Choroid Plexus Carcinoma.
Abstract: Choroid plexus carcinoma is an uncommon neoplasm of the central nervous system most commonly found in the pediatric population. It is associated with a dismal prognosis, especially if incompletely resected. Accurate histopathologic diagnosis is imperative, and this neoplasm should always be included in the differential diagnosis of a papillary intraventricular tumor. Histopathologic features include blurring of papillary architecture, layers of neoplastic choroid plexus epithelial cells with pleomorphic nuclei, increased nuclear-to-cytoplasmic ratio, increased mitotic activity, areas of necrosis, and brain invasion. Current accepted treatment is gross total surgical resection of the tumor as the goal. Use of adjuvant chemotherapy is controversial at this time; however, it is considered in some cases.
Article Type: Disease/Disorder overview
Subject: Carcinoma (Development and progression)
Carcinoma (Care and treatment)
Cancer (Development and progression)
Cancer (Care and treatment)
Brain tumors (Development and progression)
Brain tumors (Care and treatment)
Choroid plexus (Medical examination)
Choroid plexus (Genetic aspects)
Authors: Gopal, Purva
Parker, John R.
Debski, Robert
Parker, Joseph C., Jr.
Pub Date: 08/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: August, 2008 Source Volume: 132 Source Issue: 8
Topic: Canadian Subject Form: Brain tumours; Brain tumours
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230246799
Full Text: Choroid plexus tumors are uncommon neoplasms derived from choroid plexus epithelium and characterized by papillary and intraventricular growth. Within this family of tumors, there are benign and malignant variants, typically classified as choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC), respectively. Choroid plexus tumors account for approximately 0.4% to 0.6% of all brain tumors. (1) Within the pediatric population, however, these neoplasms are more common, representing approximately 1% to 4% of all childhood brain tumors, with 10% to 20% occurring during the first year of life. (1) Although reported in adults, 80% of CPCs occur in the pediatric population, and 20% to 40% of all choroid plexus tumors in children are CPCs. (1)

Choroid plexus carcinoma is a highly aggressive malignant tumor (World Health Organization [WHO] grade III) which must be distinguished from CPP (WHO grade I). Distinction between these entities is imperative but can be challenging, and it is generally based on increased necrosis, mitotic activity, and change in growth pattern. (2) According to some authors, (3,4) histologic features may have no correlation with biologic behavior in that both CPPs and CPCs have been associated with metastatic disease. (5) The "atypical choroid plexus papilloma" has been described as a tumor with a few histologic features of malignancy, but diagnostic criteria for this classification are vague.

Current treatment strategy consists of gross total surgical resection for both CPP and CPC, with controversial use of adjuvant chemotherapy and radiotherapy for patients with CPC. (3) Complete resection is difficult due to the high risk of intraoperative hemorrhage; however, review of the literature supports complete surgical resection as the major prognostic factor for patients with CPC. (4)

CLINICAL FEATURES

Choroid plexus carcinoma is an uncommon, aggressive, malignant, central nervous system neoplasm that typically occurs in children and presents with the signs and symptoms of cerebrospinal fluid obstruction. Within the pediatric population, the median age is approximately 26 to 32 months. (1) Choroid plexus carcinomas are believed to arise from the choroid plexus epithelium. In general, they occur as follows: 50% lateral ventricles, 40% fourth ventricle, 5% third ventricle, and 5% multiple ventricular involvement. (1,6) Although infrequent, CPCs can occur in the cerebellopontine angle near the foramina of Lushka, and extremely rare cases may present as a suprasellar and/or intraparenchymal mass. (6-8)

Choroid plexus carcinoma has been associated with obstruction of the cerebrospinal fluid pathways and, potentially, overproduction of cerebrospinal fluid, leading to hydrocephalus and increased intracranial pressure. (6) An infant may present with hydrocephalus manifesting with increased head circumference, and signs and symptoms of increased intracranial pressure, including delayed development, bulging fontanelles, separated sutures, strabismus, or vomiting. An older child or adult can present with features of increased intracranial pressure, including vomiting, headache, neurologic deficits, seizures, lethargy, visual, and/or behavioral changes.

NEUROIMAGING

Studies generally include computed tomography and/ or magnetic resonance imaging. These radiographic studies typically demonstrate a large, hyperdense, contrast-enhancing, intraventricular mass (Figure 1). The tumor is usually associated with hydrocephalus and may contain focal calcification and hemorrhage. The vascular nature of the neoplasm can be appreciated with multiple flow voids. (6) Choroid plexus carcinoma may have metastases along the cerebrospinal fluid pathways, so imaging the entire neuraxis is important.

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GROSS PATHOLOGY

Choroid plexus carcinomas typically have a friable papillary or "cauliflower-like" appearance. Intraoperatively, CPCs may be loosely or densely adherent to the ventricular wall and minimally or widely invade the adjacent brain parenchyma. On sectioning, the tumors display solid areas intermixed with necrotic and hemorrhagic foci. Unlike CPCs, CPPs are usually well delineated from the underlying brain parenchyma and lack necrosis. (1,6)

HISTOPATHOLOGY/ DIAGNOSIS

Choroid plexus papilloma is characterized as a WHO grade I neoplasm, and it is histologically described as a benign tumor with a papillary configuration consisting of delicate fibrovascular cores lined by a single layer of cuboidal to columnar epithelium. The epithelial cytoplasm is abundant and eosinophilic, and the tumor nuclei are basal, monomorphic, and round to oval. The difference between CPP and normal choroid plexus resides in the crowding and elongation of cells in the papilloma. There is no invasion or necrosis, and mitotic activity should be rare. When a CPP has some limited malignant features, the diagnosis "atypical choroid plexus papilloma" is appropriate; however, distinctive criteria for diagnosis are not established. (1) A 2006 study by Jeibmann et al (9) examined a series of 164 choroid plexus tumors for the presence of atypical features and correlated these features with prognosis in an effort to create criteria for the diagnosis of atypical CPP. They showed that mitotic activity is the only feature that impacted the probability of recurrence in patients diagnosed with CPP. The group proposed that a mitotic count greater than or equal to 2 per 10 high-power fields could define a choroid plexus tumor as atypical, and the same study suggested that if at least two of the following histologic features are seen, including increased cellularity, nuclear pleomorphism, solid growth pattern, and/or necrosis, a diagnosis of atypical CPP would be warranted. (9) Using these criteria, the study examined a series of 124 previously diagnosed CPPs, and 15% of these were atypical CPPs. (9) Malignant evolution of a CPP which recurred as CPC has been reported in two patients, (3) but documented transition from benign to malignant histology is extremely rare. (10)

In comparison with the papilloma, the diagnosis of CPC is rendered in the setting of increased cell density, increased mitotic figures (usually greater than 5 per 10 high-power fields), nuclear pleomorphism (Figure 2), and necrosis (Figure 3). Diffuse invasion of the adjacent brain parenchyma is often present (Figure 4). While distinct papillary configuration is a hallmark of low-grade CPP, in CPC the papillary features are blurred or can be lost in the sheets of epithelial tumor cells, and this ill-defined growth pattern can make diagnosis challenging. (3,10) Proliferation indices, such as Ki-67/MIB-1 (Figure 5) can be useful in the diagnosis of CPC, with reported mean nuclear labeling rates of 1.9% for CPP and 13.8% in CPC. Choroid plexus carcinoma is classified as a WHO grade III tumor. (1)

DIFFERENTIAL DIAGNOSIS

An expansive differential diagnosis can be created in the clinical setting of an intraventricular papillary tumor. Within the choroid plexus, in addition to CPC and CPP, another consideration is villous hypertrophy of the choroid plexus, which is a benign proliferation causing enlargement of the choroid plexus in the lateral ventricles. Microscopically, these lesions have normal choroid plexus histology (1) and can also be distinguished from a neoplastic lesion using proliferation markers. (11) Ependymoma, particularly the papillary variant, is an additional consideration; however, characteristic cytologic and morphologic features on histologic examination, especially in a well-differentiated ependymoma, should be present. These features include monomorphic cuboidal cells with a flattened surface, (6) micronucleoli, stippled chromatin, ependymal rosettes, and the presence of perivascular pseudorosettes consisting of tapered cell processes oriented toward a central blood vessel. (12) Papillary meningioma, a rare high-grade (WHO grade III) variant of meningioma, can arise in the choroid plexus, especially in patients in the pediatric age group. (12,13) This tumor is described histologically as having a pseudopapillary or perivascular pattern in part of the tumor, which makes this meningioma a WHO grade III neoplasm. In infants, some embryonal-type (primitive neuroectodermal) tumors can occur in the same area. Of these, specific attention should be given to atypical teratoid/rhabdoid tumor (AT/RT), due to its aggressive nature. Histologically, AT/RT usually has groups of rhabdoid cells with eccentric, pleomorphic nuclei, and abundant eosinophilic cytoplasm. These tumors are high grade, with increased mitoses and necrosis. Atypical teratoid/rhabdoid tumor can be somewhat challenging to distinguish from CPCs that are poorly differentiated with foci of epithelial differentiation. Immunohistochemical staining can be useful in distinguishing between the two tumors, and it will be discussed in further detail below. Finally, metastatic neoplasms to the choroid plexus, especially in the adult population, are possible. The reported incidence of solitary metastases to the choroid plexus with no evidence of tumor in the brain parenchyma is rare, accounting for 0.14% of all cerebral metastases, the most common in adults being renal cell carcinoma. (14,15)

IMMUNOHISTOCHEMISTRY

Choroid plexus carcinomas typically stain positive for cytokeratins, and display variable expression of vimentin, S100, transthyretin, and glial fibrillary acidic protein (GFAP) (Figure 6). Positivity for S100 and transthyretin is typically less than that seen in CPP. Choroid plexus carcinomas stain positive for GFAP in approximately 20% of tumors, and they can express carcinoembryonic antigen. (1,10) Choroid plexus carcinomas are typically negative for epithelial membrane antigen.

The staining characteristics of CPC are somewhat inconsistent in that the commonly used markers lack specificity. (16-18) Hasselblatt et al (2) recently described a microarray-based approach to identify new diagnostic markers for CPC. Antibodies directed against stanniocalcin 1, a glycoprotein found in choroid plexus, and Kir 7.1, a choroid plexus apical epithelial protein thought to be involved in transepithelial potassium transport, were found to be specifically expressed in CPC and CPP, and could further assist in the diagnosis of these neoplasms. (2)

Furthermore, in 2006, Judkins et al (19) developed an immunohistochemical stain using the BAF47 clone of INI1 antigen. INI1 is a tumor suppressor gene that can be deleted and/or mutated in AT/RT. The group compared INI1 staining in CPC and AT/RT and found that most CPCs (21/28) stained positively for INI1, whereas the majority of AT/RTs did not stain. This immunostain could potentially assist in distinguishing between a poorly differentiated CPC and an AT/RT with extensive epithelial differentiation (Table).

GENETICS

Choroid plexus carcinoma has been described in association with Li-Fraumeni syndrome in families that carry TP53 germline mutations. The TP53 gene is located on chromosome 17p13.1 and encodes the tumor suppressor protein p53. A mutation of this gene causes loss of p53 function and prolongs the half-life of this protein. Appropriately, immunohistochemical staining for p53 can be increased in this setting. (20) According to a 2002 study by Carlotti et al, (21) positive nuclear staining for p53 was found in 10 of 11 CPCs, whereas only 1 of 12 CPPs stained positively. Also in 2002, 5 new families of pediatric patients with CPC were identified with TP53 mutations. This strengthens the previous belief that CPC could be used as an indicator of a germline TP53 mutation, especially in the setting of a family history of cancer. (22) Somatic TP53 mutations and spontaneous germline mutations have also been identified in some CPCs. (23) The presence of this genetic defect is believed to have important implications in the prevention and treatment of cancers in affected families. (21)

Comparative genomic hybridization has demonstrated the following common chromosomal additions and deletions in CPCs: +12p, +12q, and +20p (60%);+1, +4q, and +20q (53%);+4p (47%);+8q and +14q (40%);+7q, +9p, and +21 (33%);-22q (73%);-5q (40%);and -5p and -18q (33%). (22,23) A study by Rickert et al (24) also examined the behavior of CPCs with certain chromosomal additions and deletions and concluded that tumors with a gain of 9p and loss of 10q were associated with significantly longer survival.

TREATMENT/PROGNOSIS

Choroid plexus carcinomas usually grow rapidly and have a 5-year survival rate of approximately 40%. Two thirds of these tumors disseminate throughout the cerebrospinal fluid pathway, and malignant cells may be present in cerebrospinal fluid prior to resection. Systemic metastases may be seen in patients with longer survival. (10) There is currently no established protocol for the treatment of CPC; however, complete resection of the tumor is the primary goal. Gross total resection allows for the best chance of survival and improves the overall prognosis, (4,25) but complete resection is achieved in only 40% to 50% of children with CPC. (26,27) The prognosis of CPC is grave if not totally resected. Complete resection of this neoplasm is associated with high morbidity due to such factors as patient age, widespread tumor dissemination, and tumor vascularity, which puts patients at increased risk for intra-operative hemorrhage. The use of neoadjuvant chemotherapy to reduce tumor vascularity prior to surgery has been reported (28); however, this has not been accepted as a standard approach. Adjuvant chemotherapy after surgery remains controversial. (29) Some studies have demonstrated a decrease in tumor recurrence with adjuvant chemotherapy, whereas others have not shown any benefit. (30) Although some studies have demonstrated the benefit of postsurgical radiation therapy, radiation is generally avoided in the pediatric population due to severe long-term sequelae. Radiation is considered in the treatment of adult patients with CPC. (5)

With incomplete resection of CPC, second surgery may be beneficial. (4) One study of patients with CPC who had surgery was divided into subgroups of patients with completely resected tumors and incompletely resected tumors. (4) In those with incompletely resected tumors, 22.6% had a second surgery, and these patients had an increased 2-year survival of 69% compared with a survival of 30% for patients without second surgery. (4)

CONCLUSION

Choroid plexus carcinoma is an uncommon tumor that usually occurs in the lateral and fourth ventricles. It is associated with a poor prognosis. While the median age of occurrence is 26 to 32 months, this neoplasm should be considered in the differential diagnoses of a papillary intraventricular neoplasm, especially in children and less commonly in adults. Choroid plexus carcinoma is a WHO grade III tumor which is distinguished histologically from CPP based on increased nuclear to cytoplasmic ratios, increased mitotic figures, nuclear pleomorphism, the presence of necrosis, and distortion or blurring of the papillary structure of CPP by sheets of cells in the malignant counterpart. Immunohistochemical stains, while not entirely specific, can be useful in the diagnosis of CPC. Molecular studies including microarray analysis of CPC have identified other markers that may be useful in its diagnosis. CPC has been associated with Li-Fraumeni syndrome, and five additional families with children with CPC and the TP53 mutation were recently identified, suggesting that the presence of CPC in a family could be used as an indicator of a germline TP53 mutation. The current accepted treatment for CPC is surgical excision with controversial use of adjuvant chemotherapy. Although difficult due to the excessive vascularity of the tumor, gross total resection is the surgical goal, since this is associated with the most favorable prognosis.

We would like to thank Barbara K. Pawely, MD, of the Department of Radiology at Kosair Children's Hospital for providing the neuroimaging studies.

References

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(28.) St. Clair S, Humphreys R, Pillay P, et al. Current management of choroid plexus carcinoma in children. Pediatr Neurosurg. 1991;17:225-233.

(29.) Berger C, Thiesse P, Lelouch-Tubiana A, et al. Choroid plexus carcinomas in childhood: clinical features and prognostic factors. Neurosurgery. 1998;42: 470-475.

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Purva Gopal, MD; John R. Parker, MD; Robert Debski, MD; Joseph C. Parker, Jr, MD

Accepted for publication January 10, 2008.

From the Department of Pathology and Laboratory Medicine (Dr Gopal) and the Department of Pathology and Laboratory Medicine, Division of Neuropathology (Drs J. R. Parker and J. C. Parker, Jr), University of Louisville, Louisville, Ky; and the Department of Pathology and Laboratory Medicine, Kosair Children's Hospital, Louisville, Ky (Dr Debski).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Joseph C. Parker, Jr, MD, Department of Pathology and Laboratory Medicine, University of Louisville Hospital, 530 S Jackson St, Room COF19, Louisville, KY 40202 (e-mail: jcpark01@gwise. louisville.edu).
Immunohistochemical Staining of Tumors in Differential Diagnosis of
Choroid Plexus Carcinoma (CPC) *

                                      CAM
                                      5.2      Transthyretin     GFAP

CPC                                    +            +/-          +/-
Papillary ependymoma                   -            NA            +
Papillary meningioma                   -            NA            -
Atypical teratoid/rhabdoid tumor      +/-           NA           +/-

                                      Epithelial
                                       Membrane
                                       Antigen        INI1

CPC                                       -             +
Papillary ependymoma                     +/-            +
Papillary meningioma                      +            NA
Atypical teratoid/rhabdoid tumor          -             -

                                        Kir
                                        7.1      Stanniocalcin 1

CPC                                      +              +
Papillary ependymoma                     -              -
Papillary meningioma                    NA             NA
Atypical teratoid/rhabdoid tumor         -              -

* GFAP indicates glial fibrillary acidic protein; +, present; -,
absent; and NA, not applicable.
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