lateral head acceleration. We demonstrate passage of plasma and blood cells either through tears in blood vessels and the choroidal epithelium, or through the cells of the choroidal epithelium, 20 min after injury, together with morphological changes in that epithelium. At 3 and 4 h small cells with a reniform nucleus accumulate in the connective tissue core of the choroid plexus. We suggest that these are monocytes. At 6 and 12 h cells can be seen in enlarged intercellular spaces within the choroidal epithelium. These cells possess surface ruffles and we suggest that they are monocytes differentiating into macrophages and epiplexus cells. Further evidence for transepithelial migration of monocytes/macrophages is obtained at 7 days. However, at 28 days all blood has been removed from the surface of the choroid plexus and epiplexus cells possess an appearance typical of that in uninjured animals. The possible sources of epiplexus cells are discussed with reference to studies of responses after brain insult and of development. We have obtained no evidence in support of emperipolesis by monocytes through the choroidal epithelium. We suggest that monocytes/macrophages migrate, via an intercellular route, to differentiate into epiplexus cells, thus providing additional numbers of epiplexus cells after head injury.     

Characterization of prolactin receptor in human brain and choroid plexus

We have studied the binding of¹²⁵I-labeled human prolactin (PRL) to membranes from various regions of the human brain (hypothalamus, cerebral cortex, cerebellum and choroid plexus) derived from autopsy specimens. Among the various regions studied, the choroid plexus of both male and female subjects showed the highest specific binding and a clearly detectable specific binding was also observed in the hypothalamus of both sexes, whereas it was very low in other brain regions. No significant sex differences in PRL binding to various brain regions were observed except for the hypothalamus where a higher binding was seen in female subjects. The binding did not vary with the age of the subjects. Moreover, the cause of death and the time elapsed from death to autopsy in this study did not affect the binding significantly. The binding of¹²⁵I-labeled human PRL to hypothalamus and choroid plexus membranes from female specimens was inhibited in a dose-dependent manner by both unlabeled human and ovine PRL and by human growth hormone (GH), but not by other polypeptide hormones. Scatchard analysis of the binding revealed the presence of saturable binding sites with low capacity and high affinity for human PRL ligand. These results provide strong preliminary evidence for the presence of PRL binding sites in the human brain.     

CNS-specific T cells shape brain function via the choroid plexus

Adaptive immunity was repeatedly shown to play a role in maintaining lifelong brain function. Under physiological conditions, this activity was associated with CD4⁺ T cells specific for brain self-antigens. Nevertheless, direct interactions of T cells with the healthy neuronal parenchyma are hardly detectable. Recent studies have identified the brain’s choroid plexus (CP) as an active neuro-immunological interface, enriched with CNS-specific CD4⁺ T cells. Strategically positioned for receiving signals from both the central nervous system (CNS) through the cerebrospinal fluid (CSF), and from the circulation through epithelium-immune cell interactions, the CP has recently been recognized as an important immunological compartment in maintaining and restoring brain homeostasis/allostasis. Here, we propose that CNS-specific T cells shape brain function via the CP, and suggest this immunological control to be lost as part of aging, in general, and immune senescence, in particular. Accordingly, the CP may serve as a novel target for immunomodulation to restore brain equilibrium.     

Alteration of atrial natriuretic peptide receptors in the choroid plexus of rats with induced or congenital hydrocephalus

Specific binding sites for atrial natriuretic peptide (ANP) in the choroid plexus of rats with induced or congenital hydrocephalus were examined using in vitro quantitative receptor autoradiographic methods. The number of¹²⁵I-ANP binding sites in the choroid plexus of rats with kaolin-induced hydrocephalus was significantly higher as compared to findings in the control rats, whereas no differences in the binding affinity were observed 3 days and 3 weeks after the intracisternal injection of kaolin. Conversely, rats with congenital hydrocephalus (LEW-HYR and HTX rats) had a small number of binding sites for¹²⁵I-ANP in the choroid plexus, as compared to findings in the control rats. These alterations may relate to the pathophysiology of hydrocephalus. The possibility that atrial natriuretic peptide may be involved in the regulation of cerebrospinal fluid production in the choroid plexus must be considered.     

Disseminated choroid plexus papillomas in adults: A case series and review of the literature

Choroid plexus papillomas (CPPs) are uncommon, usually intraventricular, low-grade tumors, accounting for less than 1% of all intracranial neoplasms and 2–4% of brain tumors in children. Dissemination of CPPs to multiple levels of the neuraxis has been seldom observed. Thus far, only 26 adult patients have been reported in the English language literature. With some exceptions, disseminated CPPs have been observed in adults and involved multiple sites along the cerebrospinal fluid pathways. Occasionally, intraparenchymal extension has been documented, and secondary involvement of the suprasellar region has been reported in only five patients. Postoperative treatment of CPPs has not been standardized. Most recommended therapies have been extrapolated from a series of atypical papillomas or carcinomas of the choroid plexus in children. We herein report a series of three patients of disseminated choroid plexus papillomas providing additional insights into this relatively rare entity.     

Angiotensin II regulates choroid plexus blood flow by interacting with the sympathetic nervous system and nitric oxide

Blood flow to the rat choroid plexus has minimal variability when plasma angiotensin II (AII) concentration is changed within a broad range of levels. We tested the hypothesis that a complex interplay of the vasoconstrictor and vasodilator AII actions in choroidal tissue results in small net changes in choroidal blood flow. Blood flow was measured with ¹²³I- or ¹²⁵I-N-isopropyl-p-iodoamphetamine. AII was infused intravenously (i.v.) at 30 (moderate dose) and 300 ng kg⁻¹ min⁻¹ (high dose), which respectively decreased (15%) and did not change choroidal blood flow. To determine whether AII regulates choroidal blood flow by interacting with the sympathetic nervous system, rats were given phentolamine (1 mg kg⁻¹, i.v.). This α-adrenoceptor antagonist by itself did not alter blood flow; however, it attenuated the blood flow-lowering effect of moderate AII dose. Phentolamine also unmasked the vasodilator AII actions at high peptide concentration. β-Adrenoceptor blockade, with propranolol (1 mg kg⁻¹, i.v.), reduced blood flow (18–20%) and increased vascular resistance (23–26%). During β-adrenoceptor blockade, a further decrease in blood flow (15–21%) and increase in vascular resistance (23%) was noted when high AII dose was administered. The direct vasoconstrictor effect of AII at moderate dose on choroidal vasculature was examined in rats subjected to chronic bilateral superior cervical ganglionectomy. In these animals, AII decreased blood flow (24%) and increased vascular resistance (24%). To find out whether the hemodynamic AII actions in choroidal tissue are mediated by nitric oxide (NO), N^ω-nitro- -arginine methyl ester ( -NAME) was used. -NAME (0.1 mg kg⁻¹, i.v.) by itself did not alter blood flow; however, in -NAME-treated rats high AII dose lowered blood flow (25–32%) and increased vascular resistance (30–43%). We conclude that the vasoconstrictor AII actions involve a direct peptide effect on the choroidal vascular bed, and the AII-mediated potentiation of sympathetic activity, which results in the activation of α-adrenoceptors. The AII-mediated stimulation of sympathetic nerves also results in the β-adrenoceptor-dependent relaxation of choroidal blood vessels. In addition, choroidal vasodilatory actions of AII are NO-mediated.     

Purification and characterization of endoproteases from human choroid plexus cleaving prodynorphin-derived opioid peptides

An endoprotease converting the dynorphins and alpha-neoendorphin has been purified to apparent homogeneity from soluble extracts of human choroid plexus. The purified enzyme was stained as a single band after sodium dodecyl sulphate polyacrylamide gel electrophoresis with an apparent molecular weight of around 54,000 Da. The enzyme potently cleaves dynorphin A, dynorphin B and alpha-neoendorphin at consecutive pairs of basic amino acid residues generating Leu-Enk-Arg6, but it is less active on other neuropeptides containing dibasic stretches. It is optimally active at neutral pH, sensitive to EDTA and slightly affected by the serine protease inhibitors DFP and PMSF. A similar membrane-bound enzyme present in the same tissue was solubilized with 0.5% Triton X-100 and isolated with the same purification procedure. This latter enzyme showed almost identical properties with the soluble peptidase, except for a slightly higher molecular weight.