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PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended. Clin Cancer Res; 23(12); e76–e82. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

A number of genetic syndromes have been linked to increased risk for Wilms tumor (WT), hepatoblastoma (HB), and other embryonal tumors. Here, we outline these rare syndromes with at least a 1% risk to develop these tumors and recommend uniform tumor screening recommendations for North America. Specifically, for syndromes with increased risk for WT, we recommend renal ultrasounds every 3 months from birth (or the time of diagnosis) through the seventh birthday. For HB, we recommend screening with full abdominal ultrasound and alpha-fetoprotein serum measurements every 3 months from birth (or the time of diagnosis) through the fourth birthday. We recommend that when possible, these patients be evaluated and monitored by cancer predisposition specialists. At this time, these recommendations are not based on the differential risk between different genetic or epigenetic causes for each syndrome, which some European centers have implemented. This differentiated approach largely represents distinct practice environments between the United States and Europe, and these guidelines are designed to be a broad framework within which physicians and families can work together to implement specific screening. Further study is expected to lead to modifications of these recommendations. Clin Cancer Res; 23(13); e115–e22. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz–Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107–e14. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Background Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway ranging from type I (cystic) to type II (cystic/solid) and type III (completely solid). A germline mutation in DICER1 is the genetic cause in the majority of PPB cases.

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

Childhood rhabdomyosarcoma (RMS) accounts for approximately 3.5% of cancer cases among children 0 to 14 years of age. Genetic conditions associated with high risk of childhood RMS include Li-Fraumeni syndrome, pleuropulmonary blastoma, Beckwith-Wiedemann syndrome, and some RASopathies, such as neurofibromatosis type 1, Costello syndrome (CS), and Noonan syndrome (NS). Here, we report the rare case of a 4-year-old girl with clinical features of NS who developed an embryonal RMS of the chest and needed emergent treatment. Molecular genetic testing identified a de novo, large, mosaic duplication of chromosome 2 encompassing the SOS1 gene, presumably caused by a mosaic, unbalanced translocation between chromosomes 2 and 17 found on routine cytogenetic analysis. Sequence analysis of all known genes causing Noonan spectrum disorders was negative. RMS has been reported in a few patients with NS, associated in very few with germline SOS1 mutations, but none with copy number abnormalities. This is the first report to our knowledge of early-onset RMS developing in a child with features of NS and a mosaic RAS pathway gene aberration, a large SOS1 duplication. We hypothesize that the inciting event for tumor development in this case is due to the germline mosaic duplication of SOS1, which was duplicated in all cells of the tumor, and the ultimate development of the tumor was further driven by multiple chromosomal aberrations in the tumor itself, all described as somatic events in isolated RMS tumors.

Embryonal rhabdomyosarcoma (ERMS) is the most common sarcoma of childhood and is a component of the familial Pleuropulmonary Blastoma (PPB)-predisposition syndrome. Using the PPB model, we hypothesized that DICER1 mutations would be found in familial and sporadic forms of ERMS. Blood samples from four children with familial PPB and ERMS, and an additional 52 sporadic ERMS tumors were tested for DICER1 mutations. DICER1 mutations were found in all 4 patients with familial PPB and in 2 of 52 (3.8%) patients with sporadic ERMS. Our findings confirm the pathogenetic relationship between ERMS and PPB and suggest that ERMS may result from abnormal miRNA regulation.

10022 Background: Mutations in DICER1 were first described in 2009 from individuals diagnosed with pleuropulmonary blastoma (PPB). Since then, DICER1 mutations have been found in individuals with o...

10014 Background: Pleuropulmonary blastoma (PPB) is a rare malignancy of the lung presenting in young children. PPB is the sentinel disease of the PPB-DICER1familial syndrome. The International PPB...

10060 Background: Pleuropulmonary blastoma (PPB) is a rare malignancy of the lung presenting in young children. The International PPB Registry (IPBBR) has pathologically confirmed more than 400 cas...

5520 Background: Ovarian sex cord-stromal tumors are rare tumors that tend to occur in children, adolescents and young adults. The International Ovarian and Testicular Stromal Tumor (OTST) Registry...

10024 Background: Pleuropulmonary blastoma (PPB) is a rare, aggressive childhood lung cancer that is often the first manifestation of the PPB-DICER1 familial tumor predisposition which includes other benign and malignant conditions. The initial genetic mutation is inherited by a germ-line loss of function of DICER1 gene which was discovered by Hill et al. It is proposed that loss of DICER1 expression alters miRNA regulation of key regulatory cellular mechanisms which promote tumor growth. PPB can progress from the purely cystic, curable Type I to a high-grade Type III having a dismal prognosis. We sought to determine the frequency of DICER1mutation in the largest cohort of PPB patients to date. Methods: We obtained germ-line DNA from saliva or blood samples from 113 PPB patients collected from 2005-2012. DNA was extracted using the Maxwell 16 Research System (Promega Corporation, Madison WI). Sample quality and quantity was checked using the Nanodrop 2000 (Thermo Scientific, Wilmington, DE). Sequencing was performed using the Sanger sequencer. For a subset of cases we used targeted sequencing services or full gene sequence analysis (Ambry Genetics, Aliso Viejo, CA). Results: Seventy-four (65.5%) PPB patients were found to have deleterious DICER1germ-line mutations. The most common mutation type found was small insertion/deletions. These 74 samples were composed of 7 (9.5%)Type Ir PPBs, 22 (29.7%)Type I PPBs, 24 (32.4%) Type II PPBs, and 21 (28.4%)Type III PPBs. The following Table shows a summary of mutation types identified. Conclusions: Our results confirm that DICER1 germline mutations are the most common genetic alterations in PPB making it critical for genetic testing to be performed at diagnosis. Additionally, this underscores the need for important correlative studies to describe the genotype-phenotype relationship in order for appropriate screening guidelines to be developed and implemented to allow for early detection. While a majority of cases are explained by germline DICER1 mutations using current sequencing methods, further investigation is warranted to elucidate other possible mechanisms in the development of PPB. [Table: see text]

9522 Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung neoplasm of early childhood with progression from a purely cystic Type I (T-I) lesion to cystic solid and solid high grade sarcoma (Type II and Type III). A regressed form of PPB (T-Ir) has been recognized pathologically. The outcome of both T-I and T-Ir has been only partially described. Methods: Retrospective analysis of 345 IPPBR cases showed 116 T-I or T-Ir. In all cases the PPB diagnosis was made on surgically removed cysts. The treating physician decided whether to use chemotherapy after surgery. Results: The pathologic diagnosis of the 91 PPB T-I and 25 T-Ir is now confirmed by central review (LPD and DAH). Patients with T-I were younger than T-Ir (median: 8 months vs. 48 months).Diagnosis after age 6 years included only one T-I compared to 10 T-Ir patients. Therapy is not known for 28 T-I and 2 T-Ir. Surgery was followed by chemotherapy in 31 T-I and 2 T-Ir. Six (5%) recurred with the same type, all were alive at last follow-up: 5 (5.5%) T-I, 1 (4%) T-Ir. Progression to high-grade Type II or III occurred in 9/91 (10%) T-I and 2/25 (8%) T-Ir. The addition of chemotherapy did not significantly reduce progressions (Fisher’s exact test). All of the tumor progressions were seen by 75 months of age; this finding is similar to broader IPPBR data: > 95% of patients are diagnosed with Type II/III by 72 months of age. Of the 9 patients with T-I who progressed, 5 ultimately died, whereas the 2 T-Ir who progressed were alive. At last follow-up 111/116 (95.6%) were alive. Conclusions: A cyst in an older individual most likely will be Type Ir. Type I and Type Ir are clinically similar with a small risk of progression to the advanced Type II/III up to 6 years of age. Outcome for those whose cystic PPBs progressed is poor. The role of chemotherapy remains uncertain for the prevention of progression in the pure cystic PPB Type I or Ir. [Table: see text]

9521 Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung neoplasm of early childhood with progression from a purely cystic (Type I) lesion to a solid high-grade sarcoma Type III (T-III), or a mixed solid/cystic stage Type II (T-II). Surgery and chemotherapy are required for T-II and T-III PPB, but the benefit of radiation therapy for T-II and T-III PPB is debated and is being evaluated in this study. Methods: This is a retrospective analysis of central pathology-reviewed Types II and III PPB from the IPPBR. Treatments were chosen by physician, were not randomized, and included surgery and chemotherapy. The outcome of patients treated with upfront radiation (before progression or relapse) was compared to patients who did not receive radiation. Event-free survival (EFS) and overall survival (OS) were determined to last follow-up, using the Kaplan-Meier analysis, with log-rank test. Results: Outcome for 212 patients (117 Type-II and 95 Type III) was significantly better for T-II than T-III: EFS for T-II was 68.1% vs. T-III 45.7% (P=0.002), and OS for T-II was 75.2% vs. T-III 57.9% (p=0.01). Excluding patients with incomplete therapy information, 174 were treated with surgery and chemotherapy. Of these 44 (25%) also received radiation therapy; 130 patients did not. The table below shows comparison of radiated vs. non-radiated. Radiation provided no additional survival benefit, overall or by tumor Type. Multivariate analysis showed that gender and extent of primary tumor resection (biopsy vs. gross total resection) had no effect on outcome, however T-II vs. T-III retained prognostic significance. Conclusions: For this collection of advanced-type PPB, outcome is significantly better for T-II than T-III. For patients treated initially with surgery and chemotherapy, adding radiation therapy offered no improvement in event-free or overall survival. Limitations of this study include its retrospective nature and non-uniform treatment regimens. [Table: see text]