ABSTRACT
PURPOSE Choroid plexus carcinomas are pediatric tumors with poor survival rates and a strong, but poorly understood, association with Li-Fraumeni syndrome (LFS). Currently, with lack of biologic predictors, most children are treated with aggressive chemoradiation protocols. PATIENTS AND METHODS We established a multi-institutional tissue and clinical database, which enabled the analysis of specific alterations of the TP53 tumor suppressor and its modifiers in choroid plexus tumors (CPTs). We conducted high-resolution copy-number analysis to correlate these genetic parameters with family history and outcome. Results We studied 64 patients with CPTs. All individuals with germline TP53 mutations fulfilled LFS criteria, whereas all patients not meeting these criteria harbored wild-type TP53 (P < .001). TP53 mutations were found in 50% of choroid plexus carcinomas (CPCs). Additionally, two sequence variants known to confer TP53 dysfunction, TP53 codon72 and MDM2 SNP309, coexisted in the majority of TP53 wild-type CPCs (92%) and not in TP53 mutated CPC (P = .04), which suggests a complementary mechanism of TP53 dysfunction in the absence of a TP53 mutation. High-resolution single nucleotide polymorphism (SNP) array analysis revealed extremely high total structural variation (TSV) in TP53-mutated CPC tumor genomes compared with TP53 wild-type tumors and choroid plexus papillomas (CPPs; P = .006 and .004, respectively). Moreover, high TSV was associated with significant risk of progression (P < .001). Five-year survival rates for patients with TP53-immunopositive and -immunonegative CPCs were 0% and 82 (+/- 9%), respectively (P < .001). Furthermore, 14 of 16 patients with TP53 wild-type CPCs are alive without having received radiation therapy. CONCLUSION Patients with CPC who have low tumor TSV and absence of TP53 dysfunction have a favorable prognosis and can be successfully treated without radiation therapy.
Subject(s)
Carcinoma/genetics , Choroid Plexus Neoplasms/genetics , Germ-Line Mutation , Papilloma, Choroid Plexus/genetics , Polymorphism, Single Nucleotide , Tumor Suppressor Protein p53/genetics , Carcinoma/chemistry , Carcinoma/mortality , Carcinoma/therapy , Chi-Square Distribution , Child , Child, Preschool , Choroid Plexus Neoplasms/chemistry , Choroid Plexus Neoplasms/mortality , Choroid Plexus Neoplasms/therapy , Databases as Topic , Disease-Free Survival , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Oligonucleotide Array Sequence Analysis , Ontario/epidemiology , Papilloma, Choroid Plexus/chemistry , Papilloma, Choroid Plexus/mortality , Papilloma, Choroid Plexus/therapy , Phenotype , Time Factors , Treatment Outcome , Tumor Suppressor Protein p53/analysis , United States/epidemiologySubject(s)
Carcinoma/diagnosis , Choroid Plexus Neoplasms/diagnosis , Choroid Plexus/pathology , Biomarkers, Tumor/analysis , Carcinoma/chemistry , Carcinoma, Papillary/chemistry , Carcinoma, Papillary/diagnosis , Choroid Plexus/chemistry , Choroid Plexus Neoplasms/chemistry , Diagnosis, Differential , Humans , Mucin-1/analysis , Papilloma, Choroid Plexus/chemistry , Papilloma, Choroid Plexus/diagnosis , Rhabdoid Tumor/chemistry , Rhabdoid Tumor/diagnosis , Teratoma/chemistry , Teratoma/diagnosisABSTRACT
Choroid plexus tumors are papillary neoplasms originating from the epithelium of the choroid plexus within the cerebral ventricles. They may be highly proliferative tumors, but detailed studies confirming their proliferative potential are lacking. Accordingly, we performed a clinicopathological correlation study of neoplasms arising from the choroid plexus in children using immunohistochemistry to characterize both their proliferative potential and their degree of cell cycle dysregulation when compared to non-neoplastic choroid epithelium. Twelve children with choroid plexus papillomas (CPPs) and 11 with choroid plexus carcinomas (CPCs) were identified from the time period 1982-1997. The outcome and survival of these children following treatment was determined from the medical record. Immunohistochemical studies were performed on CPPs and CPCs in this patient population and on non-neoplastic choroid epithelium using antibodies to MIB-1, p53, cyclin E, retinoblastoma protein (pRB), p107, and E2F-1. In 5 children with CPCs, tumor tissue was available for immunohistochemistry at a second surgery after cycles of chemotherapy had been given. The mean survival for patients with CPPs was 8.5 years, and with CPCs 5.2 years with a minimum follow-up of 4 years for the group. The expression of cell cycle markers and MIB-1 was greater in CPCs than in CPPs or normal choroid plexus. The expression of MIB-1, p53, pRB, and E2F-1 was significantly lower in patients with CPCs after chemotherapy than before. The MIB-1 labeling index for CPC patients who are alive and well after treatments was 15.19+/-3.2 compared to 22.63+/-3.04 for patients who have died from their disease (P<0.05). We conclude that CPCs in children are characterized by a higher MIB-1 labeling index and greater cell cycle dysregulation than are CPPs. Chemotherapy may work in part on CPCs to decrease their proliferative potential and expression of cell cycle regulatory proteins.
Subject(s)
Cell Cycle Proteins/analysis , Choroid Plexus Neoplasms/chemistry , Choroid Plexus Neoplasms/pathology , DNA-Binding Proteins , Papilloma, Choroid Plexus/chemistry , Papilloma, Choroid Plexus/pathology , Adolescent , Antigens, Nuclear , Cell Division , Child , Child, Preschool , Choroid Plexus Neoplasms/mortality , Cyclin E/analysis , E2F Transcription Factors , E2F1 Transcription Factor , Female , Glial Fibrillary Acidic Protein/analysis , Humans , Immunohistochemistry , Infant , Ki-67 Antigen , Male , Nuclear Proteins/analysis , Papilloma, Choroid Plexus/mortality , Retinoblastoma Protein/analysis , Retinoblastoma-Like Protein p107 , Survival Analysis , Synaptophysin/analysis , Transcription Factors/analysis , Tumor Suppressor Protein p53/analysisABSTRACT
An autopsy case of primary choroid plexus adenocarcinoma arising in a 40-year-old female, who was associated with a high serum level of a carbohydrate antigen 19-9 (CA19-9), is herein presented. After a subtotal removal of a tumor in the left lateral ventricle, the serum level of CA19-9 decreased rapidly, and immunohistochemical examinations of tumor tissue specimens obtained at surgery revealed intense reactivity for CA19-9. The present case may be the first example in which a primary choroid plexus carcinoma was shown to produce CA19-9.
