Cancer Genetics
-
(2014)
-
Rhabdoid tumor: the Irish experience 1986e2013 Alice Uwineza a, Harinder Gill b, Patrick Buckley c, Cormac Owens d, Michael Capra d, Catriona O’Sullivan e, Michael McDermott f, Francesca Brett g, Michael Farrell g, Jane Pears d, Maureen J. O’Sullivan a,f,h,* b a
National Children’s Research Center, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; National Center for Medical Genetics, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; c Molecular Pathology Laboratory, Clinical Directorate of Laboratory Medicine, Beaumont Hospital, Dublin, Ireland; d National Pediatric Oncology Unit, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; e Radiation Oncology Unit, St. Luke’s Hospital, Rathgar, Dublin, Ireland; f Histology Laboratory, Pathology Department, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; g Neuropathology Laboratory, Pathology Department, Beaumont Hospital, Dublin, Ireland; h Trinity College, Dublin, College Green, Dublin, Ireland Nomenclature for the three recognized forms of rhabdoid tumor reflect their anatomic localization and include malignant rhabdoid tumor of the kidney (MRTK), extrarenal extracranial rhabdoid tumor (EERT), and atypical teratoid rhabdoid tumor (ATRT) involving the central nervous system. A strikingly simple karyotype belies the fact that rhabdoid tumors are among the most lethal human cancers, and now early strides are beginning to elucidate their molecular pathogenesis. Rhabdoid tumors are largely confined to the pediatric population, where they occur preferentially during infancy. Given the rarity of this tumor, international consensus on best treatment has only recently been achieved in conjunction with the establishment of the European Rhabdoid Tumor Registry. Between 1986 and 2013, 25 pediatric patients were diagnosed with rhabdoid tumor in the Republic of Ireland. Of these patients, 13 presented with ATRT, eight had MRTK, and four had EERT. The mean age at diagnosis was 38.8 months, with an equal sex incidence. Because of the lack of a standardized treatment strategy for rhabdoid tumors, these patients have been treated largely according to anatomic site, based on sarcoma, renal, or brain tumor protocols contemporary to their diagnoses. Of the patients, 84% received chemotherapy, 80% underwent surgery, and 44% had radiation therapy. The outcome overall was poor, independent of anatomic location. The overall survival rate was 24%, and mean time to death was just under 9 months. Keywords Rhabdoid tumor, Irish, pediatric, SMARCB1 ª 2014 Elsevier Inc. All rights reserved.
Malignant rhabdoid tumor of the kidney was initially classified as a rhabdomyosarcomatoid variant of Wilms tumor (1). Over the years, studies revealed that rhabdoid tumors do not share the immunohistochemical (IHC) or ultrastructural features of rhabdomyosarcoma (2), and that they have been reported in nearly every anatomical site. Regardless of anatomic origin, rhabdoid tumors are genetically characterized by mutation of the tumor suppressor gene SMARCB1 (3,4). This gene encodes BAF47, a core subunit of the chromatin remodeling BAF or SWI/SNF complex. Although in most cases the SMARCB1 mutation arises as a somatic
Received February 28, 2014; received in revised form May 23, 2014; accepted May 31, 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.2014.05.015
event, SMARCB1 germline mutations have been reported (4,5). The latter lead to the rhabdoid tumor predisposition syndrome, and affected patients not only tend to develop tumors earlier, but also reportedly have a poorer prognosis than those patients whose tumors arise sporadically from somatic SMARCB1 inactivation. The diagnosis of rhabdoid tumors currently relies on combined histological and IHC analysis (6). Morphologically, rhabdoid cells are characterized by their large vesicular nuclei with macronucleoli, copious cytoplasm, and classic eosinophilic cytoplasmic inclusions. The loss of SMARCB1 expression, confirmed immunohistochemically, supports the diagnosis, but notably is neither confined to ‘true’ rhabdoid tumors nor essential for the diagnosis. Given the rarity of malignant rhabdoid tumors, standardized treatment protocols have not been available. In the past, various protocols, including those from the International
2
A. Uwineza et al.
Table 1
Irish pediatric patients with rhabdoid tumor between 1986 and 2013
Case number
Age in mo (y of diagnosis)
1 2
21.5 (2012) 12.25 (2011)
3
14.5 (2011)
4
22.75 (2008)
Histology: anatomic site
IHC: SMARCB1 expression
F F
ATRT ATRT
absent absent
ND ND
ND ND
M
ATRT
absent
ND
ND
M
ATRT
absent
ND
ND
Sex
Metastasis (location)
Chemotherapy
Surgery
ND ND
spine
ICE/ Dox/ MTX
subtotal resection
ND
No
total resection
No
ND
No
ACNS 0034
total rescetion
ND
No
No
ventriculoperitoneal shunt
MMT95
total resection debulking
No 4 Gy in 2 frs/ whole spine 56.96 Gy in 33 frs/ craniospinal axis, left parietal boost 36 Gy in 20 frs/ craniospinal
resection
subtotal resection/ ventriculopetoneal shunt
SMARCB1 mutation Mutation Germline Familial
5
142.5 (2002)
M
ATRT
absent
ND
ND
ND
No
6
98 (2006)
M
ATRT
absent
ND
ND
ND
meninges
7
25 (2002)
M
ATRT
ND
ND
ND
ND
8
11 (2011)
F
ATRT
absent
Yes
No
No
MMT95 Intracranial germ cell tumor No ACNS 0034 DF protocol 02-294 meninges; subsequently pons, DF protocol 13-335; antimiddle cerebellar angiogenic; Alisertib; Stem cell transplant; More peduncle
9
29.75(2012)
F
ATRT
absent
ND
ND
ND
spine, subsequently cerebellopontine angle
10
65.25 (2006)
M
ATRT
absent
ND
ND
ND
No
11
European Rhabdoid Registry/ individual antiangiogenic MMT98/A2
Outcome (mo after diagnosis)
Time to Death in mo
3.25
DFD DFD
9.5 8.5
5.25
DFD
9
-
DFD
0.15
17.5
DFD
18.75
-
DFD
24.75
No
7.5
DFD
5.5
54 Gy / stereostatic radiotherapy
10.75
AWD (30)
-
Radiotherapy (dose/ field) 40 Gy in 24 frs/ craniospinal, posterior fossa and spinal
54 Gy in 30 frs/ posterior fossa; 45 Gy in 25 frs/ craniotomy/ ventriculopetoneal shunt/ craniospinal, lumbar spine boost debulking craniotomy/ radical excision 54 Gy in 30 frs/ right fronto of recurrence parietal lobe
Time to Relapse in mo
8.25
AWD (16)
-
33.5
AWOD (98.25)
-
Data unavailable
48.25 (1988)
M
ATRT
absent
ND
ND
ND
ND
No
No
No
DFD
2
12
2.75(1990)
M
ATRT
ND
ND
ND
ND
ND
UKCCSG
No
No
-
DFD
0.75
13
25.75(2000)
M
ATRT
ND
ND
ND
ND
ND
total resection
No
Data unavailable
DFD
5.5
14
32.75 (1999)
F
MRTK
ND
ND
ND
ND
lymph nodes
No UKCCSG NMTS
nephrectomy
DFD
0.5
1 (2011)
F
MRTK
absent
Yes
Yes
No
spine*
AREN 0321
nephrectomy/ laminoplasty
No 10.8 Gy in 6 frs/ upper abdomen
-
15
-
DFD
28.75
16
20.25 (1994)
F
MRTK
ND
ND
ND
ND
No
NWTS-5
nephrectomy
10.8 Gy in 8 frs/ abdomen
-
AWOD (262.75)
-
17
7 (2004)
F
MRTK
absent
Yes
No
No
Eto/ Car/ CP/ Zof/ Max
No
No
-
DFD
4.5
18
2.75 (2007)
F
MRTK
absent
ND
ND
ND
No lymph nodes lungs
AREN 0321
19
6.5 (1999)
F
MRTK
absent
ND
ND
ND
No
NWTS-5
nephrectomy nephrectomy/ uterectomy/ adrenalectomy
AREN 0321 NWTS-5
20
20.5 (2009)
M
MRTK
absent
ND
ND
ND
lymph nodes lungs
21
8.5 (2001)
M
MRTK
absent
ND
ND
ND
brain
22
10.5(2010)
M
23
0.175 (2013)
M
EERT (neck) EERT (spine)
24
179 (2009)
F
F
25
161.5 (1986)
absent
Yes
No
No
lungs
absent
Yes
Yes
No
No
EERT (tongue)
absent
ND
ND
ND
EERT (pelvis)
ND
ND
ND
ND
lymph nodes intraabdominal dissemination; lymph nodes
No
5
DFD
7
-
AWOD (196.75)
-
nephrectomy
No 19.8 Gy in 11 frs/ para aortic lymphnodes, tumor spillage
6.5
DFD
7.5
2.75
DFD
6.5
nephrectomy
No
ICE/ Dox/ CP/ Vinc European Rhabdoid Registry
total resection thoracoscopy
30.6 Gy in 17 frs/ neck
-
AWOD (53.25)
-
laminoplasty/ debulking
No
-
DFD
1.25
Vinc/ Dox/ CP/ Car/ Eto
No
No
-
DFD
3.75
Ifos/Vcr/Adr
No
No
-
DFD
22
Abbreviations: F, female; M, male; ND, not determined; ICE, ifosfamide, carboplatin, etoposide; Dox, doxorubicin; MTX, methotrexate; Eto, etoposide; Car, carboplatin; CP, cyclophosphamide; Zof, zofran; Max, maxalon; Vinc, vincristine: frs, fractions; DFD, dead from disease; AWD, alive with disease; AWOD, alive without disease. *Spinal tumor with prior MRTK in a patient with a germline SMARCB1 mutation. aCGH performed on these samples is discussed in the text.
Society for Pediatric Oncology (SIOP), the National Wilms Tumor Study Group (NWTS), the German Medulloblastoma Group (HIT) and Children’s Cancer Study Group (CCG), were used. Generally, these protocols were based on a multimodal approach, combining surgery, radiotherapy, and chemotherapy. Despite many attempts to improve these various protocols, the overall survival of rhabdoid tumor patients remained poor (7e9). In 2010, the European Rhabdoid Registry was established, and this resource provides a framework of standard treatment protocols for the different subtypes of rhabdoid tumor.
records are all centralized to the National Pediatric Oncology Unit at Our Lady’s Children’s Hospital, Crumlin, Dublin. Patient charts were reviewed for data on age at diagnosis; sex; tumor location; treatment modality; outcomes including time to recurrence and time to death, which are calculated using the following online tool: http://
Table 2
Nature of the SMARCB1 mutations
Case number
Mutation
8
Materials and methods The study includes all patients diagnosed with rhabdoid tumors before their 17th birthdays in the Republic of Ireland between January 1986 and December 2013. Diagnosis relied on a combination of classic rhabdoid morphology with vesicular nuclei and macronucleoli, eccentrically located within cells containing abundant cytoplasm with eosinophilic inclusions and showing diffuse, uniform loss of immunoreactivity for SMARCB1, frequently accompanied by nonspecific immunoreactivity of the cytoplasmic inclusions for various intermediate filament proteins. Medical
15 17 22 23
Allele 1: deletion of exon 1 to exon 9 in SMARCB1 allele 2: deletion of SMARCB1 and surrounding the genes DGCR8 and NIPSWAP Homozygous deletion from exon 1 to exon 9 in SMARCB1 Allele 1: homozygous deletion of exon 1 allele 2: hemizygous deletion of exon 2 to exon 9 Somatic translocation involving chromosome 22 with overlapping deletions in 22q Heterozygous deletion of exon 1 in SMARCB1
Representation of all SMARCB1 mutations identified somatically or in the germline in the five cases tested from our cohort. All tumors tested showed biallelic inactivating mutations of SMARCB1.
Irish rhabdoid tumor experience Table 3
3
Genomic aberrations in case number 16
Constitutional sample (14N600)
Renal tumor (13N1072 C1)
Spinal tumor (13N1072 A1)
Deletion [chr22:24040187-24631613] Gain [chr14:106371690-106410537]
Deletion [chr22:24040187-24799476] Gain [chr14:106371690-106410537] Gain [chr6:26017272-31680358]
Deletion [chr22:24429551-24631613] Gain [chr14:106371690-106410537] Gain [chr6:26033333-27880039] Gain [chr12:14695189-20903680] Deletion [chr16:84884241-90094481]
The findings of the array analysis of the initial renal and subsequent spinal tumors in addition to the constitutional DNA from patient 16 are presented. Constitutional and tumor DNA confirm the presence of a hemizygous deletion on chromosome 22 as well as a copy number variation on chromosome 14. Variation in the size of the chromosome 22 deletion is most likely because of the quality of the tumor-derived formalin-fixed, paraffin-embedded DNA. Both tumors harbor an additional overlapping gain on chromosome 6 (renal tumor: chr6:2601727231680358; spinal tumor: Chr6:26033333-27880039). In addition, the spinal tumor is further characterized by an acquired gain on chromosome 12 (chr12:14695189:20903680) and deletion of chromosome 16 (chr16:84884241-90094481), suggesting an increase in mutational events, in keeping with this tumor representing a metastatic lesion derived from the MRTK. All samples were called against the HG19 genome build.
www.timeanddate.com/date/duration.html; and results of mutational analysis of SMARCB1 in tumor and germline DNA (and, where positive, parental germline DNA also). The mutational analysis involves a combination of Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). For a single patient (case 16) with a known germline SMARCB1 mutation, array comparative genomic hybridization (aCGH) analysis was conducted on DNA extracted from paraffin blocks from the presenting renal and subsequent spinal tumors, as well as constitutional DNA extracted from peripheral lymphocytes, in an effort to investigate whether the spinal tumor was a metachronous primary or a metastasis. All samples were called against the HG19 human build; these data did not contribute to the clinical management of the disease in the child. To this end, DNA was extracted from paraffin-embedded, formalin-fixed tissue from blocks of both tumors using the Qiagen DNeasy FFPE kit. Using the Agilent SureTag Complete DNA labeling kit (Agilent, Santa Clara, CA, USA), 500 ng of tumor DNA was labeled overnight. A total of 10 mg of labeled tumor and reference DNA (Agilent control XX DNA) were cohybridized to a 4 44K Agilent CGH microarray for 18 hours. Slides were washed according to the manufacturer’s specifications and scanned using an Axon 4000B microarray scanner. Microarray data were processed and analyzed using the Agilent Cytogenomics software 2.7.8.0.
Results The findings of our systematic review of patients with rhabdoid tumor are presented in Table 1. The age at diagnosis ranged from 5 days to almost 15 years, with a mean of 38.8 months at presentation. The observed overall male/female ratio was almost equal at 1.08:1; however, ATRTs predominated in boys, whereas MRTKs were more commonly seen in girls and the very few EERTs (n Z 4) were evenly distributed. ATRTs made up more than half the tumors. Of the 25 rhabdoid tumor cases, 13 (52.0%; male/female ratio 2.25:1) were ATRT, eight (32.0%; male/female ratio 1:3) were MRTK, and four (16.0%; male/female ratio 1:1) were EERT. The 19 cases tested by immunohistochemistry for SMARCB1 expression showed absent reactivity diffusely throughout tumor cells. A SMARCB1 mutation was identified
in the tumor DNA in all cases for which a genetic test was performed. For these five cases, germline testing was positive in two and negative in three cases. Parental testing was negative in all cases in which a patient showed a germline SMARCB1 mutation. Details of the genetic mutations, both somatic and germline, are provided in Table 2. As mentioned in the materials and methods section, one patient with a germline SMARCB1 mutation presented with MRTK at age 4 weeks and relapsed with a spinal tumor at age 2 years. The details of her constitutional and somatic mutations of both tumors are detailed in Table 3. A further patient presented with MRTK at 8.5 months and developed a brain lesion at age 15 months; this patient was not tested for germline SMARCB1 mutation. In general, a multimodal approach consisting of surgery, chemotherapy, and radiotherapy was taken. A total of 20 (80.0%) patients had surgery, including 11 of 13 with ATRT, seven of eight with MRTK, and two of four with EERT. Chemotherapy was given to 21 of 25 (84.0%) patients: nine of 13 with ATRT, eight of eight with MRTK, and four of four with EERT. In contrast, radiotherapy was given to only 11 of 25 (44%) patients total, of which seven had ATRT, three had MRTK, and one had EERT. Of the 25 patients, 10 (43.5%) relapsed. The time to relapse ranged from 2.75 to 33.5 months after diagnosis, with a mean time to relapse of 10 months. In all, 19 (76.0%) patients died of disease. The time to death ranged from 0.15 to 28.75 months after diagnosis, with a mean time to death of 8.7 months. The longest survival is 263 months for a patient who remains alive at the time of writing. In all, four patients (16%)dtwo with MRTK, one with ATRT, and one with EERTdare alive without disease, and two (8%) patients, both with ATRT, are alive with disease at 16 and 30 months after diagnosis. The findings of the array analysis of the initial renal and subsequent spinal tumors in addition to constitutional DNA from patient 16 are presented in Table 3. There is a commonality of deletions on chromosome 22 and copy number variation on chromosome 14 across constitutional and tumor DNA; however, both renal and spinal tumors show a gain on chromosome 6, and the spinal tumor, which presented more than 2 years after the MRTK, shows additional aberrations that support this being a metastasis of the renal tumor, although clinical management was unaltered by this finding.
4
Discussion As is illustrated by this review of the Irish rhabdoid tumor patient cohort between 1986 and 2013, the treatment of MRT was not standardized until relatively recently (10). Historically, treatment protocols have varied between countries and depended on the anatomic site of the tumor and age of the patient. With respect to ATRT, its designation by the World Health Organization as an embryonal tumor of the central nervous system led to medulloblastoma-type or primitive neuroectodermal tumoretype therapies being employed. The outcomes have remained very poor for the younger patients, whereas combined irradiation and treatment with high dose alkylating agents in children over 3 years can be curative (11,12). In the younger patient group, multiagent high dose chemotherapy regimens with autologous stem cell rescue have been utilized, with the aim of enabling the child to survive to an age whereby radiotherapy can then be used with less morbidity. As ATRTs have a propensity to spread throughout the neuraxis, an alternative or additional approach is to give cerebrospinal fluidedirected therapy via either the intraventricular or intrathecal route (13). As with other renal tumors, the approach for renal rhabdoid tumor management has varied between Europe and North America. Within Europe, historically the UKW2 and UKW3 protocols were used, and more recently SIOP WT 2001 (14). In North America, the NWTS series has been superseded by the Children’s Oncology Group (COG) AREN high risk renal tumor protocols. Although surgical timing may vary, there has been a common approach for chemotherapeutic agents, with combinations of vincristine, actinomycin D, doxorubicin, carboplatin, cyclophosphamide, and etoposide. The management of extrarenal extracranial rhabdoid tumors has shown the most disparity, as they have been variously viewed as undifferentiated sarcomas or carcinomas. Intergroup Rhabdomyosarcoma Study protocols within North America have evolved into COG trials, whereas in Europe, Malignant Mesenchymal Tumor (MMT) trials have latterly been superseded by the European Soft Tissue Sarcoma Study Group guidelines (15). The mean age of our cohort is somewhat higher than one might anticipate for rhabdoid tumor (16) and appears to be skewed by the presence of a small number of ATRTs with older presentation, in addition to two older children presenting with EERT. The overall survival rate is comparable to that found in the SIOP trial (17). Those patients alive without disease include some who are exceptionally long-lived, however, which is very much at odds with what one expects of rhabdoid tumor. One boy [patient 10] with ATRT had a frontoparietal craniectomy, chemotherapy as per the MMT98/A2 protocol, and radiation therapy. Following relapse, he had surgery with gross total resection of the tumor and the family refused further chemotherapy. This child remains disease-free at more than 8 years postdiagnosis and 5 years postsurgery for his recurrence. Patient 16, who had stage 1 MRTK, received multimodal treatment, including irradiation of the flank and dome of the diaphragm and chemotherapy as per NWTS-5. She remains diseasefree at almost 22 years posttreatment. Patient 19 had
A. Uwineza et al. MRTK stage 2 disease treated with primary radical nephroureterectomy and adrenalectomy followed by intensive chemotherapy as per NWTS-5 protocol. She remains disease-free at over 16 years postdiagnosis. Patient 22 had EERT treated with multimodal therapy including total gross resection at surgery, chemotherapy, and proton radiotherapy with no relapse to date at 53 months out. The two patients who are alive with disease have ATRT. Both are undergoing very extensive multimodal therapy. Patient 8 is an ATRT patient who had chemotherapy per the ACNS 0034 protocol followed by Dana-Farber protocols 02294 and 13-335, as well as antiangiogenic therapy, intrathecal cytarabine therapy, alisertib therapy, and high dose chemotherapy with stem cell transplant, and then relapsed, had stereotactic irradiation with concomitant everolimus, and remains alive with recurrence at the primary site. Patient 9 is an ATRT patient with partial tumor resection at initial surgery, treated with chemotherapy as per the European Rhabdoid protocol and irradiation of posterior fossa. Metastases to the spine precluded a second surgery, and she had craniospinal irradiation. She is now undergoing individual antiangiogenic therapy, prior to which a new lesion in the cerebellopontine angle was detected. She remains alive with disease. Neither of the patients with a known germline SMARCB1 mutation has survived. The approach to the diagnosis of rhabdoid tumors has changed insofar as BAF47 (SMARCB1) immunostaining was introduced into routine Irish pathology practice in late 2006 or early 2007, at the time that electron microscopy was also being completely phased out for tumor diagnostics. Genetic testing for SMARCB1 mutation was introduced into routine practice in January 2010, and one patient was tested retrospectively. Our clinical approach to these patients has evolved in Ireland with the establishment in 2008 of a National Pediatric Hematology-Oncology program, whereby all pediatric patients with cancer are centrally treated at Our Lady’s Children’s Hospital in Dublin. With a national population of 4.5 million, this is possible in a centralized, tertiary pediatric hospital setting, supported by 16 nationwide shared care centers. Approximately 170 new oncology patients per year are cared for by five consultants (two hematologists and three oncologists). Regular weekly solid tumor and neuro-oncology multidisciplinary meetings are held and routinely attended by all consultant staff, and many trainees and nursing staff also in pediatric oncology, pathology, radiology, surgery, radiation therapy, and palliative care. Centralized pathology review for any cases not initially biopsied in Dublin is standard. Since 2009, all neurosurgery has been performed by a dedicated team of pediatric neurosurgeons with neuropathology support. We have strong links with COG, SIOP, and Children’s Cancer and Leukaemia Group, but welcome recent efforts by the international pediatric oncology community to collaborate further by the formation of rare tumor specialty groups such as the International Rhabdoid Tumor Group and the European Rhabdoid Registry. By further refining diagnostic processes, central pathology review and accurate recording of incidence, and outcomes from unified treatment pathways we hope to contribute to positively influencing outcomes for children with this devastating diagnosis.
Irish rhabdoid tumor experience
5
Acknowledgments 7.
Funding: National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland. Grant A/13/3 Awarded to Professor M J O’Sullivan, October 2013. We wish to acknowledge the clinical input of many additional colleagues including our Consultant Neurosurgeons, Neurosurgery Department, Beaumont Hospital, Dublin 9: Mr. Darrach Crimmins; Mr. Donncha O’Brien; Mr. John Caird; Mr. David Allcutt; and Mr. Taufiq Sattar. Consultant Oncology Surgeons, past and present Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland: Mr. Sri Paran; Prof. Martin Corbally; and Prof. Ray Fitzgerald. Retired Pediatric Oncologists, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland: Dr. Anne O’Meara and Dr. Fin Breathnach. Consultant Radiologists, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland: Dr. Roisin Hayes; Dr. Ethna Phelan; Dr. Clare Brenner; Dr. David Rea; and Dr. Angela Byrne. Consultant Geneticists, National Center for Medical Genetics, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland: Professor Andrew Green; Dr. William Reardon; and Dr. Sally-Ann Lynch.
10.
References
14.
1. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumors: results from the First National Wilms’ Tumor Study. Cancer 1978;41:1937e1948. 2. Haas JE, Palmer NF, Weinberg AG, et al. Ultrastructure of malignant rhabdoid tumor of the kidney. A distinctive renal tumor of children. Hum Pathol 1981;12:646e657. 3. Versteege I, Sevenet N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 1998;394: 203e206. 4. Sevenet N, Lellouch-Tubiana A, Schofield D, et al. Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotypephenotype correlations. Hum Mol Genet 1999;8:2359e2368. 5. Proust F, Laquerriere A, Constantin B, et al. Simultaneous presentation of atypical teratoid/rhabdoid tumor in siblings. J Neurooncol 1999;43:63e70. 6. Fanburg-Smith JC, Hengge M, Hengge UR, et al. Extrarenal rhabdoid tumors of soft tissue: a clinicopathologic and immu-
8.
9.
11.
12.
13.
15.
16.
17.
nohistochemical study of 18 cases. Ann Diagn Pathol 1998;2: 351e362. van den Heuvel-Eibrink MM, van Tinteren H, Rehorst H, et al. Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: a report of the SIOP renal tumour study group. Pediatr Blood Cancer 2011;56: 733e737. Tomlinson GE, Breslow NE, Dome J, et al. Rhabdoid tumor of the kidney in the National Wilms’ Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol 2005;23:7641e7645. Geyer JR, Sposto R, Jennings M, et al. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol 2005;23:7621e7631. Fruehwald, MC. European rhabdoid registry v2.2010. Available at: http://www.kinderkrebsinfo.de/sites/kinderkrebsinfo/content/ e1676/e9032/e1758/e83294/download84621/EURHAB101115_ B_ger.pdf. Accessed February 18, 2014. Hilden JM, Meerbaum S, Burger P, et al. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 2004;22:2877e2884. 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 high-dose alkylator- based chemotherapy. J Clin Oncol 2005;23:1491e1499. 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. International Society of Paediatric Oncology (SIOP) Renal Tumor Study Group. Nephroblastoma Clinical Trial and Study interim statistical report, Tuebingen, December 2007. Available at: http://web.visu.uni-saarland.de/rtsg/fileadmin/templates/logistix/ files/SIOP_Interim_Statistical_Report.pdf. Accessed April 22, 2014. Brennan B, Stiller C, Bourdeaut F. Extracranial rhabdoid tumours: what we have learned so far and future directions. Lancet Oncol 2013;14:e329ee336. von Hoff K, Hinkes B, Dannenmann-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. van den Heuvel-Eibrink MM, Grundy P, Graf N, et al. Characteristics and survival of 750 children diagnosed with a renal tumor in the first seven months of life: a collaborative study by the SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms tumor study groups. Pediatr Blood Cancer 2008;50:1130e1134.
-
(2014)
-
Rhabdoid tumor: the Irish experience 1986e2013 Alice Uwineza a, Harinder Gill b, Patrick Buckley c, Cormac Owens d, Michael Capra d, Catriona O’Sullivan e, Michael McDermott f, Francesca Brett g, Michael Farrell g, Jane Pears d, Maureen J. O’Sullivan a,f,h,* b a
National Children’s Research Center, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; National Center for Medical Genetics, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; c Molecular Pathology Laboratory, Clinical Directorate of Laboratory Medicine, Beaumont Hospital, Dublin, Ireland; d National Pediatric Oncology Unit, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; e Radiation Oncology Unit, St. Luke’s Hospital, Rathgar, Dublin, Ireland; f Histology Laboratory, Pathology Department, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; g Neuropathology Laboratory, Pathology Department, Beaumont Hospital, Dublin, Ireland; h Trinity College, Dublin, College Green, Dublin, Ireland Nomenclature for the three recognized forms of rhabdoid tumor reflect their anatomic localization and include malignant rhabdoid tumor of the kidney (MRTK), extrarenal extracranial rhabdoid tumor (EERT), and atypical teratoid rhabdoid tumor (ATRT) involving the central nervous system. A strikingly simple karyotype belies the fact that rhabdoid tumors are among the most lethal human cancers, and now early strides are beginning to elucidate their molecular pathogenesis. Rhabdoid tumors are largely confined to the pediatric population, where they occur preferentially during infancy. Given the rarity of this tumor, international consensus on best treatment has only recently been achieved in conjunction with the establishment of the European Rhabdoid Tumor Registry. Between 1986 and 2013, 25 pediatric patients were diagnosed with rhabdoid tumor in the Republic of Ireland. Of these patients, 13 presented with ATRT, eight had MRTK, and four had EERT. The mean age at diagnosis was 38.8 months, with an equal sex incidence. Because of the lack of a standardized treatment strategy for rhabdoid tumors, these patients have been treated largely according to anatomic site, based on sarcoma, renal, or brain tumor protocols contemporary to their diagnoses. Of the patients, 84% received chemotherapy, 80% underwent surgery, and 44% had radiation therapy. The outcome overall was poor, independent of anatomic location. The overall survival rate was 24%, and mean time to death was just under 9 months. Keywords Rhabdoid tumor, Irish, pediatric, SMARCB1 ª 2014 Elsevier Inc. All rights reserved.
Malignant rhabdoid tumor of the kidney was initially classified as a rhabdomyosarcomatoid variant of Wilms tumor (1). Over the years, studies revealed that rhabdoid tumors do not share the immunohistochemical (IHC) or ultrastructural features of rhabdomyosarcoma (2), and that they have been reported in nearly every anatomical site. Regardless of anatomic origin, rhabdoid tumors are genetically characterized by mutation of the tumor suppressor gene SMARCB1 (3,4). This gene encodes BAF47, a core subunit of the chromatin remodeling BAF or SWI/SNF complex. Although in most cases the SMARCB1 mutation arises as a somatic
Received February 28, 2014; received in revised form May 23, 2014; accepted May 31, 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.2014.05.015
event, SMARCB1 germline mutations have been reported (4,5). The latter lead to the rhabdoid tumor predisposition syndrome, and affected patients not only tend to develop tumors earlier, but also reportedly have a poorer prognosis than those patients whose tumors arise sporadically from somatic SMARCB1 inactivation. The diagnosis of rhabdoid tumors currently relies on combined histological and IHC analysis (6). Morphologically, rhabdoid cells are characterized by their large vesicular nuclei with macronucleoli, copious cytoplasm, and classic eosinophilic cytoplasmic inclusions. The loss of SMARCB1 expression, confirmed immunohistochemically, supports the diagnosis, but notably is neither confined to ‘true’ rhabdoid tumors nor essential for the diagnosis. Given the rarity of malignant rhabdoid tumors, standardized treatment protocols have not been available. In the past, various protocols, including those from the International
2
A. Uwineza et al.
Table 1
Irish pediatric patients with rhabdoid tumor between 1986 and 2013
Case number
Age in mo (y of diagnosis)
1 2
21.5 (2012) 12.25 (2011)
3
14.5 (2011)
4
22.75 (2008)
Histology: anatomic site
IHC: SMARCB1 expression
F F
ATRT ATRT
absent absent
ND ND
ND ND
M
ATRT
absent
ND
ND
M
ATRT
absent
ND
ND
Sex
Metastasis (location)
Chemotherapy
Surgery
ND ND
spine
ICE/ Dox/ MTX
subtotal resection
ND
No
total resection
No
ND
No
ACNS 0034
total rescetion
ND
No
No
ventriculoperitoneal shunt
MMT95
total resection debulking
No 4 Gy in 2 frs/ whole spine 56.96 Gy in 33 frs/ craniospinal axis, left parietal boost 36 Gy in 20 frs/ craniospinal
resection
subtotal resection/ ventriculopetoneal shunt
SMARCB1 mutation Mutation Germline Familial
5
142.5 (2002)
M
ATRT
absent
ND
ND
ND
No
6
98 (2006)
M
ATRT
absent
ND
ND
ND
meninges
7
25 (2002)
M
ATRT
ND
ND
ND
ND
8
11 (2011)
F
ATRT
absent
Yes
No
No
MMT95 Intracranial germ cell tumor No ACNS 0034 DF protocol 02-294 meninges; subsequently pons, DF protocol 13-335; antimiddle cerebellar angiogenic; Alisertib; Stem cell transplant; More peduncle
9
29.75(2012)
F
ATRT
absent
ND
ND
ND
spine, subsequently cerebellopontine angle
10
65.25 (2006)
M
ATRT
absent
ND
ND
ND
No
11
European Rhabdoid Registry/ individual antiangiogenic MMT98/A2
Outcome (mo after diagnosis)
Time to Death in mo
3.25
DFD DFD
9.5 8.5
5.25
DFD
9
-
DFD
0.15
17.5
DFD
18.75
-
DFD
24.75
No
7.5
DFD
5.5
54 Gy / stereostatic radiotherapy
10.75
AWD (30)
-
Radiotherapy (dose/ field) 40 Gy in 24 frs/ craniospinal, posterior fossa and spinal
54 Gy in 30 frs/ posterior fossa; 45 Gy in 25 frs/ craniotomy/ ventriculopetoneal shunt/ craniospinal, lumbar spine boost debulking craniotomy/ radical excision 54 Gy in 30 frs/ right fronto of recurrence parietal lobe
Time to Relapse in mo
8.25
AWD (16)
-
33.5
AWOD (98.25)
-
Data unavailable
48.25 (1988)
M
ATRT
absent
ND
ND
ND
ND
No
No
No
DFD
2
12
2.75(1990)
M
ATRT
ND
ND
ND
ND
ND
UKCCSG
No
No
-
DFD
0.75
13
25.75(2000)
M
ATRT
ND
ND
ND
ND
ND
total resection
No
Data unavailable
DFD
5.5
14
32.75 (1999)
F
MRTK
ND
ND
ND
ND
lymph nodes
No UKCCSG NMTS
nephrectomy
DFD
0.5
1 (2011)
F
MRTK
absent
Yes
Yes
No
spine*
AREN 0321
nephrectomy/ laminoplasty
No 10.8 Gy in 6 frs/ upper abdomen
-
15
-
DFD
28.75
16
20.25 (1994)
F
MRTK
ND
ND
ND
ND
No
NWTS-5
nephrectomy
10.8 Gy in 8 frs/ abdomen
-
AWOD (262.75)
-
17
7 (2004)
F
MRTK
absent
Yes
No
No
Eto/ Car/ CP/ Zof/ Max
No
No
-
DFD
4.5
18
2.75 (2007)
F
MRTK
absent
ND
ND
ND
No lymph nodes lungs
AREN 0321
19
6.5 (1999)
F
MRTK
absent
ND
ND
ND
No
NWTS-5
nephrectomy nephrectomy/ uterectomy/ adrenalectomy
AREN 0321 NWTS-5
20
20.5 (2009)
M
MRTK
absent
ND
ND
ND
lymph nodes lungs
21
8.5 (2001)
M
MRTK
absent
ND
ND
ND
brain
22
10.5(2010)
M
23
0.175 (2013)
M
EERT (neck) EERT (spine)
24
179 (2009)
F
F
25
161.5 (1986)
absent
Yes
No
No
lungs
absent
Yes
Yes
No
No
EERT (tongue)
absent
ND
ND
ND
EERT (pelvis)
ND
ND
ND
ND
lymph nodes intraabdominal dissemination; lymph nodes
No
5
DFD
7
-
AWOD (196.75)
-
nephrectomy
No 19.8 Gy in 11 frs/ para aortic lymphnodes, tumor spillage
6.5
DFD
7.5
2.75
DFD
6.5
nephrectomy
No
ICE/ Dox/ CP/ Vinc European Rhabdoid Registry
total resection thoracoscopy
30.6 Gy in 17 frs/ neck
-
AWOD (53.25)
-
laminoplasty/ debulking
No
-
DFD
1.25
Vinc/ Dox/ CP/ Car/ Eto
No
No
-
DFD
3.75
Ifos/Vcr/Adr
No
No
-
DFD
22
Abbreviations: F, female; M, male; ND, not determined; ICE, ifosfamide, carboplatin, etoposide; Dox, doxorubicin; MTX, methotrexate; Eto, etoposide; Car, carboplatin; CP, cyclophosphamide; Zof, zofran; Max, maxalon; Vinc, vincristine: frs, fractions; DFD, dead from disease; AWD, alive with disease; AWOD, alive without disease. *Spinal tumor with prior MRTK in a patient with a germline SMARCB1 mutation. aCGH performed on these samples is discussed in the text.
Society for Pediatric Oncology (SIOP), the National Wilms Tumor Study Group (NWTS), the German Medulloblastoma Group (HIT) and Children’s Cancer Study Group (CCG), were used. Generally, these protocols were based on a multimodal approach, combining surgery, radiotherapy, and chemotherapy. Despite many attempts to improve these various protocols, the overall survival of rhabdoid tumor patients remained poor (7e9). In 2010, the European Rhabdoid Registry was established, and this resource provides a framework of standard treatment protocols for the different subtypes of rhabdoid tumor.
records are all centralized to the National Pediatric Oncology Unit at Our Lady’s Children’s Hospital, Crumlin, Dublin. Patient charts were reviewed for data on age at diagnosis; sex; tumor location; treatment modality; outcomes including time to recurrence and time to death, which are calculated using the following online tool: http://
Table 2
Nature of the SMARCB1 mutations
Case number
Mutation
8
Materials and methods The study includes all patients diagnosed with rhabdoid tumors before their 17th birthdays in the Republic of Ireland between January 1986 and December 2013. Diagnosis relied on a combination of classic rhabdoid morphology with vesicular nuclei and macronucleoli, eccentrically located within cells containing abundant cytoplasm with eosinophilic inclusions and showing diffuse, uniform loss of immunoreactivity for SMARCB1, frequently accompanied by nonspecific immunoreactivity of the cytoplasmic inclusions for various intermediate filament proteins. Medical
15 17 22 23
Allele 1: deletion of exon 1 to exon 9 in SMARCB1 allele 2: deletion of SMARCB1 and surrounding the genes DGCR8 and NIPSWAP Homozygous deletion from exon 1 to exon 9 in SMARCB1 Allele 1: homozygous deletion of exon 1 allele 2: hemizygous deletion of exon 2 to exon 9 Somatic translocation involving chromosome 22 with overlapping deletions in 22q Heterozygous deletion of exon 1 in SMARCB1
Representation of all SMARCB1 mutations identified somatically or in the germline in the five cases tested from our cohort. All tumors tested showed biallelic inactivating mutations of SMARCB1.
Irish rhabdoid tumor experience Table 3
3
Genomic aberrations in case number 16
Constitutional sample (14N600)
Renal tumor (13N1072 C1)
Spinal tumor (13N1072 A1)
Deletion [chr22:24040187-24631613] Gain [chr14:106371690-106410537]
Deletion [chr22:24040187-24799476] Gain [chr14:106371690-106410537] Gain [chr6:26017272-31680358]
Deletion [chr22:24429551-24631613] Gain [chr14:106371690-106410537] Gain [chr6:26033333-27880039] Gain [chr12:14695189-20903680] Deletion [chr16:84884241-90094481]
The findings of the array analysis of the initial renal and subsequent spinal tumors in addition to the constitutional DNA from patient 16 are presented. Constitutional and tumor DNA confirm the presence of a hemizygous deletion on chromosome 22 as well as a copy number variation on chromosome 14. Variation in the size of the chromosome 22 deletion is most likely because of the quality of the tumor-derived formalin-fixed, paraffin-embedded DNA. Both tumors harbor an additional overlapping gain on chromosome 6 (renal tumor: chr6:2601727231680358; spinal tumor: Chr6:26033333-27880039). In addition, the spinal tumor is further characterized by an acquired gain on chromosome 12 (chr12:14695189:20903680) and deletion of chromosome 16 (chr16:84884241-90094481), suggesting an increase in mutational events, in keeping with this tumor representing a metastatic lesion derived from the MRTK. All samples were called against the HG19 genome build.
www.timeanddate.com/date/duration.html; and results of mutational analysis of SMARCB1 in tumor and germline DNA (and, where positive, parental germline DNA also). The mutational analysis involves a combination of Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). For a single patient (case 16) with a known germline SMARCB1 mutation, array comparative genomic hybridization (aCGH) analysis was conducted on DNA extracted from paraffin blocks from the presenting renal and subsequent spinal tumors, as well as constitutional DNA extracted from peripheral lymphocytes, in an effort to investigate whether the spinal tumor was a metachronous primary or a metastasis. All samples were called against the HG19 human build; these data did not contribute to the clinical management of the disease in the child. To this end, DNA was extracted from paraffin-embedded, formalin-fixed tissue from blocks of both tumors using the Qiagen DNeasy FFPE kit. Using the Agilent SureTag Complete DNA labeling kit (Agilent, Santa Clara, CA, USA), 500 ng of tumor DNA was labeled overnight. A total of 10 mg of labeled tumor and reference DNA (Agilent control XX DNA) were cohybridized to a 4 44K Agilent CGH microarray for 18 hours. Slides were washed according to the manufacturer’s specifications and scanned using an Axon 4000B microarray scanner. Microarray data were processed and analyzed using the Agilent Cytogenomics software 2.7.8.0.
Results The findings of our systematic review of patients with rhabdoid tumor are presented in Table 1. The age at diagnosis ranged from 5 days to almost 15 years, with a mean of 38.8 months at presentation. The observed overall male/female ratio was almost equal at 1.08:1; however, ATRTs predominated in boys, whereas MRTKs were more commonly seen in girls and the very few EERTs (n Z 4) were evenly distributed. ATRTs made up more than half the tumors. Of the 25 rhabdoid tumor cases, 13 (52.0%; male/female ratio 2.25:1) were ATRT, eight (32.0%; male/female ratio 1:3) were MRTK, and four (16.0%; male/female ratio 1:1) were EERT. The 19 cases tested by immunohistochemistry for SMARCB1 expression showed absent reactivity diffusely throughout tumor cells. A SMARCB1 mutation was identified
in the tumor DNA in all cases for which a genetic test was performed. For these five cases, germline testing was positive in two and negative in three cases. Parental testing was negative in all cases in which a patient showed a germline SMARCB1 mutation. Details of the genetic mutations, both somatic and germline, are provided in Table 2. As mentioned in the materials and methods section, one patient with a germline SMARCB1 mutation presented with MRTK at age 4 weeks and relapsed with a spinal tumor at age 2 years. The details of her constitutional and somatic mutations of both tumors are detailed in Table 3. A further patient presented with MRTK at 8.5 months and developed a brain lesion at age 15 months; this patient was not tested for germline SMARCB1 mutation. In general, a multimodal approach consisting of surgery, chemotherapy, and radiotherapy was taken. A total of 20 (80.0%) patients had surgery, including 11 of 13 with ATRT, seven of eight with MRTK, and two of four with EERT. Chemotherapy was given to 21 of 25 (84.0%) patients: nine of 13 with ATRT, eight of eight with MRTK, and four of four with EERT. In contrast, radiotherapy was given to only 11 of 25 (44%) patients total, of which seven had ATRT, three had MRTK, and one had EERT. Of the 25 patients, 10 (43.5%) relapsed. The time to relapse ranged from 2.75 to 33.5 months after diagnosis, with a mean time to relapse of 10 months. In all, 19 (76.0%) patients died of disease. The time to death ranged from 0.15 to 28.75 months after diagnosis, with a mean time to death of 8.7 months. The longest survival is 263 months for a patient who remains alive at the time of writing. In all, four patients (16%)dtwo with MRTK, one with ATRT, and one with EERTdare alive without disease, and two (8%) patients, both with ATRT, are alive with disease at 16 and 30 months after diagnosis. The findings of the array analysis of the initial renal and subsequent spinal tumors in addition to constitutional DNA from patient 16 are presented in Table 3. There is a commonality of deletions on chromosome 22 and copy number variation on chromosome 14 across constitutional and tumor DNA; however, both renal and spinal tumors show a gain on chromosome 6, and the spinal tumor, which presented more than 2 years after the MRTK, shows additional aberrations that support this being a metastasis of the renal tumor, although clinical management was unaltered by this finding.
4
Discussion As is illustrated by this review of the Irish rhabdoid tumor patient cohort between 1986 and 2013, the treatment of MRT was not standardized until relatively recently (10). Historically, treatment protocols have varied between countries and depended on the anatomic site of the tumor and age of the patient. With respect to ATRT, its designation by the World Health Organization as an embryonal tumor of the central nervous system led to medulloblastoma-type or primitive neuroectodermal tumoretype therapies being employed. The outcomes have remained very poor for the younger patients, whereas combined irradiation and treatment with high dose alkylating agents in children over 3 years can be curative (11,12). In the younger patient group, multiagent high dose chemotherapy regimens with autologous stem cell rescue have been utilized, with the aim of enabling the child to survive to an age whereby radiotherapy can then be used with less morbidity. As ATRTs have a propensity to spread throughout the neuraxis, an alternative or additional approach is to give cerebrospinal fluidedirected therapy via either the intraventricular or intrathecal route (13). As with other renal tumors, the approach for renal rhabdoid tumor management has varied between Europe and North America. Within Europe, historically the UKW2 and UKW3 protocols were used, and more recently SIOP WT 2001 (14). In North America, the NWTS series has been superseded by the Children’s Oncology Group (COG) AREN high risk renal tumor protocols. Although surgical timing may vary, there has been a common approach for chemotherapeutic agents, with combinations of vincristine, actinomycin D, doxorubicin, carboplatin, cyclophosphamide, and etoposide. The management of extrarenal extracranial rhabdoid tumors has shown the most disparity, as they have been variously viewed as undifferentiated sarcomas or carcinomas. Intergroup Rhabdomyosarcoma Study protocols within North America have evolved into COG trials, whereas in Europe, Malignant Mesenchymal Tumor (MMT) trials have latterly been superseded by the European Soft Tissue Sarcoma Study Group guidelines (15). The mean age of our cohort is somewhat higher than one might anticipate for rhabdoid tumor (16) and appears to be skewed by the presence of a small number of ATRTs with older presentation, in addition to two older children presenting with EERT. The overall survival rate is comparable to that found in the SIOP trial (17). Those patients alive without disease include some who are exceptionally long-lived, however, which is very much at odds with what one expects of rhabdoid tumor. One boy [patient 10] with ATRT had a frontoparietal craniectomy, chemotherapy as per the MMT98/A2 protocol, and radiation therapy. Following relapse, he had surgery with gross total resection of the tumor and the family refused further chemotherapy. This child remains disease-free at more than 8 years postdiagnosis and 5 years postsurgery for his recurrence. Patient 16, who had stage 1 MRTK, received multimodal treatment, including irradiation of the flank and dome of the diaphragm and chemotherapy as per NWTS-5. She remains diseasefree at almost 22 years posttreatment. Patient 19 had
A. Uwineza et al. MRTK stage 2 disease treated with primary radical nephroureterectomy and adrenalectomy followed by intensive chemotherapy as per NWTS-5 protocol. She remains disease-free at over 16 years postdiagnosis. Patient 22 had EERT treated with multimodal therapy including total gross resection at surgery, chemotherapy, and proton radiotherapy with no relapse to date at 53 months out. The two patients who are alive with disease have ATRT. Both are undergoing very extensive multimodal therapy. Patient 8 is an ATRT patient who had chemotherapy per the ACNS 0034 protocol followed by Dana-Farber protocols 02294 and 13-335, as well as antiangiogenic therapy, intrathecal cytarabine therapy, alisertib therapy, and high dose chemotherapy with stem cell transplant, and then relapsed, had stereotactic irradiation with concomitant everolimus, and remains alive with recurrence at the primary site. Patient 9 is an ATRT patient with partial tumor resection at initial surgery, treated with chemotherapy as per the European Rhabdoid protocol and irradiation of posterior fossa. Metastases to the spine precluded a second surgery, and she had craniospinal irradiation. She is now undergoing individual antiangiogenic therapy, prior to which a new lesion in the cerebellopontine angle was detected. She remains alive with disease. Neither of the patients with a known germline SMARCB1 mutation has survived. The approach to the diagnosis of rhabdoid tumors has changed insofar as BAF47 (SMARCB1) immunostaining was introduced into routine Irish pathology practice in late 2006 or early 2007, at the time that electron microscopy was also being completely phased out for tumor diagnostics. Genetic testing for SMARCB1 mutation was introduced into routine practice in January 2010, and one patient was tested retrospectively. Our clinical approach to these patients has evolved in Ireland with the establishment in 2008 of a National Pediatric Hematology-Oncology program, whereby all pediatric patients with cancer are centrally treated at Our Lady’s Children’s Hospital in Dublin. With a national population of 4.5 million, this is possible in a centralized, tertiary pediatric hospital setting, supported by 16 nationwide shared care centers. Approximately 170 new oncology patients per year are cared for by five consultants (two hematologists and three oncologists). Regular weekly solid tumor and neuro-oncology multidisciplinary meetings are held and routinely attended by all consultant staff, and many trainees and nursing staff also in pediatric oncology, pathology, radiology, surgery, radiation therapy, and palliative care. Centralized pathology review for any cases not initially biopsied in Dublin is standard. Since 2009, all neurosurgery has been performed by a dedicated team of pediatric neurosurgeons with neuropathology support. We have strong links with COG, SIOP, and Children’s Cancer and Leukaemia Group, but welcome recent efforts by the international pediatric oncology community to collaborate further by the formation of rare tumor specialty groups such as the International Rhabdoid Tumor Group and the European Rhabdoid Registry. By further refining diagnostic processes, central pathology review and accurate recording of incidence, and outcomes from unified treatment pathways we hope to contribute to positively influencing outcomes for children with this devastating diagnosis.
Irish rhabdoid tumor experience
5
Acknowledgments 7.
Funding: National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland. Grant A/13/3 Awarded to Professor M J O’Sullivan, October 2013. We wish to acknowledge the clinical input of many additional colleagues including our Consultant Neurosurgeons, Neurosurgery Department, Beaumont Hospital, Dublin 9: Mr. Darrach Crimmins; Mr. Donncha O’Brien; Mr. John Caird; Mr. David Allcutt; and Mr. Taufiq Sattar. Consultant Oncology Surgeons, past and present Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland: Mr. Sri Paran; Prof. Martin Corbally; and Prof. Ray Fitzgerald. Retired Pediatric Oncologists, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland: Dr. Anne O’Meara and Dr. Fin Breathnach. Consultant Radiologists, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland: Dr. Roisin Hayes; Dr. Ethna Phelan; Dr. Clare Brenner; Dr. David Rea; and Dr. Angela Byrne. Consultant Geneticists, National Center for Medical Genetics, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland: Professor Andrew Green; Dr. William Reardon; and Dr. Sally-Ann Lynch.
10.
References
14.
1. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumors: results from the First National Wilms’ Tumor Study. Cancer 1978;41:1937e1948. 2. Haas JE, Palmer NF, Weinberg AG, et al. Ultrastructure of malignant rhabdoid tumor of the kidney. A distinctive renal tumor of children. Hum Pathol 1981;12:646e657. 3. Versteege I, Sevenet N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 1998;394: 203e206. 4. Sevenet N, Lellouch-Tubiana A, Schofield D, et al. Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotypephenotype correlations. Hum Mol Genet 1999;8:2359e2368. 5. Proust F, Laquerriere A, Constantin B, et al. Simultaneous presentation of atypical teratoid/rhabdoid tumor in siblings. J Neurooncol 1999;43:63e70. 6. Fanburg-Smith JC, Hengge M, Hengge UR, et al. Extrarenal rhabdoid tumors of soft tissue: a clinicopathologic and immu-
8.
9.
11.
12.
13.
15.
16.
17.
nohistochemical study of 18 cases. Ann Diagn Pathol 1998;2: 351e362. van den Heuvel-Eibrink MM, van Tinteren H, Rehorst H, et al. Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: a report of the SIOP renal tumour study group. Pediatr Blood Cancer 2011;56: 733e737. Tomlinson GE, Breslow NE, Dome J, et al. Rhabdoid tumor of the kidney in the National Wilms’ Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol 2005;23:7641e7645. Geyer JR, Sposto R, Jennings M, et al. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol 2005;23:7621e7631. Fruehwald, MC. European rhabdoid registry v2.2010. Available at: http://www.kinderkrebsinfo.de/sites/kinderkrebsinfo/content/ e1676/e9032/e1758/e83294/download84621/EURHAB101115_ B_ger.pdf. Accessed February 18, 2014. Hilden JM, Meerbaum S, Burger P, et al. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 2004;22:2877e2884. 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 high-dose alkylator- based chemotherapy. J Clin Oncol 2005;23:1491e1499. 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. International Society of Paediatric Oncology (SIOP) Renal Tumor Study Group. Nephroblastoma Clinical Trial and Study interim statistical report, Tuebingen, December 2007. Available at: http://web.visu.uni-saarland.de/rtsg/fileadmin/templates/logistix/ files/SIOP_Interim_Statistical_Report.pdf. Accessed April 22, 2014. Brennan B, Stiller C, Bourdeaut F. Extracranial rhabdoid tumours: what we have learned so far and future directions. Lancet Oncol 2013;14:e329ee336. von Hoff K, Hinkes B, Dannenmann-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. van den Heuvel-Eibrink MM, Grundy P, Graf N, et al. Characteristics and survival of 750 children diagnosed with a renal tumor in the first seven months of life: a collaborative study by the SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms tumor study groups. Pediatr Blood Cancer 2008;50:1130e1134.
