M.A. Hayat (ed.)Tumors of the Central Nervous SystemTumors of the Central Nervous System, Volume 132014Types of Tumors, Diagnosis, Ultrasonography, Surgery, Brain Metastasis, and General CNS Diseases10.1007/978-94-007-7602-9_21
© Springer Science+Business Media Dordrecht 2014
21. Differentiating Choroid Plexus Tumors from Metastatic Carcinomas: Use of Inwardly Rectifying K+ Channel KIR7.1 and Excitatory Amino Acid Transporter-1
(1)
Institute of Pathology and Neuropathology, Department of Neuropathology, University Hospital Tübingen, Tübingen, Germany
Abstract
The choroid plexus is a villous structure within the ventricular system of the brain and consists of a fibrovascular stroma with fenestrated blood vessels, which is covered by the choroid plexus epithelium. The choroid plexus epithelium is of neuroectodermal origin and bears both features of glial and epithelial cells. Tumors of the choroid plexus (CPT) include choroid plexus papilloma (CPP), atypical CPP and choroid plexus carcinoma (CPC). CPP and atypical CPP are typically papillary tumors that may contain areas of solid growth. CPC are typically pleomorphic tumors with predominantly solid growth. Thus, histological distinction of CPT may be difficult from both, metastasis from well differentiated papillary adenocarcinomas and from less differentiated carcinomas. CPTs are rare neoplasm’s most frequently affecting children. In contrast, brain metastases from adenocarcinomas are rather frequent but usually arise in adult and elderly patients. The overall frequency of solitary metastases to the choroid plexus or its direct vicinity outnumbers primary CPT. Thus, the differential diagnosis of CPT and brain metastasis should always be considered and additional immunostainings are required, especially in adult patients. Under this point of view, the value and the limits of several antibodies are summarized and the most significant role of Kir7.1 and EAAT1 is sustained.
Introduction
Choroid plexus tumors (CPT) are rare neoplasm’s accounting for 0.3–0.6% of all brain tumors and arise most frequently in the first decade of life but may occur at any age (Paulus and Brandner 2007). CPT may occur at any site where the choroid plexus is physiologically present, i.e., within any of the four cerebral ventricles or at the cerebellopontine angle. CPT may spread through the cerebrospinal fluid. According to the World Health Organization (WHO) classification of tumors of the CNS, primary tumors of the choroid plexus (CPT) are classified as choroid plexus papilloma (CPP, grade I WHO), atypical CPP (grade II WHO) and choroid plexus carcinoma (CPC, grade III WHO) (Paulus and Brandner 2007). Besides a typical papillary growth pattern closely resembling normal choroid plexus, CPTs may rarely show unusual histological features, such as tubular glandular architecture or mucinous degeneration or a solid growth pattern. Thus, the histological distinction of CPTs from metastatic (adeno-) carcinomas may be difficult. CPP can usually be cured by surgery and even for CPC a 10-year survival rate of ~35% can be expected. In contrast, overall survival of patients with brain metastases is usually <1 year. Thus, prognosis and therapeutic consequences differ between primary CPT and metastasis to the choroid plexus.
In contrast to CPT, metastatic tumors are much more common CNS neoplasms, and carcinomas are the most frequent source of brain metastases. Brain metastases usually occur in adult and elderly patients, an age group in which CPT are less common. Metastatic carcinomas can also be located within the choroid plexus or at sites where choroid plexus tissue might physiologically be present (intraventricular, cerebellopontine angle) (Kohno et al. 1996; Cha et al. 2000; Gopal et al. 2008). The incidence of solitary metastasis to the choroid plexus accounts for approximately 0.14% of all brain metastasis (Gopal et al. 2008). Taking together these data, the overall incidence of primary CPT is approximately only two to fourfold higher than the incidence of solitary metastasis to the choroid plexus. Consequently, in adult and elderly patients, the incidence of metastatic adenocarcinomas at these locations is probably equally or even higher than primary CPT. Thus, especially in adult and elderly cases, additional immunohistochemical examinations are needed to make an appropriate diagnosis. A suggestion of useful immunostainings to prove choroid plexus origin is given in this chapter. If initially a brain metastasis is expected, the panel of helpful antibodies depends on histology and clinical data, especially if a primary carcinoma is not reported in the files.
Immunoreactivity of Normal and Neoplastic Choroid Plexus Epithelium
Both, non-neoplastic choroid plexus epithelium and CPT show immunohistochemically a variable expression pattern, and there is no single immunohistochemical marker proved to be specific for choroid plexus. Normal choroid plexus epithelium and CPTs are consistently immunoreactive to antibodies against cytokeratin (CK) in the majority of cells. Among CPT subtypes that express CK in normal and neoplastic choroid plexus, CK7 is more frequently found than CK20. The most frequent combination of CK7 and CK20 observed in CPT is CK7+/CK20-, but any other combination may also be present in CPT (Gyure and Morrison 2000). CK8 and CK18 have also been noted in normal and neoplastic choroid plexus (Gianella-Borradori et al. 1992; Gertz et al. 1990).
The carcinoembryonic antigen (CEA) is usually negative in CPP but may be expressed in a subset of CPC (Ang et al. 1990; Coffin et al. 1986). However, expression of CEA may point to metastatic adenocarcinomas than CPT (Paulus and Janisch 1990).
The inwardly rectifying potassium channel Kir7.1 (Nakamura et al. 1999) has been reported to be expressed in 34/35 (97%) samples from normal choroid plexus and in 17/23 (74%) of CPT, including 5/5 CPC (Hasselblatt et al. 2006b). In our experience, all samples from normal (n = 5) and neoplastic (n = 75) choroid plexus are strongly Kir7.1 positive, including five CPCs.
The excitatory amino acid transporter-1 (EAAT1, homologous to rodent glutamate/aspartate transporter/GLAST) is a glial glutamate transporter that is predominantly expressed in astrocytes (Williams et al. 2005). In normal choroid plexus, membranous expression of EAAT1 is exceptional and significantly decreases with age. Expression levels of EAAT1 in the choroid plexus decrease throughout fetal life, and is usually absent in choroid plexus after birth. In normal choroid plexus, only a minority of pediatric samples may show few EAAT1 positive cells, whereas in adult cases EAAT1 immunostaining is constantly negative (Beschorner et al. 2009). In contrast, the majority of CPT (81%) is immunoreactive for EAAT1, and there is a significant increase in EAAT1 expression with age. CPTs from adult and elderly patients express EAAT1 in 90% of cases. This makes EAAT1 the sole marker to distinguish between normal and neoplastic choroid plexus, especially in adult cases (Beschorner et al. 2009).
S100 and transthyretin (prealbumin/TTR) are also frequently expressed in normal and neoplastic choroid plexus (Gaudio et al. 1998; Jacobsen et al. 1982; Redzic et al. 2005). Similarly, E-cadherin and aquaporin-1 are frequently expressed in both, normal and neoplastic choroid plexus (Figarella-Branger et al. 1995; Rickert and Paulus 2001). Immunoreactivity for vimentin and podoplanin (D2-40) may be found in normal and neoplastic choroid plexus (Nakamura et al. 2006).
Expression of Antibodies Applied in Diagnosis of Choroid Plexus Tumors, in Adenocarcinomas and Other Brain Tumors
Antibodies that are frequently applied in the diagnosis of CPT are also expressed in a variable frequency in adenocarcinomas of different primary sites. Depending on the origin of a metastatic carcinoma, besides pan-cytokeratin, cytokeratin subtypes such as CK7 and/or CK20 may be expressed, and the expected combination of CK7 and CK20 expression depends mainly on the anatomic origin of the tumor and may vary among histological subtypes. Thus, as in CPT, any combination of CK7/CK20 expression may be present in a brain metastasis. Expression of CK8 and CK18, which has also been noted in normal and neoplastic choroid plexus (Gianella-Borradori et al. 1992; Gertz et al. 1990), is not uncommon in metastatic adenocarcinomas of various origins. Furthermore, other primary brain tumors may be cytokeratin-positive (e. g., papillary tumor of the pineal region, atypical teratoid-rhabdoid tumor). The CEA is also not specific for CPT and is frequently expressed in gastrointestinal carcinomas. However, one study pointed out that expression of CEA may indicate metastatic adenocarcinoma instead of CPT (Paulus and Janisch 1990).
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