Anne K. Harris

Pleuropulmonary Blastoma: A Report on 350 Central Pathology–Confirmed Pleuropulmonary Blastoma Cases by the International Pleuropulmonary Blastoma Registry

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.

DICER1 Mutations and Differentiated Thyroid Carcinoma: Evidence of a Direct Association

CONTEXTnDICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established.nnnCASE DESCRIPTIONnWe report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings.nnnCONCLUSIONSnThis family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.

Quantification of thyroid cancer and multinodular goiter risk in the DICER1 syndrome: a family-based cohort study.

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.

Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model

Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition,xa0 DICER1xa0syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics ofxa0 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 ofxa0 DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposingxa0 DICER1xa0mutations and sought correlations with clinical phenotypes. Over 70% have inherited orxa0 de novoxa0germline LOF mutations, most of which truncate thexa0 DICER1xa0open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposingxa0 DICER1xa0mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category ofxa0 DICER1xa0syndrome 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 inxa0 DICER1-associated xa0tumorigenesis, 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.

The effects of Dexamethasone on sleep in young children with Acute Lymphoblastic Leukemia

PURPOSEnCorticosteroids, which are a mainstay in the treatment of acute lymphoblastic leukemia (ALL), have a well-documented adverse effect on sleep. We sought to characterize the effects of dexamethasone on sleep over an entire 28-day treatment cycle using actigraphy, an objective measure of sleep.nnnMETHODSnThe sleep of 25 children aged 2-9 years (mean 4.5 years) with ALL treated with dexamethasone were evaluated during maintenance chemotherapy using a within-subject experimental design, actigraphy, and standardized questionnaires to assess sleep, sleep problems, and fatigue.nnnRESULTSnDuring the five days of dexamethasone treatment, sleep time increased during the night (535 vs. 498u2009min; pu2009=u20090.004) and daytime napping increased the following day (14 vs. 0u2009min; pu2009=u20090.002), and the number of wake episodes during the night was lower (14 vs. 20; pu2009=u2009u2009≤u20090.001). However, when assessed individually, sleep-onset time, efficiency, and wake after sleep onset during the night were unchanged during dexamethasone treatment; when the cumulative effect of all of these factors was assessed, there was a statistically and clinically significant increase in nighttime sleep duration during dexamethasone treatment.nnnCONCLUSIONSnDuring the five days of treatment with dexamethasone, an increase in nighttime sleep as well as daytime napping was observed in young children with ALL. The increases in sleep duration return to baseline one day after the discontinuation of dexamethasone.

Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model

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 PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) 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.

Pathologic Risk Factors for Metastatic Disease in Postpubertal Patients With Clinical Stage I Testicular Stromal Tumors

OBJECTIVEnTo systematically review the existing literature to analyze the impact of previously identified pathologic risk factors on harboring occult metastatic disease (OMD) in patients with Clinical Stage I testicular stromal tumors (TSTs).nnnMATERIALS AND METHODSnA literature search using PubMed was conducted using the following terms: testicular stromal tumors, testicular Leydig cell tumors, testicular Sertoli tumors, testicular interstitial tumors, testicular granulosa tumor, and testicular sex cord tumors. For analysis, we included only studies with data on available recurrence, survival, and time-to-event. We hypothesized that patients with ≥2 risk factors would experience lower 5-year OMD-free survival (OMDFS) than those with <2 risk factors.nnnRESULTSnTwo hundred ninety-two patients from 47 publications were included with a median age at diagnosis of 35xa0years (range 12-76). Five-year OMDFS and overall survival in patients with Stage I TSTs were 91.2% and 93.2%, respectively. When comparing those who harbored OMD to those who did not, we observed an increased risk of OMD for each additional risk factor (Pu2009<u2009.001). Five-year OMDFS was 98.1% for those with <2 risk factors vs 44.9% for those with ≥2 risk factors (Pu2009<u2009.001).nnnCONCLUSIONnThe existing literature on pathologic risk factors for OMD in this population is insufficient to make broad clinical recommendations. However, these factors appear to risk-stratify patients and may be useful for future research investigating adjuvant therapy in higher-risk patients. This review indicates that such a stratification system has a rational basis.

Comment on: DICER1‐Negative Pleuropulmonary Blastoma in a Patient With Selective IgA Deficiency

To the Editor: We read with interest the recent Letter to the Editor describing a 4-year-old female with a pleuropulmonary blastoma (PPB) and selective immunoglobulin IgA deficiency (SIgAD) but no detected germline DICER1 mutation.[1] Three statements in the letter merit clarification and additional comment. First, the authors suggest that the co-occurrence of PPB and SIgAD “suggests a genetic linkage toward immune deficiency.” The authors are correct that immunodeficiency unrelated to chemotherapy in children with PPB is rare. The International PPB Registry (IPPBR, founded in 1988) is not aware of any cases of SIgAD among more than 450 histologically confirmed PPB cases, although such data have not been intentionally collected. In the natural history study of the DICER1 syndrome at the U.S. National Cancer Institute, there were no significant differences in serum IgA, IgG, and IgM levels in DICER1-mutation carriers versus mutation-negative family controls in our study (Table I and Supplementary Table SI). In our experience, the co-segregation of two rare disorders in a single individual is not uncommon. SIgAD is estimated to affect 1:1615–1:4100 healthy Chinese.[2] This prevalence roughly approximates the prevalence of neurofibromatosis type 1 (NF1).[3] There are three children with NF1 and PPB in the IPPBR, both are rare, unrelated, independent genetic disorders. The cooccurrence of SIgAD (or NF1) and PPB in a child is probably a coincidence. Caution is needed in inferring causality in a child with multiple, apparently unrelated, rare disorders. Second, the authors describe genetic testing of “50 PPBassociated genes,” including “full-length DICER1 gene and its 2 kB promoter.” To date, only germline mutations in DICER1 are unequivocally linked with PPB risk.[4] Although “no DICER1 mutation” was detected, the authors do not state if they assayed for deletions, including determination of exon copy-number with a method such as multiplex ligationdependent probe amplification or if they performed sequencing on tumor tissue. Faced with a negative germline DICER1 result, it is important to determine if the patient was a DICER1 germline mosaic (e.g., by testing multiple somatic tissues), preferably using next-generation sequencing methods. Lacking this, documentation of other DICER1-associated phenotypes (e.g., cystic nephroma, multinodular goiter, etc.) may support the diagnosis.[5] In our experience, 72.6% of individuals with PPB have a detectable germline DICER1 mutation detected by coding region sequencing and deletion testing.[6] For individuals with aDICER1-associated tumor but no detectableDICER1 mutation, about 9% will have mosaic DICER1 mutations and 10% will have biallelic DICER1 mutations in tumor tissue only. Third, the authors note that the proband, sister and mother harbor KDR and TP53 homozygous mutations; the father is noted to carry a TP53 mutation. Although minimal phenotype data are provided for other family members, the authors may be referring to nonpathogenic variants in these genes. TABLE I. Serum Immunoglobulins (IgA) in DICER1-Mutation Carriers and Family Controls Evaluated at the NIH Clinical Center