Choroid Plexus Carcinoma Research Articles

Abstract 2479: TP53 status as a marker of recurrence and survival in choroid plexus carcinomas

Abstract Choroid plexus carcinoma (CPC) is a rare intraventricular tumor more frequently observed in children, accounting for ∼20% of brain tumors in children under 2 yrs of age. This malignant neoplasm is categorized as a grade III tumor by the WHO, while benign choroid plexus papilloma (CPP) and atypical choroid plexus papilloma (aCPP) are categorized as grade I and II, respectively. More than 50% of CPC's carry a mutation in TP53. The role of p53 in the malignant progression of this tumor is not well understood, yet this knowledge is crucial to optimize patient treatment, increase survival and reduce long-term sequelae. The current treatment approach for CPC includes surgical resection and combination chemo- and radiation therapy. However, treatment response is highly variable; tumor progression and relapse is observed in ∼60% of patients, and most survivors experience significant long-term deficits. In this study, we sought to determine whether TP53 status could be used as a reliable marker to predict tumor aggressiveness and response to treatment in CPC patients. Thirty CPC, 26 CPP and 8 aCPP tumor samples for which TP53 status was available were selected from the SickKids Cancer Genetics tissue bank. Sequencing analysis revealed somatic TP53 in 60% of CPCs. These mutations were significantly less frequent in CPPs (12%, p=1.84x10−4). All aCPPs were wildtype (wt) for TP53. Relapse-free survival was only 12% in TP53 mut CPC patients compared to 40% for TP53 wt patients. Only 1 CPP patient relapsed 9 months after initial diagnosis. Five-year overall survival for TP53 mut CPC patients was significantly lower than that of TP53 wt patients (39% vs. 80%, respectively, p=0.04). Overall survival for 18 CPP patients for which we had 5-year survival data was 94%, and 100% for aCPP patients. Allele-specific copy number (ASCN) and FISH analysis, revealed extensive chromosomal imbalances in CPC tumors with TP53 mutations. TP53 wt CPCs had fewer chromosomal imbalances or none at all, very similar to CPPs. Gene expression data was used to examine the unsupervised clustering of our tumors. As expected, CPCs and CPPs cluster independently according to raw gene expression intensity, with TP53 wt CPCs segregating from the CPC mutant samples and clustering more closely to CPPs. Using an integrative analysis, we were able to identify unique behaviors and molecular characteristics that distinguish TP53 wt from TP53 mut CPCs. The clinical outcomes observed, supported by the genomic and transcriptomic data analyzed, suggest that TP53 mut and wt CPCs indeed form two distinct subgroups. This molecular genotyping approach may be valuable in stratifying patients to modulated therapy protocols in order to diminish treatment-related toxicity, and improve disease response and survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2479. doi:1538-7445.AM2012-2479

Abstract 1435: Phenotype:Genotype correlations of p53 mutation carriers: The 20-year Toronto experience

Abstract Introduction: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with germline mutations of the p53 gene. LFS is associated with early age of onset of breast cancer in women, childhood sarcomas and other malignancies. Previous studies have suggested potential correlations between p53 mutation type and clinical cancer phenotypes. For example, missense mutations within the DNA binding loop were found to be associated with higher prevalence of brain tumors and breast cancer whereas missense mutations outside the DNA binding loops were associated with higher prevalence of adrenocortical carcinoma. Through our Cancer Genetics Program (CGP), we have ascertained and conducted p53 mutation analysis on LFS patients/families from 1992 to the present. This represents one of the largest collections in the world. Here we set out to collate and characterize potentially novel genotype:phenotype associations from this database. Methods: TissueMetrix (Artificial Intelligence in Medicine (AIM), Toronto) was used to develop the CGP database. Clincal-pathologic data including family pedigrees, age of tumor onset, tumor type (confirmed with pathology reports where available were collected. From 1992-1998, Sanger sequencing of p53 encompassing the DNA binding domain (exons 5-8) was performed. Since 1998, the entire coding region and additional 50-100 bases spanning intron/exon splice sites have been sequenced and since 2007, MLPA testing has been performed to look for allelic deletion/duplication. Results: p53 mutations have been identified in 110 individuals, of whom 61 (55%) are less than 18years of age. Missense mutations the most common sequence alteration (83/110= 75%). The most commonly observed mutation was the dominant-negative Arg248Gln substitution (n=12). Monoallelic complete or partial gene deletion was observed in 10 cases, several of whom exhibited a non-cancer, developmental delay phenotype. The most common cancer were brain tumors (n=21), of which 10 were choroid plexus carcinomas. ADCC, breast cancer and sarcomas were commonly observed; non-classical LFS tumors, including neuroblastoma, papillary carcinoma of the thyroid and Wilms tumor are also seen. Conclusion: Our program, being situated in a pediatric tertiary centre has an inherent ascertainment bias which likely explains the high frequency of young p53 mutation carriers, as well as a disproportionate prevalence of childhood cancers. Nevertheless, unique correlations emerge from this rich resource including that of p53 deletion and hypotonia/developmental delay, as well as de novo and novel non-coding mutations. These correlations provide the foundation on which to develop practical genetic screening and clinical surveillance approaches to at-risk children and young adults. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1435. doi:1538-7445.AM2012-1435

Choroid Plexus Carcinoma: Prenatal Characterization by 3‐Dimensional Sonography and Magnetic Resonance Imaging, Perinatal Management, and Natural History

Choroid Plexus Carcinoma: Prenatal Characterization by 3‐Dimensional Sonography and Magnetic Resonance Imaging, Perinatal Management, and Natural History

Endoscopic coagulation of choroid plexus hyperplasia

Hydrocephalus is a clinical disorder resulting from an imbalance between the production of CSF and its resorption, of which the latter is mostly a disadvantage. In rare cases of choroid plexus papilloma or carcinoma, hydrocephalus is due to an overproduction of CSF. Choroid plexus hyperplasia (CPH) is a distinct clinicopathological entity in which the enlarged choroid plexus produces large amounts of CSF. Historically, patients with CPH were treated by shunt procedures or by microsurgical removal of the choroid plexus, which is associated with a high complication rate. In this paper the authors show that endoscopic plexus coagulation can result in restoring the equilibrium of the intracranial fluid volumes, resulting in shunt independency. In this way, both the shunt-related complications and the bleeding risks of microsurgical plexectomy are avoided. In instances of hydrocephalus, thorough efforts should be made to demonstrate the underlying pathophysiology to choose the optimal treatment, of which shunt procedures should receive the least priority.

A novel TP53 somatic mutation involved in the pathogenesis of pediatric choroid plexus carcinoma

SummaryBackgroundChoroid plexus carcinoma (CPC) is an uncommon, aggressive, malignant, central nervous system neoplasm that typically occurs in children, presenting with the signs and symptoms of intracranial hypertension and cerebrospinal fluid obstruction.Case ReportWe report the case of a 2.5-year-old girl with CPC. The tumor was subtotally removed by microsurgery, followed by gamma knife radiosurgery for the residual lesion. H&E staining indicated that this was a rare case of CPC. Neuropathological studies, assayed by immunohistochemical staining, showed that the tumor sample was positive to antibodies against S-100, CgA, AE1/AE3 (cytokeratin), Ki-67, INI1 and TP53, and was negative to antibodies against Nestin, GFAP, CD133, EMA and AFP. Moreover, stainings for transthyretin and vimentin were focally positive. Interestingly, direct DNA sequencing of the paraffin-embedded tumor sample identified a novel R248Q mutation in the TP53 gene. In contrast to previous reports suggesting that TP53 germline mutations were associated with the pathogenesis of CPC, here we provide a rare case of CPC with TP53 somatic mutation, as evidence that the peritumoral tissue possesses the non-mutant TP53 allele.ConclusionsOur finding suggests that TP53 somatic mutations, in addition to its germline mutations, may also be involved in the pathogenesis of pediatric CPC.

Choroid plexus carcinoma in an adult

Choroid plexus carcinoma is a very rare tumor in adults. Here we report a rare case of choroid plexus carcinoma in an adult patient. A 24-year-old male presented with a right temporal intraventricular tumor with a cystic component also extending up to the cortex. Histological examination revealed complex papillary structures and glandular spaces showing stratification and multilayering of cells with nuclear crowding and numerous mitotic figures and large areas of necrosis. The patient went through a complete search for a possible primary keeping in mind the differential diagnosis of metastatic carcinoma that is more common in adults but there was no evidence of any other tumor. Finally a diagnosis of choroid plexus carcinoma was rendered. Immunohistochemical analysis for p53 protein showed positivity. Choroid plexus carcinoma is exceptionally rare in adults but cases do occur.

Choroid plexus carcinoma: Case report and review of literature

Choroid plexus carcinoma: Case report and review of literature

Preliminary experience with personalized and targeted therapy for pediatric brain tumors

A new generation of anticancer drugs has reached clinical care in common diseases, but their use in rare diseases such as pediatric brain tumors lags behind since conventional clinical trial design requires larger patient numbers. We designed individualized treatment protocols for pediatric patients with relapsed brain tumors, based upon the patient's treatment history. In addition, each tumor was analyzed with morphoproteomics using a panel of markers to show treatment targets, resulting in a list of potential novel drugs to be added to chemotherapy. Here, we present the concept and report the experiences of the first patients enrolled in the program. Eleven treatment protocols were designed using morphoproteomic information and given to eight patients. The histological diagnoses included: medulloblastoma (n = 3), glioblastoma multiforme (n = 2), atypical teratoid rhabdoid tumor (n = 1), choroid plexus carcinoma (n = 1), and primitive neuroectodermal tumors (n = 1). Tumor markers included p-ERK, Topoisomerase IIa, Bcl-2, VEGF-A, p-STAT3, ER-beta, p-mTOR, and p-NF-kappaBp65. The novel agents included sorafenib, bevacizumab, fulvestrant, rapamycin, bortezomib, and curcumin. The response to the first protocol was complete response: 1, partial response: 1, stable disease: 0, progressive disease: 4, and continuous complete remission: 2. The median Event-Free Survival was 0.32 year ± 0.4. For the comparison with the institutional control group, the individual response probability was calculated. The observed response was superior to the historical controls (P = 0.006 Whitman U-test). This approach warrants further, systematic evaluation as proof of concept and then expansion to drug-specific hypotheses.

Aberrant E-cadherin, β-catenin, and glial fibrillary acidic protein (GFAP) expression in canine choroid plexus tumors

Expression of E-cadherin and β-catenin has been widely studied in various human and canine epithelial tumors and has been correlated with dedifferentiation, invasiveness, and metastasis. Choroid plexus tumors (CPTs) are of epithelial origin, and the most important prognostic factor in human medicine is the tumor grade. Limited information is available regarding E-cadherin and β-catenin expression in human CPTs, and no information is found in the veterinary literature. In the current study, 42 canine CPTs (19 choroid plexus papillomas and 23 choroid plexus carcinomas) were retrospectively reviewed, and the intensity and cellular staining pattern of E-cadherin and β-catenin were correlated with histological features, paying special attention to grade, invasion, and metastasis. In addition, cytokeratin and glial fibrillary acidic protein (GFAP) antibodies were evaluated as markers for canine CPTs. It was found that loss of E-cadherin and β-catenin expression was uncommon in canine CPTs. Rather, membranous expression of both molecules was increased in CPTs compared to normal choroid plexus (NCP), regardless of tumor grade. Additionally, aberrant cytoplasmic or nuclear expression of both E-cadherin and β-catenin was often observed in CPTs. GFAP was frequently expressed in CPTs in contrast to NCP. None of these parameters were correlated with malignancy, and therefore, do not appear to be useful for prognostic information. Nevertheless, a panel of antibodies including E-cadherin and GFAP might be useful to support the diagnosis of CPTs and help to differentiate them from other tumors, such as ependymomas and metastatic epithelial tumors.

Choroid plexus tumors; management, outcome, and association with the Li–Fraumeni syndrome: The Children's Hospital Los Angeles (CHLA) experience, 1991–2010

Choroid plexus tumors (CPT) are rare, and predominate in early childhood. An association with the Li-Fraumeni syndrome (LFS) has been reported, but the biological and clinical implications of this association remain poorly defined. We have investigated the clinical features and overall survival of all CPT patients treated at Children's Hospital Los Angeles (CHLA) over a 20-year period, with particular attention to the association of CPT with LFS. A retrospective evaluation of the course of therapy and clinical outcome was undertaken on the 42 patients diagnosed with and treated for CPT at CHLA from January 1991 to December 2010. Any association with multiple primary tumors and family histories consistent with LFS was investigated in all patients. Six of the 42 patients (16.7%), demonstrated either phenotypic and/or genotypic characteristics consistent with LFS, with either a distinct family history of cancer, a synchronous diagnosis of a different type of cancer, or the subsequent development of metachronous cancers. Of 11 patients with choroid plexus carcinoma tested for TP53 germline mutations, four (36.4%) were positive. A single patient with a choroid plexus papilloma had phenotypic characteristics of LFS but tested negative for TP53. Children with CPC appear to have a high frequency of TP53 germline mutations in association with LFS. This raises the question whether all children with CPC should be tested for TP53 germline mutations in order to institute screening to enhance early detection and treatment of subsequent cancers.

Hereditary cancer syndromes: If you look, you will find them

H ereditary cancer syndromes are estimated to account for up to 10% of all new cancer diagnoses in children and adults [1–4]. Given the current incidence of pediatric cancer, this translates to greater than 1,300 children in the United States and Canada diagnosed each year with a cancer related to a hereditary cancer syndrome. However, this widely quoted 10% rate is just an estimate extrapolated from the most common cancers known to be associated with inherited mutations and has not been systematically investigated. One publication last year described the population prevalence of familial cancer and common hereditary cancer syndromes based on 33,197 eligible respondents ages 18–64 years old in the 2005 California Health Interview Survey [5]. The investigators who conducted this survey assigned 14.6% of the cohort as having moderate familial risk associated with a twofold increase in cancer, and 7.7% of the cohort as having strong familial risk with a five to sevenfold increase in cancer. A similar type of population-based prevalence study to determine the true estimate of hereditary cancer in children has yet to be performed. Moreover, one could easily speculate that cancer in children is much more likely to be due to underlying genetic causes than in older adults who have diminishing DNA repair capability and longer environmental exposures. One of the best ways to identify children with an inherited cancer predisposition syndrome is to obtain an accurate family history. Due to the immediate life-threatening nature of a new cancer diagnosis in children (and its accompanying emotional toll), discussions with a newly diagnosed pediatric cancer patient’s family must focus on treatment strategies, and rightly so. Following a new cancer diagnosis, the coordination of staging CT scans, port placements, and chemotherapy orders often reduces the time needed for clinicians to obtain a very detailed cancer family history. However, collection of a more accurate family history ultimately could identify children and families who would benefit from a clinical cancer genetics referrals and even potentially participate in research. In addition to the family history, pediatric hereditary cancer syndromes can be suggested by a specific type of tumor or pattern of multiple cancers in a single individual [6–8]. For example, an extremely high percentage of patients with bilateral Wilms tumor will have a mutation in one of the WT genes (Wilms Tumor Syndrome). More than 80% of children with adrenocortical carcinomas (ACCs) will have TP53 germline mutations (Li-Fraumeni Syndrome), and this percentage is even higher in children with choroid plexus carcinomas. Eighty percent of children with bilateral retinoblastoma and 20% of children with unilateral retinoblastoma will have a germline mutation of the RB gene. Over 70% of pediatric patients with metastatic paragangliomas or pheochromocytomas may harbor underlying SDHB mutations (Familial Pheochromocytoma/Paraganglioma Syndrome). Approximately one-third of newly diagnosed patients with rhabdoid tumor will have an inherited INI1/SMARCB1 mutation (Rhabdoid Predisposition Syndrome). Twelve percent of pediatric gastrointestinal tumors (GISTs) have been described to have mutations in one of the SDH genes. Even hepatoblastoma has been associated with a 10% risk of carrying an APC mutation (Familial Adenomatous Polyposis [FAP] Syndrome). Cancers diagnosed in children that are usually seen in older adults such as colorectal or thyroid cancer also can indicate an inherited cancer predisposition syndrome. The list of pediatric tumors associated with hereditary cancer syndromes seems to grow longer every day. In this issue of Pediatric Blood & Cancer, Knapke et al. publish one of the first systematic pediatric hereditary cancer risk assessments by embedding a certified genetic counselor within a pediatric oncology follow-up clinic. Using this approach, they accurately determined the total percentage of 370 childhood cancer survivors who were appropriate for referral for cancer genetic screening. As Knapke and her colleagues report, with the help of their dedicated genetic counselor, they could identify a surprising 29% of childhood cancer survivors who qualified for genetic counseling. The majority of these referrals (61%) were based on family history, while tumor type accounted for 18%. The study was not designed to determine the mutation results for the 109 patients eligible for genetic testing, so we do not know how many referrals actually resulted in a hereditary cancer syndrome diagnosis for patients or their families. Nevertheless, the fact that they found over a quarter of all childhood cancer survivor patients met eligibility for cancer genetics referrals is remarkable. Moreover, this study population consisted of patients at least 5 years from their diagnosis and may underestimate the true percentage of pediatric patients eligible for genetic testing due to early deaths of certain patients. For instance, no patients were identified for

Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study

To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(2). The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m(2)/dose. At 260 mg/m(2)/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m(2); apparent volume of distribution, 7.36 (24%) L/m(2); and k(a), 0.358 (99%) hr(-1). MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m(2)/dose once daily.

Congenital CNS Tumors Diagnosed on Prenatal MRI

Congenital tumors form a unique group among pediatric neoplasms. They are different from other tumor groups in this population not only due to the onset time but also to their histopathology, anatomic location, biologic behavior and prognosis. The development of fetal MRI allowed early diagnosis of these tumors. Three fetuses with congenital central nervous system (CNS) tumors were diagnosed prenatally and confirmed with histopathology. Prenatal ultrasonography (US) and magnetic resonance imaging (MRI) were performed. After birth MRI or computed tomography (CT) were carried out. In one case a large intra-axial brain tumor was diagnosed with solid, cystic and hemorrhagic elements. After surgery the tumor turned out to be choroid plexus carcinoma. In the second case craniopharyngioma arising from the suprasellar region was diagnosed on the basis of prenatal MRI and confirmed. In the third case extra-axial meningioma-like tumor was visualized on fetal MRI. After surgery it turned out to be desmoplastic infantile astrocytoma. Intracranial teratoma, the most typical CNS congenital tumor, was not diagnosed in our material. Our cases were rarely encountered neoplasms: choroid plexus carcinoma, craniopharyngioma and desmoplastic infantile astrocytoma. The examinations were repeated after birth and did not add significant information. In utero diagnostics is easier and safer than postnatal imaging of the sick baby that may require life-support equipment, and provides information of equal value.

Carcinoma de plexo coroide: relato de caso e revisão de literatura

ResumoTumores do plexo coroide são tumores raros de origem neuroectodérmica, Correspondem a 0,4% a 0,6% de todos os tumores cerebrais, com incidência anual de 0,3 caso por milhão. Em sua maioria, são tumores benignos, raramente se apresentando na forma maligna. Os locais mais comumente relatados são os ventrículos. Relato de caso: Trata-se de carcinoma de plexo coroide em criança de 6 anos de idade que iniciou quadro com cefaleia, paresia do oculomotor, evoluindo com distúrbio de marcha. Foi submetida à biopsia, com confirmação histopatológica do carcinoma de plexo coroide. Esse paciente foi submetido à cirurgia, evolui bem com recuperação quase total no pós-cirúrgico imediato.

Fourth ventricular choroid plexus papilloma

Dear Editors, A 19-year-old girl presented with headache and dizziness over a 6–month-period. The headaches were frontal and postoccipital with dull throbbing quality and she was taking over the counter pain medications. Her headaches did not occur with coughing or straining. She initially thought that this was related to her recent 90 lb weight loss since being on a diet and exercise. She also noted intermittent dizziness accompanied by gait difficulty and a generalized weakness. The week prior to the admission, she had a severe headache, nausea, dizziness, shortness of breath and diffuse weakness. Her physical examination was remarkable for slight bilateral dysmetria, occasional bilateral hypometric saccades, and nystagmus on end gaze. The T1-weighted MRI with gadolinium revealed a heterogeneously enhancing mass fungating into the fourth ventricle and an obstructive hydrocephalus (Fig. 1). The patient underwent surgical resection, and the pathology confirmed a diagnosis of choroid plexus papilloma. Choroid plexus papillomas, which account for about 0.3–0.7 of all intracranial tumors, are more commonly seen in the pediatric population. The most common reported locations are the lateral ventricles (50%), followed by the fourth (40%) and third ventricles (10%) [1–3]. Given their hypervascularity, they usually demonstrate an intense enhancement on postcontrast images [1, 2]. From histopathologic perspective, choroid plexus papillomas are the most common tumor type arising from choroid plexus. Other pathologies include choroid plexus carcinomas and diffuse choroid plexus hyperplasia. Surgical resection is the treatment of choice for choroid plexus papillomas and progression-free survival approaches 100% even despite an incomplete resection [4]. However, choroid plexus carcinomas, which account for about 8–25% of all choroid plexus tumors, have a strong tendency to spread along the cerebrospinal fluid pathway with a variable response to surgery and adjuvant therapy. Hence, it is important to differentiate benign choroid plexus papillomas from this type of tumors [5].

MGMT promoter methylation and temozolomide response in choroid plexus carcinoma

Choroid plexus carcinoma (CPC) is a malignant tumor with a strong tendency to spread along the cerebrospinal fluid pathway. There is no standardized chemotherapy protocol for this rare tumor. We report a 38-year-old man with CPC in the lateral ventricle with obstructive hydrocephalus. Because of the poor demarcation between thalamus and fornix, subtotal tumor resection was performed. Postoperative spine magnetic resonance (MR) image revealed whole spinal axis dissemination. After diagnosis of CPC, the patient was treated with whole ventricular and spine radiation concomitant with temozolomide chemotherapy, although the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter was found to be unmethylated. Although MR images revealed transient stable disease during adjuvant therapy, tumor progression was depicted after four cycles of temozolomide therapy. We discuss the ineffectiveness of adjuvant temozolomide therapy for CPC in connection with O(6)-methylguanine-DNA methyltransferase promoter methylation.

Increased Incidence of Choroid Plexus Carcinoma Due to the Germline TP53 R337H Mutation in Southern Brazil

BackgroundChoroid plexus carcinomas (CPC) are rare tumors predominantly found in children. Given the high frequency of the germline R337H mutation in the TP53 gene in southern Brazil, we have evaluated the frequency of the R337H mutation in families with CPC in children.Methodology/Principal FindingsThe present series included 29 patients that were admitted to the same institution from 1992 to 2010, including 22 children with CPC (0.08–13.6 years of age at diagnosis) and 7 children with papilloma of the choroid plexus (Pp; 0.5–9.8 years of age). Surgical resection was possible in 28 children. Blood and/or tumor DNA was extracted and analyzed using PCR-RFLP and results were confirmed by sequencing 240 bp of the TP53 exon 10. The patients, all parents, and some relatives submitted samples for blood DNA analysis. In addition, we have also examined the presence of the mutation in DNA from paraffin-embedded tumor samples to evaluate loss of heterozygosity. We found 63.3% (14/22) of the CPC patients positive for the germline R337H mutation; CPC samples were either heterozygous (n = 7), lost only the wild-type (n = 4), or only the R337H copy (n = 2). One CPC sample was not available. All Pp cases (7/7, 100%) were negative for R337H. Cure (>5 years survival free of disease) was observed in 18.1% of the CPC cases with the R337H mutation (2/11), 71.4% of the Pp (5/7), and 25% of CPC cases negative for the R337H mutation (2/8). Family history of cancer (with 2 or more cancer cases) was exclusively identified on the parental side segregating the R337H mutation, and 50% (7/14) of them were compatible with Li-Fraumeni-like syndrome.SignificanceOur results show for the first time that the R337H TP53 mutation is responsible for 63% of the CPC cases in children, suggesting a higher incidence of CPC in southern Brazil.

Clinicopathological and immunohistochemical study of 20 choroid plexus tumors: their histological diversity and the expression of markers useful for differentiation from metastatic cancer

The aim of this study was to summarize the clinicopathological features and the histological diversity of choroid plexus tumors and to examine the expression of immunohistochemical markers that are useful for their differentiation from metastatic cancer. Twenty cases were collected, including 11 choroid plexus papillomas, 5 choroid plexus adenomas, 1 atypical choroid plexus papilloma, and 3 choroid plexus carcinomas. The choroid plexus papillomas showed various parenchymal and stromal changes: focal solid growth, oncocytic alterations, melanin deposition, calcification, ossification, and xanthogranulomatous reactions. The choroid plexus tumors showed the following cytokeratin (CK) 7 and 20 staining patterns: CK7(+)/CK20(+) (11/19 cases), CK7(+)/CK20(-) (7/19 cases), CK7(-)/CK20(-) (1/19 cases), and CK7(-)/CK20(+) (0/19 cases). Positivity for CK5/6 and thyroid transcription factor-1 was found in 3 of 18 and 1 of 19 cases, respectively. All cases were negative for the estrogen receptor (0/18 cases). The choroid plexus tumors showed various CK7/CK20 staining patterns, and the staining of CK7 and CK20 in most CK7(+)/CK20(+) and CK7(+)/CK20(-) cases was focal, in contrast to that observed in carcinomas. Therefore, nondiffuse staining of CK, rather than the CK7/CK20 panel itself, is important for discriminating between a choroid plexus tumor and metastatic cancer.

Rhabdoid predisposition syndrome

Note The following observations have suggested that a new cancer-prone disease, related to the gene hSNF5/INI, could be delineated: Two siblings with a paravertebral malignant rhabdoid tumor in the first year of life and a poor outcome; no family history; renal rhabdoid tumors associated with tumors of the central nervous system in a given patient; germ-line mutations of INI1 identified in four children, three with renal rhabdoid tumors and one with an atypical teratoid tumor of the brain (out of 18 atypical teratoid and rhabdoid tumors studied); and 4 recent pedigrees with malignant rhabdoid tumor, choroid plexus carcinoma, atypical teratoid tumor, medulloblastoma, and/or primitive neuroectodermal tumor, either occurring in sibs or in a given patient, with a INI1 point mutation in the tumor DNA and loss of wild type allele and/or heterozygosity for the mutation in constitutional DNA.

Rhabdoid predisposition syndrome

Note The following observations have suggested that a new cancer-prone disease, related to the gene hSNF5/INI, could be delineated: Two siblings with a paravertebral malignant rhabdoid tumor in the first year of life and a poor outcome; no family history; Renal rhabdoid tumors associated with tumors of the central nervous system in a given patient; Germ-line mutations of INI1 identified in four children, three with renal rhabdoid tumors and one with an atypical teratoid tumor of the brain (out of 18 atypical teratoid and rhabdoid tumors studied); And 4 recent pedigrees with malignant rhabdoid tumor, choroid plexus carcinoma, atypical teratoid tumor, medulloblastoma, and/or primitive neuroectodermal tumor, either occurring in sibs or in a given patient, with a INI1 point mutation in the tumor DNA and loss of wild type allele and/or heterozygosity for the mutation in constitutional DNA.