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Pediatr Blood Cancer. Author manuscript; available in PMC 2015 Mar 1.
Published in final edited form as:
PMCID: PMC4139105
NIHMSID: NIHMS599018
Judicious DICER1 Testing and Surveillance Imaging Facilitates Early Diagnosis and Cure of Pleuropulmonary blastoma
Kris Ann P. Schultz
1International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, Minneapolis, MN
2International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
3Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
Anne Harris
1International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, Minneapolis, MN
2International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
3Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
Gretchen M. Williams
1International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, Minneapolis, MN
2International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
3Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
Shari Baldinger
1International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, Minneapolis, MN
4Virgina Piper Cancer Institute, Allina Health. Minneapolis, MN
Leslie Doros
1International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, Minneapolis, MN
2International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
5Department of Oncology, Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington DC
Patricia Valusek
6Division of Surgery, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN And Pediatric Surgical Associates, Ltd. Minneapolis, MN
A. Lindsay Frazier
1International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, Minneapolis, MN
7Dana-Farber/Children's Cancer Care, Boston, MA
Louis P. Dehner
2International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
8Lauren V. Ackerman Division of Surgical Pathology, Washington University Medical Center, St. Louis, MO
Yoav Messinger
1International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, Minneapolis, MN
2International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
3Department of Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
D. Ashley Hill
1International Ovarian and Testicular Stromal Tumor Registry, Children's Hospital and Clinics of Minnesota, Minneapolis, MN
2International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
9Department of Pathology and Center for Genetic Medicine Research, Children's National Medical Center, Department of Integrative Systems Biology, George Washington University School of Medicine & Health Sciences, Washington DC
Abstract
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.
Keywords: Pleuropulmonary blastoma, DICER1, Sertoli-Leydig cell tumor, lung cysts, genetic testing
Introduction
PPB is a rare but potentially aggressive tumor of the lung. More than 90% of PPB cases are diagnosed in children under 72 months of age. PPB is believed to progress along a continuum from Type I, a purely cystic lesion diagnosed at a median age of 9 months, to Type II PPB, a mixed cystic and solid lesion diagnosed at a median age of 36 months, to Type III PPB, a solid, aggressive sarcoma diagnosed at a median age of 43 months. [1,2] Survival rate decreases along the continuum with overall survival (OS) of >90% for Type I PPB, [3] 75% for Type II PPB and 58% for Type III PPB. [4] For Type I PPB, treatment includes complete surgical excision followed by observation alone or complete surgical excision followed by intermediate intensity chemotherapy. For Types II and III PPB, surgical resection followed by intensive, anthracycline-based chemotherapy with or without radiation therapy are required for cure. [5] Based on this data, patients diagnosed at the Type I stage will have improved survival and decreased toxicity from chemotherapy.
Case Report
A 33-year-old woman with a history of ovarian Sertoli-Leydig cell tumor (SLCT) enrolled in the International Ovarian and Testicular Stromal Tumor (OTST) Registry. She presented at 17 years of age with amenorrhea. Imaging revealed a pelvic mass measuring 11 cm in largest diameter. She underwent a left oophorectomy. Pathologic examination showed SLCT with intermediate differentiation. No adjuvant therapy was administered and she remains well 15 years following diagnosis. Family history is remarkable for multiple relatives with thyroid nodules and thyroid cancer. Germline DICER1 testing showed a heterozygous loss of function mutation.
Umbilical cord blood from her third child, sampled at the time of delivery, showed inheritance of the same deleterious germline DICER1 mutation. A chest radiograph at birth was normal. The child was clinically well without respiratory symptoms. Following the recommendation of the International Pleuropulmonary Blastoma Registry (IPPBR) physicians, the infant underwent computed tomography (CT) at 3 months of age. CT images revealed an 8.8 × 6.2 × 3.1 cm multi-septated cyst in the right lower lobe (RLL) without mediastinal shift (Figure 1). Preoperative planning involved the oncology, surgery and pathology teams. A thoracoscopic RLL lobectomy was performed taking care not to disrupt the cyst upon removal from the chest cavity. Pathologic examination showed a lung cyst and long interconnecting septa with variable cellularity. No well-developed cambium layers were noted, but there were scattered subepithelial collections of primitive, mitotically active cells (Figure 2). The cyst did not extend to the surgical resection margin. The final pathologic diagnosis was Type I PPB.
A) Chest radiograph performed at 3 months of age showing cystic lesion in right lower lobe. B) Computed tomography of the chest performed at 3 months of age showing an 8.8 × 6.2 × 3.1 multi-septated cyst in the right lower lobe.
Pathologic examination showed characteristic features of Type I PPB. A) The lung cyst shows long interconnecting septa with variable cellularity. B) Small cartilage nodules were seen focally. C,D) No well-developed cambium layers were noted, but there were scattered subepithelial collections of primitive, mitotically active cells. (Hematoxylin and eosin: original magnification × 100 (A); × 200 (B); × 400 (C,D).
DICER1 testing also showed an identical mutation in the 5-year-old brother. His initial screening chest CT was normal. To screen for cystic nephroma, abdominal ultrasounds were performed in both children and were normal.
Discussion
PPB is the hallmark of the familial cancer predisposition syndrome recently attributed to germline mutations in DICER1 [6] (OMIM # 606200, 606241). Other conditions seen in the syndrome include ovarian SLCT, cystic nephroma (CN), ciliary body medulloepithelioma (CBME), embryonal rhabdomyosarcoma of the uterine cervix (ERMS), nasal chondromesenchymal hamartoma (NCMH), thyroid nodular hyperplasia and thyroid carcinoma and rarely, Wilms tumor and central nervous system tumors. [7-9] Testing has shown germline DICER1 mutations in 65.5% of patients with PPB. When germline and tumor DNA from patients with PPB and CN are both analyzed, the incidence of DICER1 mutations is nearly 100%. [10,11,12] In PPB and CN, DICER1 incurs two hits, one, a loss of function mutation and the second, a missense mutation in one of six amino acids in the RNase IIIb domain. The combination of mutations result in defective cleavage of the mature miRNA from the 5p end of precursor miRNAs and may promote cell proliferation and immaturity. [7,10] The International OTST Registry has found germline DICER1 mutations in 56% of SLCT as well as in a small number of juvenile granulosa cell tumor and gynandroblastoma cases (unpublished data, accepted for presentation at American Society of Clinical Oncology meeting in June 2014).[13-15] The incidence of tumor DICER1 mutations in ERMS is 3.8%, [7] but expected to be much higher in the subset occurring in the uterine cervix. DICER1 mutations appear rare in Wilms tumors. [10,16-18] The incidence of DICER1 mutations in other tumors seen within the familial syndrome is not as well studied. [10,16-18]
Treating physicians may consider who should be tested for DICER1 mutation. The OTST Registry and IPPBR recommend that individuals of any age with one of the typical DICER1-related conditions be tested for germline DICER1 mutation with parents, siblings and children tested as indicated by the result. [19] A normal germline DICER1 sequence result from an affected individual may indicate they do not have a germline DICER1 mutation or that they have a mutation not detected by standard sequencing as in the case of a deletion or intronic mutation. [20] Further, tumors may arise from somatic alterations of each the DICER1 alleles in patients who do not have germline mutations. [9]
Although children with germline DICER1 mutations are at risk for PPB, the optimal timing and number of radiographic studies which should be performed for early detection in children with germline DICER1 mutations has not been established. Based on the epidemiology of PPB, with > 90% of PPB cases diagnosed before 72 months of age, screening should focus on young children. Chest radiograph may miss small cysts which may progress rapidly to aggressive forms of PPB. CT offers higher sensitivity especially for small lesions but is accompanied by radiation exposure and potential need for sedation. Formal recommendations for surveillance have not yet been defined. However, based on available information, the IPPBR suggests treating physicians consider an initial chest CT (using pediatric doses) at 3 months of age. If a cyst is identified, as in this case, then surgical management should be considered. If no concerning findings are seen on initial chest CT, then one additional CT is recommended (between 1 and 2 years). This child, with resected Type I PPB, will undergo follow-up imaging 3 months after surgery with further plans determined by the results of that study.
In addition to chest imaging, the IPPBR recommends abdominal ultrasound to screen for CN during childhood. Age of diagnosis of CN in the PPB Registry ranged from 1-179 months. [10] Germline DICER1 mutations also predispose to thyroid nodular hyperplasia. Mutation carriers should undergo annual thyroid palpation during their regular health care visits. Ultrasound should be obtained if suspicious findings are noted. Patients, parents and physicians should also be educated about signs and symptoms of ovarian tumors, eye tumors, and nasal polyps in older children and adults with germline mutations in DICER1.
This case demonstrates the potential for early identification of PPB to prevent progression to the more aggressive and potentially fatal Type II or III PPB. Preemptive testing for DICER1 in an appropriate clinical setting followed by judicious screening of others in the family most at risk for DICER1-related cancers may increase the likelihood of early identification of PPB with opportunities for surgical cure and decreased long term morbidities related to the administration of chemotherapy and/or radiation in early childhood.
Acknowledgments
The authors wish to thank the family discussed in this report for their kind support of DICER1-related research. We are also grateful to the many patients, families and treating physicians who participate in the International OTST Registry and the International PPB Registry and to the Pine Tree Apple Tennis Classic, St. Baldrick's Foundation, Hyundai Hope on Wheels and Randy Shaver Community Cancer Fund for their ongoing support of children's cancer research. The International OTST Registry was established in 2011 and is a collaboration between Children's Hospitals and Clinics of Minnesota, Children's National Medical Center and the Dana Farber Cancer Institute. The International PPB Registry was established in 1988 and is a collaboration of Children's Hospitals and Clinics of Minnesota, Children's National Medical Center and the Lauren V. Ackerman Division of Surgical Pathology, Washington University Medical Center.
Source of Funding: This work is supported by National Institutes of Health grant NCI R01CA143167 and The Parson's Foundation (DAH,YM), PPB Registry support, The International Ovarian and Testicular Stromal Tumor Registry is supported by St. Baldrick's Foundation, Pine Tree Apple Tennis Classic, Hyundai Hope on Wheels and the Randy Shaver Community Cancer Fund.
Footnotes
Conflicts of Interest: The authors each state that he/she has no conflicts of interest to disclose.
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