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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.

PURPOSE Germ-line mutations in DICER1 increase the risk of various tumors, including pleuropulmonary blastoma. Macrocephaly and symmetric overgrowth have been reported in some, but not all, patients with mosaic DICER1 RNase IIIb mutations. The prevalence of these features in individuals with constitutional germ-line DICER1 mutations is unknown. METHODS We analyzed prospectively collected auxology data from 67 DICER1 mutation carriers and 43 family controls. We assessed differences between groups using an exact test for proportions and generalized estimating equations for continuous dependent variables. RESULTS Twenty-eight DICER1 mutation carriers (42%) were macrocephalic, and none had an occipitofrontal circumference (OFC) below the third centile, which significantly differed from family controls, of whom five were macrocephalic (12%) and two had OFC below the third centile (5%) (P < 0.001). DICER1 mutation carriers were taller than familial controls after controlling for gender (P = 0.048), but similar proportions of both groups were above the 97th centile of population norms. Head circumference remained increased after adjusting for differences in height. CONCLUSION For the first time, we establish macrocephaly as a common finding in the DICER1 syndrome. Like some other tumor-predisposition disorders, macrocephaly may be a useful, albeit a subtle, clinical clue to the DICER1 syndrome diagnosis.Genet Med 19 2, 244-248.

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.

Context: The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown. Objective: To quantify the risk of thyroid cancer and MNG in individuals with DICER1 syndrome. Design: Family-based cohort study. Setting: National Institutes of Health (NIH) Clinical Center (CC). Participants: The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families. Interventions: Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC. Main Outcome Measures: The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing. Results: By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P < 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P < 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations. Conclusions: We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome., In a family-based cohort study of the DICER1 syndrome, we quantified the remarkably elevated rates of multinodular goiter and propose a model of DICER1-associated thyroid carcinogenesis.

Pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT) are both associated with germline mutations in DICER1. In this brief report, a maternal history of SLCT led to identification of a deleterious DICER1 mutation in the patient and her asymptomatic infant. Radiographic screening revealed a large Type I PPB, which was completely resected. Identification of DICER1 mutation carriers and imaging of children at risk for PPB may allow detection of PPB in its earliest and most curable form, leading to increased likelihood of surgical cure and decreased risks of treatment-related late effects.

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.

Nasal chondromesenchymal hamartoma (NCMH) is a rare nasal tumor that typically presents in young children. We previously reported on NCMH occurrence in children with pleuropulmonary blastoma (PPB), a rare pulmonary dysembryonic sarcoma that is the hallmark neoplasm in the PPB-associated DICER1 tumor predisposition disorder. Original pathologic materials from individuals with a PPB, PPB-associated tumor and/or a DICER1 mutation were centrally reviewed by the International PPB Registry. Paraffin-embedded NCMH tumor tissue was available in three cases. Laser-capture microdissection was used to isolate mesenchymal spindle cells and cartilage in one case for Sanger sequencing of DICER1. Nine patients (5F/4M) had PPB and NCMH. NCMH was diagnosed at a median age of 10 years (range 6-21 years). NCMH developed 4.5-13 years after PPB. Presenting NCMH symptoms included chronic sinusitis and nasal congestion. Five patients had bilateral tumors. Local NCMH recurrences required several surgical resections in two patients, but all nine patients were alive at 0-16 years of follow-up. Pathogenic germline DICER1 mutations were found in 6/8 NCMH patients tested. In 2 of the patients with germline DICER1 mutations, somatic DICER1 missense mutations were also identified in their NCMH (E1813D; n = 2). Three additional PPB patients developed other nasal lesions seen in the general population (a Schneiderian papilloma, chronic sinusitis with cysts, and allergic nasal polyps with eosinophils). Two of these patients had germline DICER1 mutations. Pathogenic germline and somatic mutations of DICER1 in NCMH establishes that the genetic etiology of NCMH is similar to PPB, despite the disparate biological potential of these neoplasms.

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.Patients confirmed to have PPB by central pathology review were included, and their clinical characteristics and outcomes were reported. Germline DICER1 mutations were sought with Sanger sequencing.There were 435 cases, and a central review confirmed 350 cases to be PPB; 85 cases (20%) were another entity. Thirty-three percent of the 350 PPB cases were type I or type I regressed (type Ir), 35% were type II, and 32% were type III or type II/III. The median ages at diagnosis for type I, type II, and type III patients were 8, 35, and 41 months, respectively. The 5-year overall survival (OS) rate for type I/Ir patients was 91%; all deaths in this group were due to progression to type II or III. OS was significantly better for type II versus type III (P = .0061); the 5-year OS rates were 71% and 53%, respectively. Disease-free survival (DFS) was also significantly better for type II versus type III (P = .0002); the 5-year DFS rates were 59% and 37%, respectively. The PPB type was the strongest predictor of outcome. Metastatic disease at the diagnosis of types II and III was also an independent unfavorable prognostic factor. Sixty-six percent of the 97 patients tested had a heterozygous germline DICER1 mutation. In this subset, the DICER1 germline mutation status was not related to the outcome.Cystic type I/Ir PPB has a better prognosis than type II, and type II has a better outcome than type III. Surveillance of DICER1 carriers may allow the earlier detection of cystic PPB before its progression to type II or III PPB and thereby improve outcomes.

Pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT) are both associated with germline mutations in DICER1. In this brief report, a maternal history of SLCT led to identification of a deleterious DICER1 mutation in the patient and her asymptomatic infant. Radiographic screening revealed a large Type I PPB, which was completely resected. Identification of DICER1 mutation carriers and imaging of children at risk for PPB may allow detection of PPB in its earliest and most curable form, leading to increased likelihood of surgical cure and decreased risks of treatment-related late effects.

Umbilical metastases, also named Sister Mary Joseph's nodules, are well documented in the adult population and most often represent an underlying intra-abdominal malignancy, usually a carcinoma of gastrointestinal or gynecologic origin. They are indicative of widespread abdominal disease and are associated with a poor prognosis. An extensive review of the literature reveals only two such presentations in the pediatric population. A 14-year-old male presented with an umbilical mass, which was found to be a metastatic lesion of a desmoplastic small round cell tumor (DSRCT) of the abdomen. The diagnosis of an intra-abdominal malignancy, most commonly a DSRCT, should be considered in the presence of an umbilical mass in a child.

Germline mutations in DICER1 are associated with increased risk for a wide variety of neoplastic conditions, including pleuropulmonary blastoma (PPB), cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors, botryoid embryonal rhabdomyosarcoma of the uterine cervix, ciliary body medulloepithelioma, pineoblastoma, pituitary blastoma and nodular thyroid hyperplasia or thyroid carcinoma. These tumors may be seen in isolation or in constellation with other characteristic tumor types in individuals or family members. Here we describe the medical history of a child with a heterozygous, loss of function germline DICER1 mutation and multiple tumors associated with the syndrome.. Although germline mutations in DICER1 are rare, tumors of these types will be seen by practicing pathologists and should prompt consideration of an underlying DICER1 mutation.

We thank Bailey et al for highlighting this additional aspect of surveillance in individuals with DICER1 mutations.[1] We read with interest the report by Murray et al in which a 2-year-old patient with type III PPB of the hemithorax was found to have elevated levels of specific miRNAs with early treatment-related reductions.[2] We were pleased to see that the highest circulating miRNAs reported by Murray et al were miR-125-3p family miRNAs.[2] A recent report by our group showed that mature 5p-miRNAs produced in cells with biallelic loss of function and RNase IIIb mutations retain precursor miRNA hairpin loop sequence while 3p mature miRNAs (processed by the RNase IIIa domain) are cut normally.[3] The 3p strand bias noted by us and others[2,4] likely reflects rapid degradation of the extended 5p miRNAs.[3] A likely application for serum measurements of miR-125a-3p and miR-125b-3p would be monitoring therapy response and detecting recurrence. Identification of PPB in its earliest, cystic form provides the best opportunity for cure with lowest risk of therapy related side effects.[5] The cystic stage, however, is characterized by a microscopic population of primitive mesenchymal cells. It is unknown whether such a small population of cells would elaborate sufficient miR-125-3p family miRNAs to allow early detection. The goal remains detection in the paucicellular, cystic phase with resection prior to progression to Type II or III PPB. The incidence of PPB in DICER1 mutation carriers appears low but this has not been systematically studied. On the other hand, preliminary data from our NCI phenotyping cohort suggests that lung cysts are the second most common manifestation of the DICER1 syndrome after thyroid disease. Approximately 25% of mutation positive relatives of children with PPB have lung cysts detectable by CT scan (unpublished data; http://dceg.cancer.gov/research/clinical-studies/dicer1-ppb-study). When found in very young children, there is no reliable method to determine which cysts are destined for regression. Although pathologic examination can differentiate between Type I PPB and Type I-regressed (Ir) PPB, it has been shown that patients with Type Ir can progress to Type II or Type III PPB.[6] In addition to sarcomatous progression, these cysts can be large, compress vital structures, and have a risk for pneumothorax and cerebral air embolism with air travel or deep sea diving.[7,8] Is it beneficial to diagnose these? If yes, then CT scans are likely to remain a mainstay for detecting lung pathology in DICER1 mutation carriers. CT scan currently provides the highest resolution for detection of pulmonary lesions. Principles to reduce radiation exposure to young children should be followed while ensuring that resolution is sufficient to detect cystic lesions. Our case report and a recent GeneReviews,[9,10] convey the most recent recommendations from the International PPB Registry. Although it remains to be seen whether cystic PPB is associated with detectable alterations in the serum miRNA profile, we agree that a prospective trial of the use of miRNAs in conjunction with radiographic imaging in monitoring response and detecting recurrence of advanced PPB is indicated.

Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.

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]