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Claudin 6 is a positive marker for atypical teratoid/rhabdoid tumors.

ABSTRACT: Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive pediatric brain tumors characterized by the presence of rhabdoid cells and negative immunostaining for INI1 (BAF47). Histogenesis is unknown and diagnosis can be challenging because of their extreme morphological and immunophenotypic heterogeneity. Currently no signature markers other than INI1 loss have been identified. To search for possible candidate proteins of interest in AT/RTs, Affymetrix GeneChip microarrays were utilized to investigate nine AT/RTs vs. 124 other tumor samples. The most distinctive gene identified was claudin 6 (CLDN6), a key component of tight junctions. CLDN6 showed moderate or higher mRNA expression in eight of nine AT/RTs, with little to no expression in 114 of 115 other tumors. Average expression was 38-fold higher in AT/RTs vs. other samples. Immunohistochemical (IHC) staining of 33 tumor specimens found positive membrane staining in seven of seven AT/RTs, and was negative in 26 of 27 other brain tumor samples. Notably, none of the 16 medulloblastomas/primitive neuroectodermal tumors showed IHC staining for CLDN6. IHC staining results closely matched the level of mRNA expression detected by microarray. CLDN6 may be a useful positive marker to help further identify AT/RTs for diagnostic and treatment purposes.

SUBMITTER: Birks DK

PROVIDER: S-EPMC8094697 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Claudin 6 is a positive marker for atypical teratoid/rhabdoid tumors.

Birks Diane K DK Kleinschmidt-DeMasters Bette K BK Donson Andrew M AM Barton Valerie N VN McNatt Sean A SA Foreman Nicholas K NK Handler Michael H MH

Brain pathology (Zurich, Switzerland) 20090209 1

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive pediatric brain tumors characterized by the presence of rhabdoid cells and negative immunostaining for INI1 (BAF47). Histogenesis is unknown and diagnosis can be challenging because of their extreme morphological and immunophenotypic heterogeneity. Currently no signature markers other than INI1 loss have been identified. To search for possible candidate proteins of interest in AT/RTs, Affymetrix GeneChip microarrays were utilized t ...[more]

PMID: 19220299

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Project description:BACKGROUND: To describe therapeutic approaches in children with atypical Teratoid Rhabdoid Tumours (ATRT) in France. METHODS: Observational study including all children less than 18 years old diagnosed with ATRT in France between 2009 and 2011. RESULTS: Forty seven children were included in this retrospective study. Six patients received no curative treatment while forty-one patients had a curative project. Median age was 1.5 years (range 0-16). The disease was disseminated in 10 patients. Surgical resection was complete in 21 cases. Chemotherapy was administered in 41 children. Twenty-six patients received upfront Vincristine-Methotrexate (5g/m2 x 3) with intra-thecal Methotrexate, which was stopped in eleven patients: in four cases the disease progressed and in seven cases the toxicities were manageable. Fifteen children received different chemotherapy courses and in four of them the diseases progressed. Eight patients underwent second-look surgery. Radiotherapy was administered in 17 patients at a median time of 19 weeks (13-44) after diagnosis. High-dose chemotherapy (HDCT) was given in 9 children and maintenance therapy in 5 children, starting at respectively 35 and 42 weeks after diagnosis. Median follow-up was 26 months (0.6-47). Median time for progression was 5 months. Two-years overall survival was 32% + /-8%. Median survival was 8 months. DISCUSSION: The survival rate of children with ATRT remains poor, the addition of VM is easily manageable but its benefit remains uncertain. The disease progressed mostly before radiotherapy. Future trials should focus on the delay of radiotherapy and the benefit of HDCT. Because ATRT is a rare disease of infancy carrying grim prognosis, focus on long term outcome, especially neurocognitive remain very limited. With the new era of multimodality therapy, some patients are now long term survivors. We reviewed the neuropsychological (NP) status of the survivors from the Canadian ATRT registry. Among patients diagnosed between 1995-2012, 16/72 were survivors (22%). Formal NP assessments were available in 7 patients. Four patients could not be tested (3 too young, 1 blind significantly impaired, 1 lost to follow up). Additionally 1 patient was in special education class (grade 12), one received educational assistance (grade 8), one meet academic expectation (grade 4). Data on last survivor is pending. For the 7 patients with comprehensive NP, the median age at diagnosis was 28.2 months (11.2-60.7). Four tumors were infratentorial and 3 were metastatic. Four patients underwent complete resection. All patients received post operative sequential high dose chemotherapy (Carpoplatin/Thiotepa). Five patients received intrathecal chemotherapy. Two patients underwent radiation (1focal, 1CSI). Median age at time of NP was 7.3 years (3.9-9.28). Full Scale Intellectual Quotient (FSIQ) ranged from 60 to 119 (median = 71). Simple expressive and receptive language appeared relatively preserved (low average to superior). Three most recently diagnosed patients assessed at a median time of 2.6 years (2.6-4.7) from diagnosis had average to high average scores for FSIQ, academic and visual spatial skills, visual and verbal memory. Four other diagnosed earlier tested at a median time of 5.1 years (3.3-8.3) post-diagnosis had a FSIQ ranging from 60 to 71 (median = 68). Approximately 50% of their scores were in the impaired range. Whether these findings suggest further decline overtime or reflect improvement in overall management of these recently diagnosed patients remain unclear. Nevertheless this cohort of infants appears significantly impaired at school age despite the absence of systematic radiotherapy. Larger series focusing on neurocognition are definitely needed before embracing adjuvant radiotherapy as standard of care.

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Claudin 6 is a positive marker for atypical teratoid/rhabdoid tumors.

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Claudin 6 is a positive marker for atypical teratoid/rhabdoid tumors.

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