Cancer Genetics 207 (2014) 429e433
BRIEF COMMUNICATION
Synchronous congenital malignant rhabdoid tumor of the orbit and atypical teratoid/rhabdoid tumordfeasibility and efficacy of multimodal therapy in a long-term survivor Angela Seeringer a, Harald Reinhard b, Martin Hasselblatt c, Reinhard Schneppenheim d, Reiner Siebert e, Kerstin Bartelheim a, €hwald a,g,* Ivo Leuschner f, Michael C. Fru a b
Swabian Children’s Cancer Center, Children’s Hospital Augsburg, Augsburg, Germany; Department of Pediatric Oncology, € nster, Children’s Hospital St. Augustin, Sankt Augustin, Germany; c Institute of Neuropathology, University Hospital Mu € nster, Germany; d Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Mu Hamburg, Germany; e Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital SchleswigHolstein, Campus Kiel, Kiel, Germany; f Institute of Pathology, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; g Department of Pediatric Hematology and Oncology, University Children’s € nster, Mu € nster, Germany Hospital Mu Among infant malignancies, congenital tumors, especially those of the central nervous system (CNS), constitute a rather unique subgroup. Poor survival rates (28% in CNS tumors) may be attributed to the aggressive biology as well as specific therapeutic limitations innate to the young age of affected patients. Our patient developed synchronous congenital tumors: an atypical teratoid/rhabdoid tumor (AT/RT) localized in the right lateral ventricle of the brain and a malignant rhabdoid tumor (MRT) in the soft tissue of the right orbit. A de novo germline chromosomal deletion in 22q encompassing the SMARCB1 gene was detected, prompting the diagnosis of a de novo rhabdoid tumor predisposition syndrome 1 (RTPS1). The patient was reported to the European Rhabdoid Registry (EU-RHAB) and treated according to the Rhabdoid 2007 recommendation. Despite the very young age of the patient, the initially desperate situation of RTPS1, and the synchronous localization of congenital rhabdoid tumors, intensive chemotherapy was well tolerated; the child is still in complete remission 5 years following diagnosis. In conclusion, RTPS1 with congenital synchronous MRTs is not necessarily associated with a detrimental outcome. Intensive multidrug chemotherapy, including high dose chemotherapy, may be feasible and justified. Keywords Atypical teratoid/rhabdoid tumor, rhabdoid tumor predisposition syndrome 1, synchronous congenital tumors, multimodal therapy ª 2014 Elsevier Inc. All rights reserved.
Congenital tumors are a very rare and specific subgroup of infant malignancies.(1) The aggressive behavior of the tumors combined with the specificities of an infant organism limit the therapeutic options that are, in most cases, multidrug approaches and surgery. Especially in congenital
Received February 28, 2014; received in revised form June 25, 2014; accepted June 26, 2014. * Corresponding author. E-mail address: [email protected] 2210-7762/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2014.06.028
rhabdoid tumors, survival rates are rather poor (e.g., Isaacs reported only 10% survivors (2)). Like other rhabdoid tumors, congenital rhabdoid tumors can arise in various locations. Here, we describe a patient with a synchronous congenital rhabdoid tumor localized in the central nervous system (CNS) (an atypical teratoid/rhabdoid tumor (AT/RT)) and a malignant rhabdoid tumor (MRT) in the soft tissue around the orbit. The patient was reported to the European Rhabdoid Registry (EU-RHAB), which is the first European registry of rhabdoid tumors. EU-RHAB registers rhabdoid tumors of any anatomical site and proposes a consensus therapy.
430
A. Seeringer et al.
Material and methods Immunohistochemical staining of the SMARCB1/INI1 status of the tumor as well as its molecular analysis is part of the routine evaluation of every rhabdoid tumor reported to EURHAB. If available, a genetic analysis of the blood for detection of a potential germline mutation completes the assessment of the tumor. All analyses are performed at the EU-RHAB reference centers at the University Hospital in Kiel and the University Medical Center Hamburg-Eppendorf.
Results Case report The female newborn was delivered at full term (birth weight 3.1 kg, birth size 50 cm) without complications, following an
Figure 2
Figure 1 The congenital malignant rhabdoid tumor presented as a periorbital mass. (A) A photograph of the patient with the periorbital mass as it presented at birth. (B) A photograph of the patient after complete resection of the periorbital mass.
A magnetic resonance image of the AT/RT.
unremarkable pregnancy, as the first child of healthy parents. At birth, a periorbital mass infiltrating the periorbital musculature and the right orbit was encountered (Figure 1A; the mass had not been obvious on prenatal ultrasonograph). Interventional embolization of the tumor vasculature was performed 2 days after birth, followed by gross total resection (GTR) 3 days later (Figure 1B). Histopathologic examination established the diagnosis of MRT, and the case was reported to EU-RHAB. Chemotherapy according to the Rhabdoid 2007 protocol employing vincristine, cyclophosphamide, and doxorubicin (VCD) followed by ifosfamide, carboplatin, and etoposide (ICE) started 16 days after birth of the infant (therapeutic schedule: first, VCD 100%; second, VCD 100%; third, ICE 66%; fourth, ICE 80%; fifth, VCD 80%; and sixth, VCD 70%). Chemotherapy was generally well tolerated. The infant developed recurrent fever of unknown origin because of the chemotherapy-induced neutropenia but recovered rapidly. At the age of 4½ months, the patient developed relapsing vomiting. Magnetic resonance imaging of the brain revealed a tumor located within the right lateral ventricle with beginning blockage of the foramen of Monro (Figure 2). On GTR, a neuropathologic diagnosis of AT/RT was established. In retrospect, a discrete opacity had already been present on earlier magnetic resonance imaging studies at the location of the now obvious intracerebral lesion. No recurrent orbital tumor growth was detected. Chemotherapy was adapted and started with ICE 80% and four doses of methotrexate (MTX) intrathecally. No tumor cells were detected in the cerebrospinal fluid (CSF). The 7-month-old infant received tandem high dose chemotherapy (HDCT) with peripheral blood stem cell rescue employing carboplatin and etoposide (66% of scheduled dose) followed by cyclophosphamide and thiotepa (100% of scheduled dose) 2 months later. At the age of 10
Multimodal therapy in congenital malignant rhabdoid tumor of the orbit and AT/RT
431
Figure 3 Results of MLPA analysis. (A) Results of MLPA of the tumor DNA showing a homozygous deletion of SMARCB1 exon 1e9. (B) Results of MLPA of peripheral blood DNA showing a heterozygous deletion of SMARCB1 exon 1e9.
months, the patient began maintenance chemotherapy with cyclophosphamide and vinblastine; this regimen was administered for 1 year. Currently, the child remains well and has been in complete remission for 4½ years.
Outcome The child, now 5½ years old, has been in complete remission for >4½ years, and continues to be in remission (Figure 4).
Pathology and genetics Immunohistochemical staining confirmed the diagnosis of an MRT showing loss of SMARCB1/INI1 expression. A clone with a homozygous deletion of the SMARCB1 gene on a background of cells with heterozygous SMARCB1 loss could be detected in the tumor material by fluorescence in situ hybridization (FISH) analysis (3) and by multiplex ligationdependent probe amplification (MLPA) (Figure 3A). Analysis of peripheral blood cells by FISH and of genomic DNA from peripheral blood by MLPA revealed a heterozygous germline deletion in 22q encompassing the SMARCB1 gene (Figure 3B). Chromosomal analysis supplemented by FISH ruled out a deletion or other chromosomal aberration affecting the SMARCB1 locus in both parents. Therefore, the chromosomal loss affecting the SMARCB1 gene in the patient appeared de novo and rhabdoid tumor predisposition syndrome 1 (RTPS1, OMIM #609322) was diagnosed.
Figure 4
A photograph of the patient in complete remission.
432 She is an agile and lively child with adequate fine motor skills, and she attends a regular kindergarten. No psychomotor deficits have been found. Recently, a pre-excitation syndrome of the heart (WolffeParkinsoneWhite syndrome) was diagnosed.
Discussion Congenital tumors are rare (2% of all childhood malignancies) (4), and their management is rather challenging. Multidrug approaches and early resection are the most common therapeutic approaches, but the very young age of the patients limits therapeutic options. Surgical procedures are prone to complications, and radiotherapy is mostly avoided in fear of late effects on the developing brain (5). Especially in cases of congenital MRTs, overall survival (OS) remains poor despite aggressive approaches (5,6). To our knowledge, our case is the first description of a long-term survivor with synchronous congenital tumors in the context of RTPS1 (i.e., an orbital MRT and a supratentorial AT/RT). Only 10% of patients with congenital MRT survived in a study by Isaacs et al., despite surgical resection and multidrug therapy (2). These authors concluded that higher stage and the presence of a CNS tumor were significant determinants of poor outcome. This assessment was confirmed by a study by Manoranjan and Provias (7). Only one of six patients with a congenital brain tumor recruited in a 10-year retrospective study had survived (7). Few cases of congenital AT/RT are on record. Shamji et al. reported on two children with congenital AT/RT treated at the Montreal Children’s Hospital in a 22-year period. Both patients died, the first one expired at 16 months, the second one at 11 days (8). The complex and, in most cases, incidental diagnosis of a congenital brain tumor (only in 18% of cases was the tumor found before birth) (7) may delay the initiation of a consistent therapy, which may further contribute to the poor prognosis. In our case, the diagnosis of AT/RT was established only after 4 months, when the tumor became symptomatic. The therapeutic protocol was adapted accordingly, and intrathecal (IT) MTX and HDCT were administered. The administration of IT chemotherapy in our infant is supported by a report by Athale et al., who demonstrated higher OS in children with AT/RT who had received IT chemotherapy (9). Furthermore, complete resection of the AT/RT may have significantly contributed to the positive outcome. A positive effect of GTR on OS in AT/RT has repeatedly been discussed (9e15). In congenital rhabdoid tumors, Kordes et al. presented four long-term survivors, three of whom had undergone a GTR (16). To what extent the following consolidation therapy added a survival benefit remains to be determined. Klingebiel et al. (2008) demonstrated a benefit of maintenance therapy when compared with HDCT in patients suffering from Rhabdomyosarcoma-like stage IV tumors (17). But even though several authors discuss the pros and cons of various chemotherapeutic regimens for OS (18), to our knowledge, there are no data to definitively clarify this point. The administration of HDCT in young children is a source of controversy. Whereas some studies reported an improved outcome with manageable side effects and showed that radiotherapy could be avoided or deferred until 3 years of
A. Seeringer et al. age in cases in infants and very young children (10,19e22), five toxic deaths were reported by the Head Start III trial (23). In this trial, 19 children (median age 14 mo) had been treated with surgical resection, multidrug chemotherapy, and HDCT. The results were still rather poor (OS 26%) (23). In the present case, conventional and HDCT were well tolerated. The MRT could be cured with local therapy (resection and conventional chemotherapy), which was not sufficient for the treatment of the AT/RT (which required additional administration of HDCT and IT MTX). A complete remission resulted and has lasted for more than 4½ years. In this individual case of a synchronous congenital MRT, the EU-RHAB protocol was feasible and led to an optimal outcome, which confirms our previous results in infants (24). However, regarding the various HDCT treatment regimens with diverse outcome and safety, the superiority of one therapeutic approach cannot yet be seen. This is also et al., who summarized various treatmentioned by Garre ment regimens, including multidrug therapy and HDCT, for the treatment of congenital AT/RT (18). Whereas HDCT with alkylator-based regimens combined with craniospinal irradiation have shown greater impact on therapeutic outcome in children above 3 years of age (25), a greater progression rate in children treated with the cyclophosphamide/etoposide/carboplatino/thiotepa (CECAT) regimen compared with ICE was reported by Fidani et al. (26). Overall, the role of HDCT for the treatment of congenital tumors remains unclear, and the treatment is prone to severe side effects. Therefore, new therapeutic approaches are desperately needed for the treatment of congenital MRTs. In conclusion, RTPS1 with congenital synchronous MRTs is not necessarily associated with detrimental outcome. Intensive multidrug chemotherapy including HDCT may be feasible and justified.
Acknowledgments This work was supported by the Deutsche Kinderkrebsstiftung (DKS 2014.04 A/B), the Gesellschaft of Kinderkrebsforschung e.V., “Horizont” Kinderkrebshilfe Weseke e.V., KinderKrebsInitiative Buchholz/Holm-Seppensen, €rdergemeinschaft Kinderkrebszentrum Hamburg e.V., and Fo €nster (HA3/016/11). IZKF Mu
References 1. Isaacs HJ. II. Perinatal brain tumors: a review of 250 cases. Pediatr Neurol 2002;27:333e342. 2. Isaacs H Jr. Fetal and neonatal rhabdoid tumor. J Pediatr Surg 2010;45:619e626. €hwald MC, et al. Clinical and molecular 3. Kordes U, Gesk S, Fru features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor. Genes Chromosomes Cancer 2010; 49:176e181. 4. Orbach D, Sarnacki S, Brisse HJ, et al. Neonatal cancer. Lancet Oncol 2013;14:e609ee620. 5. Ferrari A, Orbach D, Sultan I, et al. Neonatal soft tissue sarcomas. Semin Fetal Neonatal Med 2012;17:231e238. 6. Bourdeaut F, Freneaux P, Thuille B, et al. Extra-renal noncerebral rhabdoid tumours. Pediatr Blood Cancer 2008;51: 363e368.
Multimodal therapy in congenital malignant rhabdoid tumor of the orbit and AT/RT 7. Manoranjan B, Provias JP. Congenital brain tumors: diagnostic pitfalls and therapeutic interventions. J Child Neurol 2011;26: 599e614. 8. Shamji MF, Vassilyadi M, Lam CH, et al. Congenital tumors of the central nervous system: the MCH experience. Pediatr Neurosurg 2009;45:368e374. 9. Athale UH, Duckworth J, Odame I, et al. Childhood atypical teratoid rhabdoid tumor of the central nervous system: a metaanalysis of observational studies. J Pediatr Hematol Oncol 2009;31:651e663. 10. Lafay-Cousin L, Hawkins C, Carret AS, et al. Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience. Eur J Cancer 2012;48:353e359. 11. Buscariollo DL, Park HS, Roberts KB, et al. Survival outcomes in atypical teratoid rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology, and End Results analysis. Cancer 2012;118:4212e4219. 12. Morgenstern DA, Gibson S, Brown T, et al. Clinical and pathological features of paediatric malignant rhabdoid tumours. Pediatr Blood Cancer 2010;54:29e34. 13. Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol 2009;27:385e389. 14. von Hoff K, Hinkes B, Dannemann-Stern E, et al. Frequency, risk-factors and survival of children with atypical teratoid rhabdoid tumors (AT/RT) of the CNS diagnosed between 1988 and 2004, and registered to the German HIT database. Pediatr Blood Cancer 2011;57:978e985. 15. Pai Panandiker AS, Merchant TE, Beltran C, et al. Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system. Int J Radiat Oncol Biol Phys 2012;82:1756e1763. 16. Kordes U, Bartelheim K, Modena P, et al. Favorable outcome of patients affected by rhabdoid tumors due to rhabdoid tumor predisposition syndrome (RTPS). Pediatr Blood Cancer 2014; 61:919e921. 17. Klingebiel T, Boos J, Beske F, et al. Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial. Pediatr Blood Cancer 2008;50:739e745.
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ML, Tekautz T. Role of high-dose chemotherapy (HDCT) 18. Garre in treatment of atypical teratoid/rhabdoid tumors (AT/RTs). Pediatr Blood Cancer 2010;54:647e648. 19. Mason WP, Goldman S, Yates AJ, et al. Survival following intensive chemotherapy with bone marrow reconstitution for children with recurrent intracranial ependymoma - a report of the Children’s Cancer Group. J Neurooncol 1998;37:135e143. 20. Fangusaro JR, Jubran RF, Allen J, et al. Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue. Pediatr Blood Cancer 2008;50:715e717. 21. Gidwani P, Levy A, Goodrich J, et al. Successful outcome with tandem myeloablative chemotherapy and autologous peripheral blood stem cell transplants in a patient with atypical teratoid/rhabdoid tumor of the central nervous system. J Neurooncol 2008;88:211e215. 22. Park ES, Sung KW, Baek HJ, et al. Tandem high-dose chemotherapy and autologous stem cell transplantation in young children with atypical teratoid/rhabdoid tumor of the central nervous system. J Korean Med Sci 2012;27: 135e140. 23. Zaky W, Dhall G, Ji L, et al. Intensive induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for young children newly-diagnosed with central nervous system atypical teratoid/ rhabdoid tumors: the Head Start III experience. Pediatr Blood Cancer 2014;61:95e101. 24. Seeringer A, Bartelheim K, Kerl K, et al. Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors d experience of the EU-RHAB registry. Klin Padiatr 2014;226: 143e148. 25. Tekautz TM, Fuller CE, Blaney S, et al. Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and highdose alkylator-based chemotherapy. J Clin Oncol 2005;23: 1491e1499. 26. Fidani P, De Ioris MA, Serra A, et al. A multimodal strategy based on surgery, radiotherapy, ICE regime and high dose chemotherapy in atypical teratoid/rhabdoid tumors: a single institution experience. J Neurooncol 2009;92:177e183.
BRIEF COMMUNICATION
Synchronous congenital malignant rhabdoid tumor of the orbit and atypical teratoid/rhabdoid tumordfeasibility and efficacy of multimodal therapy in a long-term survivor Angela Seeringer a, Harald Reinhard b, Martin Hasselblatt c, Reinhard Schneppenheim d, Reiner Siebert e, Kerstin Bartelheim a, €hwald a,g,* Ivo Leuschner f, Michael C. Fru a b
Swabian Children’s Cancer Center, Children’s Hospital Augsburg, Augsburg, Germany; Department of Pediatric Oncology, € nster, Children’s Hospital St. Augustin, Sankt Augustin, Germany; c Institute of Neuropathology, University Hospital Mu € nster, Germany; d Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Mu Hamburg, Germany; e Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital SchleswigHolstein, Campus Kiel, Kiel, Germany; f Institute of Pathology, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; g Department of Pediatric Hematology and Oncology, University Children’s € nster, Mu € nster, Germany Hospital Mu Among infant malignancies, congenital tumors, especially those of the central nervous system (CNS), constitute a rather unique subgroup. Poor survival rates (28% in CNS tumors) may be attributed to the aggressive biology as well as specific therapeutic limitations innate to the young age of affected patients. Our patient developed synchronous congenital tumors: an atypical teratoid/rhabdoid tumor (AT/RT) localized in the right lateral ventricle of the brain and a malignant rhabdoid tumor (MRT) in the soft tissue of the right orbit. A de novo germline chromosomal deletion in 22q encompassing the SMARCB1 gene was detected, prompting the diagnosis of a de novo rhabdoid tumor predisposition syndrome 1 (RTPS1). The patient was reported to the European Rhabdoid Registry (EU-RHAB) and treated according to the Rhabdoid 2007 recommendation. Despite the very young age of the patient, the initially desperate situation of RTPS1, and the synchronous localization of congenital rhabdoid tumors, intensive chemotherapy was well tolerated; the child is still in complete remission 5 years following diagnosis. In conclusion, RTPS1 with congenital synchronous MRTs is not necessarily associated with a detrimental outcome. Intensive multidrug chemotherapy, including high dose chemotherapy, may be feasible and justified. Keywords Atypical teratoid/rhabdoid tumor, rhabdoid tumor predisposition syndrome 1, synchronous congenital tumors, multimodal therapy ª 2014 Elsevier Inc. All rights reserved.
Congenital tumors are a very rare and specific subgroup of infant malignancies.(1) The aggressive behavior of the tumors combined with the specificities of an infant organism limit the therapeutic options that are, in most cases, multidrug approaches and surgery. Especially in congenital
Received February 28, 2014; received in revised form June 25, 2014; accepted June 26, 2014. * Corresponding author. E-mail address: [email protected] 2210-7762/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2014.06.028
rhabdoid tumors, survival rates are rather poor (e.g., Isaacs reported only 10% survivors (2)). Like other rhabdoid tumors, congenital rhabdoid tumors can arise in various locations. Here, we describe a patient with a synchronous congenital rhabdoid tumor localized in the central nervous system (CNS) (an atypical teratoid/rhabdoid tumor (AT/RT)) and a malignant rhabdoid tumor (MRT) in the soft tissue around the orbit. The patient was reported to the European Rhabdoid Registry (EU-RHAB), which is the first European registry of rhabdoid tumors. EU-RHAB registers rhabdoid tumors of any anatomical site and proposes a consensus therapy.
430
A. Seeringer et al.
Material and methods Immunohistochemical staining of the SMARCB1/INI1 status of the tumor as well as its molecular analysis is part of the routine evaluation of every rhabdoid tumor reported to EURHAB. If available, a genetic analysis of the blood for detection of a potential germline mutation completes the assessment of the tumor. All analyses are performed at the EU-RHAB reference centers at the University Hospital in Kiel and the University Medical Center Hamburg-Eppendorf.
Results Case report The female newborn was delivered at full term (birth weight 3.1 kg, birth size 50 cm) without complications, following an
Figure 2
Figure 1 The congenital malignant rhabdoid tumor presented as a periorbital mass. (A) A photograph of the patient with the periorbital mass as it presented at birth. (B) A photograph of the patient after complete resection of the periorbital mass.
A magnetic resonance image of the AT/RT.
unremarkable pregnancy, as the first child of healthy parents. At birth, a periorbital mass infiltrating the periorbital musculature and the right orbit was encountered (Figure 1A; the mass had not been obvious on prenatal ultrasonograph). Interventional embolization of the tumor vasculature was performed 2 days after birth, followed by gross total resection (GTR) 3 days later (Figure 1B). Histopathologic examination established the diagnosis of MRT, and the case was reported to EU-RHAB. Chemotherapy according to the Rhabdoid 2007 protocol employing vincristine, cyclophosphamide, and doxorubicin (VCD) followed by ifosfamide, carboplatin, and etoposide (ICE) started 16 days after birth of the infant (therapeutic schedule: first, VCD 100%; second, VCD 100%; third, ICE 66%; fourth, ICE 80%; fifth, VCD 80%; and sixth, VCD 70%). Chemotherapy was generally well tolerated. The infant developed recurrent fever of unknown origin because of the chemotherapy-induced neutropenia but recovered rapidly. At the age of 4½ months, the patient developed relapsing vomiting. Magnetic resonance imaging of the brain revealed a tumor located within the right lateral ventricle with beginning blockage of the foramen of Monro (Figure 2). On GTR, a neuropathologic diagnosis of AT/RT was established. In retrospect, a discrete opacity had already been present on earlier magnetic resonance imaging studies at the location of the now obvious intracerebral lesion. No recurrent orbital tumor growth was detected. Chemotherapy was adapted and started with ICE 80% and four doses of methotrexate (MTX) intrathecally. No tumor cells were detected in the cerebrospinal fluid (CSF). The 7-month-old infant received tandem high dose chemotherapy (HDCT) with peripheral blood stem cell rescue employing carboplatin and etoposide (66% of scheduled dose) followed by cyclophosphamide and thiotepa (100% of scheduled dose) 2 months later. At the age of 10
Multimodal therapy in congenital malignant rhabdoid tumor of the orbit and AT/RT
431
Figure 3 Results of MLPA analysis. (A) Results of MLPA of the tumor DNA showing a homozygous deletion of SMARCB1 exon 1e9. (B) Results of MLPA of peripheral blood DNA showing a heterozygous deletion of SMARCB1 exon 1e9.
months, the patient began maintenance chemotherapy with cyclophosphamide and vinblastine; this regimen was administered for 1 year. Currently, the child remains well and has been in complete remission for 4½ years.
Outcome The child, now 5½ years old, has been in complete remission for >4½ years, and continues to be in remission (Figure 4).
Pathology and genetics Immunohistochemical staining confirmed the diagnosis of an MRT showing loss of SMARCB1/INI1 expression. A clone with a homozygous deletion of the SMARCB1 gene on a background of cells with heterozygous SMARCB1 loss could be detected in the tumor material by fluorescence in situ hybridization (FISH) analysis (3) and by multiplex ligationdependent probe amplification (MLPA) (Figure 3A). Analysis of peripheral blood cells by FISH and of genomic DNA from peripheral blood by MLPA revealed a heterozygous germline deletion in 22q encompassing the SMARCB1 gene (Figure 3B). Chromosomal analysis supplemented by FISH ruled out a deletion or other chromosomal aberration affecting the SMARCB1 locus in both parents. Therefore, the chromosomal loss affecting the SMARCB1 gene in the patient appeared de novo and rhabdoid tumor predisposition syndrome 1 (RTPS1, OMIM #609322) was diagnosed.
Figure 4
A photograph of the patient in complete remission.
432 She is an agile and lively child with adequate fine motor skills, and she attends a regular kindergarten. No psychomotor deficits have been found. Recently, a pre-excitation syndrome of the heart (WolffeParkinsoneWhite syndrome) was diagnosed.
Discussion Congenital tumors are rare (2% of all childhood malignancies) (4), and their management is rather challenging. Multidrug approaches and early resection are the most common therapeutic approaches, but the very young age of the patients limits therapeutic options. Surgical procedures are prone to complications, and radiotherapy is mostly avoided in fear of late effects on the developing brain (5). Especially in cases of congenital MRTs, overall survival (OS) remains poor despite aggressive approaches (5,6). To our knowledge, our case is the first description of a long-term survivor with synchronous congenital tumors in the context of RTPS1 (i.e., an orbital MRT and a supratentorial AT/RT). Only 10% of patients with congenital MRT survived in a study by Isaacs et al., despite surgical resection and multidrug therapy (2). These authors concluded that higher stage and the presence of a CNS tumor were significant determinants of poor outcome. This assessment was confirmed by a study by Manoranjan and Provias (7). Only one of six patients with a congenital brain tumor recruited in a 10-year retrospective study had survived (7). Few cases of congenital AT/RT are on record. Shamji et al. reported on two children with congenital AT/RT treated at the Montreal Children’s Hospital in a 22-year period. Both patients died, the first one expired at 16 months, the second one at 11 days (8). The complex and, in most cases, incidental diagnosis of a congenital brain tumor (only in 18% of cases was the tumor found before birth) (7) may delay the initiation of a consistent therapy, which may further contribute to the poor prognosis. In our case, the diagnosis of AT/RT was established only after 4 months, when the tumor became symptomatic. The therapeutic protocol was adapted accordingly, and intrathecal (IT) MTX and HDCT were administered. The administration of IT chemotherapy in our infant is supported by a report by Athale et al., who demonstrated higher OS in children with AT/RT who had received IT chemotherapy (9). Furthermore, complete resection of the AT/RT may have significantly contributed to the positive outcome. A positive effect of GTR on OS in AT/RT has repeatedly been discussed (9e15). In congenital rhabdoid tumors, Kordes et al. presented four long-term survivors, three of whom had undergone a GTR (16). To what extent the following consolidation therapy added a survival benefit remains to be determined. Klingebiel et al. (2008) demonstrated a benefit of maintenance therapy when compared with HDCT in patients suffering from Rhabdomyosarcoma-like stage IV tumors (17). But even though several authors discuss the pros and cons of various chemotherapeutic regimens for OS (18), to our knowledge, there are no data to definitively clarify this point. The administration of HDCT in young children is a source of controversy. Whereas some studies reported an improved outcome with manageable side effects and showed that radiotherapy could be avoided or deferred until 3 years of
A. Seeringer et al. age in cases in infants and very young children (10,19e22), five toxic deaths were reported by the Head Start III trial (23). In this trial, 19 children (median age 14 mo) had been treated with surgical resection, multidrug chemotherapy, and HDCT. The results were still rather poor (OS 26%) (23). In the present case, conventional and HDCT were well tolerated. The MRT could be cured with local therapy (resection and conventional chemotherapy), which was not sufficient for the treatment of the AT/RT (which required additional administration of HDCT and IT MTX). A complete remission resulted and has lasted for more than 4½ years. In this individual case of a synchronous congenital MRT, the EU-RHAB protocol was feasible and led to an optimal outcome, which confirms our previous results in infants (24). However, regarding the various HDCT treatment regimens with diverse outcome and safety, the superiority of one therapeutic approach cannot yet be seen. This is also et al., who summarized various treatmentioned by Garre ment regimens, including multidrug therapy and HDCT, for the treatment of congenital AT/RT (18). Whereas HDCT with alkylator-based regimens combined with craniospinal irradiation have shown greater impact on therapeutic outcome in children above 3 years of age (25), a greater progression rate in children treated with the cyclophosphamide/etoposide/carboplatino/thiotepa (CECAT) regimen compared with ICE was reported by Fidani et al. (26). Overall, the role of HDCT for the treatment of congenital tumors remains unclear, and the treatment is prone to severe side effects. Therefore, new therapeutic approaches are desperately needed for the treatment of congenital MRTs. In conclusion, RTPS1 with congenital synchronous MRTs is not necessarily associated with detrimental outcome. Intensive multidrug chemotherapy including HDCT may be feasible and justified.
Acknowledgments This work was supported by the Deutsche Kinderkrebsstiftung (DKS 2014.04 A/B), the Gesellschaft of Kinderkrebsforschung e.V., “Horizont” Kinderkrebshilfe Weseke e.V., KinderKrebsInitiative Buchholz/Holm-Seppensen, €rdergemeinschaft Kinderkrebszentrum Hamburg e.V., and Fo €nster (HA3/016/11). IZKF Mu
References 1. Isaacs HJ. II. Perinatal brain tumors: a review of 250 cases. Pediatr Neurol 2002;27:333e342. 2. Isaacs H Jr. Fetal and neonatal rhabdoid tumor. J Pediatr Surg 2010;45:619e626. €hwald MC, et al. Clinical and molecular 3. Kordes U, Gesk S, Fru features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor. Genes Chromosomes Cancer 2010; 49:176e181. 4. Orbach D, Sarnacki S, Brisse HJ, et al. Neonatal cancer. Lancet Oncol 2013;14:e609ee620. 5. Ferrari A, Orbach D, Sultan I, et al. Neonatal soft tissue sarcomas. Semin Fetal Neonatal Med 2012;17:231e238. 6. Bourdeaut F, Freneaux P, Thuille B, et al. Extra-renal noncerebral rhabdoid tumours. Pediatr Blood Cancer 2008;51: 363e368.
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