An Increased Risk of Second Malignant Neoplasms After Rhabdomyosarcoma: Population-based Evidence for a Cancer Predisposition Syndrome?

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1 Pediatr Blood Cancer 2016;63: An Increased Risk of Second Malignant Neoplasms After Rhabdomyosarcoma: Population-based Evidence for a Cancer Predisposition Syndrome? Natasha M. Archer, MD, MPH, 1 * Renata Parada Amorim, 2 Rafaela Naves, 2 Simone Hettmer, MD, 3 Lisa R. Diller, MD, 1 Karina Braga Ribeiro, DDS, PhD, 2 and Carlos Rodriguez-Galindo, MD 1 Background. Rhabdomyosarcoma survivors have an increased risk of developing second malignant neoplasms (SMN); this risk is traditionally attributed to the effects of multidisciplinary management required for cure. However, the impact of constitutional predisposition has not been properly analyzed. Methods. We analyzed the risk of SMN among 1,151 children diagnosed with rhabdomyosarcoma and reported to the Surveillance, Epidemiology, and End Results registries (SEER-9) from 1973 to Standardized incidence ratios (SIR) and corresponding 95% confidence intervals (CI) were calculated using SEERStat Results. Children with pleomorphic and embryonal rhabdomyosarcoma had an increased risk of developing a SMN (SIR ¼ 15.77, 95%CI and SIR ¼ 5.6, 95%CI , respectively). The risk was agedependent; the highest was among children <2 years (SIR ¼ 13.38, 95%CI ) and the lowest was in children >10 years (SIR ¼ 3.35, 95%CI ). The risk for the youngest patients was higher for those with embryonal rhabdomyosarcoma (SIR ¼ 14.72, 95%CI ) compared to other histiotypes. Additionally, the risk of SMN was independent of the use of radiation to the primary (SIR ¼ 6.50, 95%CI and SIR ¼ 4.57, 95%CI , for children receiving and not receiving radiation, respectively). The pattern of SMN observed was consistent with the Li-Fraumeni spectrum. Conclusions. Children with rhabdomyosarcoma are at high risk of developing SMN. This risk is higher for a subgroup of young children with pleomorphic and embryonal histologies, and is independent of the use of radiation. This suggests that a subgroup of children with pleomorphic and embryonal rhabdomyosarcoma may have a constitutional cancer predisposition. Pediatr Blood Cancer 2016;63: # 2015 Wiley Periodicals, Inc. Key words: anaplasia; rhabdomyosarcoma; second malignancy; SEER program; TP53 INTRODUCTION Survival of children with cancer has greatly increased over the last several decades; in part, this is due to the optimization of multidisciplinary care, with risk-adjusted intensification of chemotherapy and radiation therapy. However, progress has also revealed that childhood cancer survivors have a high risk of developing second malignant neoplasms (SMN).[1,2] This risk has also been documented to be increased in children treated for rhabdomyosarcoma, and has been mostly attributed to the treatment received. [1,3 5] However, an inherent predisposition may also contribute; rhabdomyosarcoma has been associated with several cancer predisposition syndromes, including Li-Fraumeni, Gorlin, and Beckwith Wiedeman syndromes.[3,6 8] Recently, we described a small cohort of children with anaplastic embryonal rhabdomyosarcoma and germline TP53 mutations, and proposed that this anaplastic histological subtype in young children may be a marker of a cancer predisposition, thus suggesting the need to refer these patients for proper genetic evaluation.[9] To test this hypothesis, we designed a populationbased study assessing the risk of SMN according to the different rhabdomyosarcoma subtypes, age groups, and treatment received available in the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute. If this hypothesis were to be true, using this approach we might identify a high-risk patient group defined by young age and non-alveolar tumor histology that would be candidate for additional studies. METHODS The SEER program is a respected source of information on cancer incidence and survival in the United States, currently collecting data from 18 population-based cancer registries covering approximately 28% of the US population. We analyzed the incidence of SMN among children and adolescents (0 19 years) diagnosed with C 2015 Wiley Periodicals, Inc. DOI /pbc Published online 20 July 2015 in Wiley Online Library (wileyonlinelibrary.com). rhabdomyosarcoma between 1973 and 2010 and residing in one of the nine SEER program registries (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, and Utah). To select for primary rhabdomyosarcoma, we used the following International Classification of diseases for Oncology 3rd edition (ICD-O-3) codes: 8900/3 rhabdomyosarcoma not otherwise specified (); 8902/3 mixed; 8901/3 pleomorphic; 8920/3 alveolar; and 8910/3 and 8912/3 embryonal. Histologic subtypes available in SEER are based on institutional pathology review rather than expert central review. SEER Stat software version was used to calculate the standardized incidence ratio (SIR) Abbreviations: CI, 95% confidence intervals; RMS, rhabdomyosarcoma; SEER, surveillance, epidemiology, and end results; SIR, standardized incidence ratios; SMN, second malignant neoplasm 1 Pediatric Hematology/Oncology, Dana-Farber/Boston Children s Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts; 2 Faculdade de Ci^encias Medicas da Santa Casa de S~ao Paulo, S~ao Paulo, Brazil; 3 Department of Pediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany Grant sponsor: NIH; Grant number: 5T32HL007574; Grant sponsor: Doris Duke Charitable Foundation; Grant number: ; Grant sponsor: Faculdade de Ci^encias Medicas da Santa Casa de S~ao Paulo, S~ao Paulo, Brazil Natasha M. Archer and Renata P. Amorim contributed equally to this work. Conflict of interest: Nothing to declare. Correspondence to: Natasha M. Archer, Pediatric Hematology/ Oncology, Dana-Farber/Boston Children s Cancer and Blood Disorders Center, 300 Longwood Avenue, BCH 3141, Boston, MA Natasha_archer@dfci.harvard.edu Received 22 February 2015; Accepted 30 June 2015

2 Second Malignant Neoplasms After Rhabdomyosarcoma 197 with 95% confidence intervals (CI). Case listing function was used to collect individual SMN data. RESULTS We identified 1,151 children age 0 19 years (median age of 7 years at diagnosis, 59.3% male) in the SEER-9 database with a primary rhabdomyosarcoma diagnosed from 1973 to 2010; 27 of these patients developed a SMN. Table I describes the rhabdomyosarcoma cohort as well as the subgroup of patients who developed a SMN. There was no difference between the two groups in age at diagnosis of primary tumor; sex, race, and ethnicity distribution; and use of radiation therapy. There was a predominance of embryonal rhabdomyosarcomas seen in the overall cohort. The majority of SMN was observed in patients diagnosed with their primary RMS between 2000 and Compared to the general population, survivors of childhood rhabdomyosarcoma had a fivefold increased risk (SIR ¼ 5.69, 95%CI ) of developing SMN. The increased risk of SMN was only significant for second solid malignancies (SIR ¼ 5.74, 95%CI , vs. 5.08, 95%CI , for leukemias). Twenty-seven children (2.3%) developed 29 malignancies, including 26 solid tumors, one lymphoma, and two leukemias (Table II). The median age at diagnosis of the primary tumor and at development of the SMN were 5 years (range, 0 15) and 18 years (range, 5 42), respectively, with a median time to the development of a SMN of 13 years (range, 2 29). The most common SMN was a sarcoma, including three osteosarcomas, two chondrosarcomas, and four soft tissue sarcomas. One child (case #19) was noted to have developed an alveolar rhabdomyosarcoma as a second malignancy in the radiation field 20 years after a primary alveolar rhabdomyosarcoma. Although it is unlikely that this represents a recurrence given the time that elapsed between the two presentations, we were unable to confirm the diagnosis and we elected to keep this case in the analysis. Other SMN that occurred in more than one child included renal cell carcinoma, papillary carcinoma of the thyroid, infiltrating duct carcinoma of the breast, and melanoma. The majority of the children who developed SMN had been diagnosed with embryonal rhabdomyosarcoma (63%), at less than 10 years of age (69%). Eighteen individuals (66%) received radiation as part of their initial treatment and of the 20 SMN they developed, 11 occurred in what we estimated, based on tumor location and standard of care, to be the radiation field. In total, 18 of the 29 SMN (62%) developed outside of the radiation field. In order to investigate clinical and treatment associations, we evaluated whether the increased incidence of SMN was associated with the histology of the primary tumor, age at diagnosis of rhabdomyosarcoma, and use of radiation therapy. The risk of developing a SMN varied according to the histologic subtype; it was significantly increased for pleomorphic (SIR ¼ 15.77, 95%CI ) and embryonal subtypes (SIR¼ 5.60, 95%CI ), whereas children with alveolar rhabdomyosarcoma did not show an increase in the incidence of SMN. The risk of SMN was age-dependent; it was the highest among children younger than 2 years (SIR 13.38, 95%CI ) and the lowest in children aged 10 years or older TABLE I. Demographic and Clinical Characteristics of Children With Rhabdomyosarcoma, SEER 9 Cohort (%) Variables Categories All RMS patients (N ¼ 1,151) SMN (N ¼ 27) Sex Male 682 (59.3) 14 (48.3) Female 469 (40.7) 15 (51.7) Age at diagnosis (first primary) (years) (35.7) 10 (34.5) (25.9) 10 (34.5) (38.4) 9 (31.0) Year of diagnosis (16.3) 0 (0.0) (24.5) 2 (6.9) (27.2) 6 (20.7) (32.0) 21 (72.4) RMS type Rhabdomyosarcoma, 165 (14.3) 6 (20.7) Pleomorphic 15 (1.3) 2 (6.9) Mixed 16 (1.4) 0 (0.0) Embryonal 670 (58.2) 18 (62.1) Alveolar 285 (24.8) 3 (10.3) Race White 901 (78.3) 24 (82.8) Black 169 (14.7) 2 (6.9) Other 75 (6.5) 3 (10.3) Unknown 6 (0.5) 0 (0.0) Ethnicity Non-Hispanic 1051 (91.3) 25 (86.2) Hispanic 93 (8.1) 4 (13.8) Unknown 7 (0.6) 0 (0.0) Radiation therapy Yes 745 (64.7) 20 (69.0) No 390 (33.9) 9 (31.0) Unknown 16 (1.4) 0 (0.0) SEER 9, surveillance, epidemiology, and end results program 9; RMS, rhabdomyosarcoma; SMN, second malignant neoplasm;, not otherwise specified.

3 198 Archer et al. TABLE II. Clinical Characteristics of Patients With Second Malignant Neoplasms Case # Sex Age (years) 1st tumor histology 1st tumor site XRT-1st tumor Age at diagnosis 2nd tumor (years) 2nd tumor histology 2nd tumor site 1 M 7 RMS, Soft palate, No 15 Osteosarcoma, Lower limb 2 F 1 ERMS Cheek mucosa No 8 Osteosarcoma, Mandible 3 M 10 ERMS Nasopharynx, posterior wall Yes 30 Undifferentiated sarcoma ST, head, and neck 4 a F 6 ERMS Nasopharynx, Yes 26 Superficial spreading Skin of trunk melanoma 5 M 3 RMS, Middle ear No 5 Acute myeloid leukemia Bone marrow 6 F 16 ERMS ST, head and neck No 42 Infiltrating duct carcinoma, Breast 7 F 13 ARMS ST, head and neck No 16 Papillary carcinoma, Thyroid follicular variant 8 M 1 ERMS ST, head and neck Yes 29 Renal cell carcinoma Kidney 9 M 4 ERMS ST, head and neck Yes 31 Acute myeloid leukemia Bone marrow 10 M 6 ERMS ST, head and neck Yes 18 Osteosarcoma, Mandible 11 F 6 ERMS ST, head and neck Yes 10 Mesenchymal Bones of skull chondrosarcoma 12 F 6 ARMS ST, head and neck No 8 Hepatoblastoma Liver 13 F 3 RMS, ST, upper limb/shoulder No 33 Chondrosarcoma, Upper limb/scapula 14 M 15 ARMS ST, lower limb/hip No 42 Squamous cell carcinoma, Tonsil 15 F 5 PRMS ST, lower limb/hip No 13 Glioma, malignant Frontal lobe 16 M 5 ERMS ST, lower limb/hip Yes 14 Malignant melanoma in giant Scrotum, pigment nevus 17 M 13 PRMS ST, lower limb/hip Yes 35 Glioblastoma, Frontal lobe 18 b F 11 RMS, ST, lower limb/hip Yes 18 Leiomyosarcoma, Vulva 19 F 0 RMS, ST, pelvis Yes 20 Alveolar rhabdomyosarcoma ST, pelvis 20 F 13 ERMS ST, trunk Yes 26 Infiltrating duct carcinoma, Breast, central portion 21 M 1 ERMS Prostate Yes 11 Non-Hodgkin lymphoma Cecum 22 M 15 ERMS Testis Yes 36 Adenocarcinoma, Unknown primary site 23 M 2 ERMS Bladder, Yes 16 MPNST Pelvis 24 F 1 ERMS Bladder, Yes 13 MPNST Lower limb/hip 25 F 5 ERMS Orbit, Yes 34 Neoplasm, malignant Lung 26 M 2 ERMS Orbit, Yes 18 Renal cell carcinoma Kidney 27 M 6 ERMS Eye, Yes 35 Papillary transitional cell carcinoma Bladder neck M, male; F, female; RMS, rhabdomyosarcoma;, not otherwise specified; ERMS, embryonal rhabdomyosarcoma; ARMS, alveolar rhabdomyosarcoma; ST, soft tissue; MPNST, malignant peripheral nerve sheath tumor. a Patient had also a third primary neoplasm Papillary adenocarcinoma of thyroid age at diagnosis ¼ 30 years. b Patient had also a third primary neoplasm Renal cell carcinoma age at diagnosis ¼ 23 years. (SIR 3.35, 95%CI ). We then evaluated the risk of SMN in relation to histology and the use of radiation therapy. The incidence of second cancers was significantly increased regardless of the history of radiation treatment; the SIR was 6.50 (95%CI ) for children who received radiation, and it was 4.57 (95%CI ) for those who did not (Table III). In order to further define subgroups of children at highest risk of developing SMN, we then investigated the interaction of age with histology and radiation treatment (Table IV). When age and histology were combined, the greatest risk was seen in children 5 9 years old with pleomorphic type rhabdomyosarcoma (SIR ¼ , 95%CI ,754.80). Embryonal histology was associated with a significantly increased incidence of SMN in children younger than 10 years of age, but not in older children. When the age groups were further defined, children younger than 2 years with embryonal rhabdomyosarcoma had the greatest increased risk of SMN (SIR ¼ 14.72, 95%CI ). Alveolar histology was not associated with an increased SIR in any age group. When we analyzed the radiation effect by age, patients younger than 10 years had an increased risk of SMN regardless of radiation treatment; this increased risk was only associated with the exposure to radiation therapy for children aged 10 years or older. (Table IV). Finally, we investigated the association of age, histology, and radiation and the risk of developing SMN (Table V). The use of radiation therapy was associated with a significantly increased

4 Second Malignant Neoplasms After Rhabdomyosarcoma 199 TABLE III. Risk of Second Malignant Neoplasm According to Age, Rhabdomyosarcoma Histology, and Radiation Therapy Variable Category Number of cases SIR 95%CI Age <2 years years years years Histologic type RMS, Pleomorphic Mixed Embryonal Alveolar Radiation therapy Yes No SIR, standardized incidence ratio; CI, confidence interval; RMS, rhabdomyosarcoma;, not otherwise specified. incidence of SMN for children younger than 10 years with embryonal histology, but not for those aged 10 years or older. Children with alveolar rhabdomyosarcoma treated with radiation therapy did not have an increased risk of SMN at any age. DISCUSSION Herein, we have identified a potential subgroup of survivors of rhabdomyosarcoma that are at a significant high risk of developing SMN. This group is characterized by having embryonal or pleomorphic histology and young age. Importantly, while risk is higher among young children treated with radiation, it is also significantly increased in young children who did not receive radiation therapy. The risk of developing SMN is well known in cancer survivors; it is estimated that approximately 1.5% of childhood cancer survivors develop a second cancer within 30 years.[10] This proportion is similar in patients who have been treated for rhabdomyosarcoma; in a study of children treated on the Intergroup Rhabdomyosarcoma Study Group I and II studies between 1972 and 1984, 22 out of 1,170 patients (1.8%) developed SMN.[3] This increased risk seen in childhood cancer survivors is considered to be mostly related to the deleterious effects of chemotherapy and radiation therapy.[1,3 5] However, TABLE IV. Risk of Second Malignant Neoplasm According to Age at Diagnosis, Stratified by Rhabdomyosarcoma Histology and Radiation Therapy Variable Age (years) Category Number of cases SIR 95%CI Histology <5 RMS, Pleomorphic Mixed Embryonal Alveolar RMS, Pleomorphic , Mixed Embryonal Alveolar RMS, Pleomorphic Mixed Embryonal Alveolar Radiation therapy <5 Yes No Yes No Yes No SIR, Standardized incidence ratio; CI, confidence interval; RMS, rhabdomyosarcoma;, not otherwise specified.

5 200 Archer et al. TABLE V. Risk of Second Malignant Neoplasm After Rhabdomyosarcoma Stratified by Age at Diagnosis and Histology According to the Therapy Delivered for the First Primary Radiotherapy Yes No Age (years) Histology Number of cases SIR 95%CI Number of cases SIR 95%CI <5 RMS, Pleomorphic Mixed Embryonal Alveolar RMS, Pleomorphic , , Mixed , Embryonal Alveolar RMS, Pleomorphic Mixed , Embryonal Alveolar SIR, standardized incidence ratio; CI, confidence interval; RMS, rhabdomyosarcoma;, not otherwise specified. constitutional determinants are also known to increase the risk of second neoplasms in this population. A recent study by our group showed a strong association between germline TP53 mutations and anaplastic embryonal rhabdomyosarcoma diagnosed at a young age.[9] The association of RMS and Li-Fraumeni syndrome has been previously described. Diller et al. reported a frequency of TP53 germline mutations of 9.1% among children with rhabdomyosarcoma and no family history of cancer or second primary cancers; this proportion was 23% in patients younger than 3 years of age.[7] However, Magnusson et al. found that only 5% of children younger than 5 years of age with RMS had an identifiable TP53 mutation. The families of these same patients did have a slightly increased overall cancer incidence (SIR ¼ 1.2; 95%CI: ) but those cancers were not consistent with Li-Fraumeni syndrome.[11] Thus, while the true incidence of germline TP53 or other predisposition syndromes in patients with rhabdomyosarcoma is not known, it is important to identify patients that may be at risk for such a constitutional predisposition in order to appropriately identify their risk, counsel patients and their families, and plan their therapy. Although SEER does not document the presence of anaplasia, our finding of a significantly increased incidence of SMN in young patients with embryonal or pleomorphic histologies suggests the existence of this small subgroup of patients with constitutional risk. The inability to conduct a central review as part of the study limits the strength of our conclusions; however, we believe that the population-based nature of the study has allowed us to identify a pattern to be confirmed with cooperative group, centrally reviewed, data. SEER does not provide specific information about the radiation field used in treatment; however, we have estimated the radiation field based on tumor location and standard of care. Interestingly, the risk of SMN in our study was independent of the use of radiation therapy to the primary site; approximately half of the second solid malignancies in children who had received radiation therapy, and two-thirds of all malignancies developed outside of the radiation field. Thus it is possible that our analysis underestimates the radiation-independent risk of SMN in this population. We found a significant increase in the incidence of SMN in young children (<10 years) with embryonal histology tumors receiving radiation therapy, further supporting the hypothesis of the potential existence of a subgroup of children with constitutional risk. Furthermore, the majority of the SMNs identified are consistent with the Li-Fraumeni spectrum, including sarcomas, breast cancer, adenocarcinoma, and renal cell carcinoma. Of particular interest is that three of the 29 secondary malignancies were renal cell carcinoma; this is an exceptionally rare cancer in pediatric patients and young adults, but in our study group it occurred in patients aged 18, 23, and 29 years. Also worth noting, the increased risk of SMN was only significant for second solid malignancies and not leukemias. Although we believe this may be secondary to the small number of leukemia events within our study population, hematologic malignancies in survivors of rhabdomyosarcoma are mostly treatment related, rather than resulting from a cancer predisposition syndrome. As noted, the increased risk of SMN was limited to pleomorphic and embryonal histologies. Pleomorphic rhabdomyosarcoma is a rare subtype used to describe, typically in adults, tumors with large and atypical pleomorphic polygonal rhabdomyoblasts.[12] A link between pleomorphic and anaplastic rhabdomyosarcoma, the histologic equivalent of pleomorphic in children, was first described by Kodet in 1993.[13] Using the criterion of cells with lobated, hyperchromatic nuclei at least three times larger than the common tumor cell population, Kodet et al. identified 110 tumors from

6 Second Malignant Neoplasms After Rhabdomyosarcoma 201 pediatric patients with anaplastic features, the majority (105) of which also had embryonal rhabdomyosarcoma features; this led the authors of the study to believe that most pleomorphic rhabdomyosarcoma had likely been diagnosed as embryonal rhabdomyosarcoma in children.[14] Although a pathology review of the tumors identified in our study as pleomorphic and embryonal was not possible, it is possible that the predominant driver of the identified increased risk within these two histologic subtypes is the presence of pleomorphism, or more commonly called in children anaplasia, which we have found to be associated with germline TP53 mutations. Although the study by Kodet et al. suggested that only a small subset (approximately 3%) of patients with RMS have anaplasia, Qualman et al. found that 13% of childhood RMS registered in the Intergroup Rhabdomyosarcoma Study Group trials from 1995 to 1998 demonstrated anaplasia.[14] The retrospective nature of our study presents several limitations. First, the majority of the primary rhabdomyosarcoma tumors were diagnosed prior to the introduction of the term anaplasia in the description of rhabdomyosarcoma tumors for the cooperative groups, and a central review of the cases is not possible for obvious reasons. Second, the details on the treatment administered, particularly dose and field of radiation, were not available, thus limiting our ability to conduct proper correlation between treatment administered and risk of SMN. Third, our median follow-up time is short. A minimum of 30 years of follow-up would have been desirable to estimate a cumulative risk of SMN. Lastly, our sample size and thus our number of SMN are small, thus limiting our ability to properly power the analysis to evaluate risks for all the histologic subtypes. In summary, using a population-based approach, we have identified a potential subgroup of children with rhabdomyosarcoma who have an increased risk of developing SMN; this group is characterized by younger age and tumors of embryonal histology, and the risk is independent of the use of radiation therapy. The features of the cases and of the SMNs are suggestive of a possible cancer predisposition and support additional studies exploring the genetic contributions to SMN in young children with embryonal or pleomorphic rhabdomyosarcoma. Future studies, preferably using large clinical trial datasets that include expert pathology review, are needed to further define this subgroup. ACKNOWLEDGMENTS NA was supported by NIH Training Grant 5T32HL and Doris Duke Charitable Foundation Grant RPA and RN were supported by a scholarship offered by the Program Pesquisadores do Futuro, Faculdade de Ci^encias Medicas da Santa Casa de S~ao Paulo, S~ao Paulo, Brazil. REFERENCES 1. Cohen RJ, Curtis RE, Inskip PD, Fraumeni JF. The risk of developing second cancers among survivors of childhood soft tissue sarcoma. Cancer 2005;103: Bardeesy N, Petruzzi MJ, Nowak N, Zabel B, Adam M, Aguiar MC, Grundy P, Shows T, Pelletier J. Anaplastic Wilms tumour, a subtype displaying poor prognosis, harbours p53 gene mutations. Nat Genet 1994;7: Heyn R, Haeberlen V, Newton WA, Ragab AH, Raney RB, Tefft M, Wharam M, Ensign LG, Maurer HM. Second malignant neoplasms in children treated for rhabdomyosarcoma. J Clin Oncol 1993;11: Tucker MA, D Angio GJ, Boice JDJ, Strong LC, Li FP, Stovall M, Stone BJ, Green DM, Lombardi F, Newton W, Hoover RN, Fraumeni JF. 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