NORD gratefully acknowledges Kris Ann Schultz, MD, Anne Harris, MPH, CCRP and Gretchen Williams, BS, CCRP, Cancer and Blood Disorders Program of Children's Hospitals and Clinics of Minnesota, and the International Pleuropulmonary Blastoma/DICER1 Registry, for assistance in the preparation of this report.
Pleuropulmonary blastoma (PPB) is a rare childhood cancer occurring in the chest, specifically in the lungs or in the coverings of the lungs called "pleura". Four subtypes of PPB exist: type Ir, type I, type II, and type III PPB. Type I, II, and III PPB are usually found in children under the age of approximately 7-8 years; PPB occurs rarely in older children or teenagers, and even more rarely in adults, but type Ir PPB may be found at any age.
Type I PPB takes the form of one or more cysts in the lungs (air-filled pockets) and may be found in very young children (from birth to about 3 years of age). Type III PPB is an entirely solid tumor. Type II PPB includes both cystic and solid parts. Types II and III PPB tend to be found more often after 2 years of age. Type Ir (the “r” stands for regressed/regressing) is a type of PPB that is similar to type I PPB in terms of how the cells appear under the microscope, but cancerous cells are not present.
Children with type I PPB have a better outlook ("prognosis") than children with types II and III PPB. Most children with type I PPB are cured (89%) but type I PPB can sometimes recur (“come back”) as type II or III PPB. Treatment for type I consists of surgery and sometimes chemotherapy. Treatment for types II and III PPB consists of surgery and chemotherapy and possibly radiation therapy. At present, about 50-70% of children with types II and III PPB are cured.
PPB is a childhood cancer in the family of cancers called soft tissue cancers, which are scientifically called sarcomas. PPB is, therefore, a soft tissue sarcoma. Physicians classify diseases this way in order to compare features and to compare treatments. PPB occurs in the lungs and is the most common lung cancer of childhood but PPB has no connection to lung cancers in adults that are often related to tobacco use or asbestos exposure. Like many cancers, PPB can spread through the blood to other areas of the body. When a cancer spreads to another part of the body it is called a "metastasis" of the cancer. Types II and III PPB can metastasize. The most common location for a PPB metastasis is the brain. PPB may also spread to remaining part of the lung, bones, liver and rarely to other organs. PPB can also spread by growing directly into tissues next to the lung like the diaphragm.
Two different sets of symptoms are found in children with PPB, based generally on the child’s age and the type of PPB:
Respiratory distress or breathing difficulty (dyspnea) may be mild to severe. Large pockets of air in the chest may prevent normal breathing. The air may be in large pockets in the lung (cysts) that compress the normal lung. Air also sometimes escapes from cysts into the chest cavity (pneumothorax). A chest x-ray or computed tomography (CT) scan will discover these air pockets and further investigations will lead to surgery to remove them.
These symptoms tend to be found in children with types II and III PPB. These children PPB may present with signs of pneumonia or another general illness including cough, fever, difficulty breathing, fatigue, loss of energy and decreased appetite. Chest or abdominal pain may also occur. Occasionally there is weight loss. A chest x-ray will show a problem that may look like pneumonia (lung infection). Because PPB is rare and other conditions of the lung are more common, PPB may not be initially suspected when a child has these symptoms. Children are often treated with antibiotics for 2-3 weeks, but when these symptoms are caused by PPB, they generally do not improve with antibiotics. Further investigations are done, such as a chest CT scan; these tests raise the possibility of a tumor in the chest/lung.
Sometimes PPB occurs without any other conditions in the individual or family but PPB may also be an indication of an underlying variation in a gene called DICER1 (see Related Disorders).
PPB occurs in boys and girls approximately equally. Children under the age of 7-8 years are most often affected, but rarely teenagers or young adults may be diagnosed with PPB. Other conditions sometimes associated with PPB may be seen in individuals throughout the life span (see Related Disorders).
When a child presents with symptoms of PPB, a chest x-ray may show an air filled pocket (cyst) or a solid mass. Chest CT may be performed to look at the lungs in more detail. Surgery, either a biopsy or removal of the cyst or mass, is performed to diagnose and often remove the tumor. Microscopic examination of the specimen is needed. Review by the International PPB/DICER1 Registry pathology specialists is often helpful in confirming the diagnosis. This is offered at no cost to families or hospitals.
After surgery to remove type I PPB, some physicians recommend use of chemotherapy to attempt to remove any remaining small collections of malignant cells; some physicians recommend watchful waiting. Whether chemotherapy or observation is chosen depends on very specific factors for each individual child. Radiation therapy is not used for type I PPB. If type I PPB recurs in a child as type II or type III PPB, then the treatments for types II and III disease must be used.
Type II and III PPB are both serious (aggressive) malignancies. Surgery is the first step in treatment but sometimes due to the size and location of the tumor, only biopsy can be performed. In these situations, chemotherapy is given to shrink the remaining tumor and remove the malignant cells left behind after surgery. Sometimes radiation therapy is also used. All children with type II or III PPB require additional treatment after tumor removal.
The medications usually used for treatment of PPB are the same or similar to drugs used for more common childhood cancers. Even though PPB is rare, pediatric cancer specialists have experience using these drugs. Their use in children with PPB is guided by their use in other children.
The use of radiation therapy is highly individualized in PPB patients. In general if there is a small area of tumor which could not be removed by surgery and which does not seem to disappear with chemotherapy, then radiation may be considered. Radiation can damage lung tissue so the doses and locations of radiation therapy are limited by the radiation oncology team. When PPB spreads to the brain, surgery followed by radiation therapy is often advised.
Another possible therapy for PPB is high dose chemotherapy followed by autologous stem cell transplantation. This overall approach may be useful in cases where PPB has not been eliminated by more standard therapy.
When standard treatments are not successful at eliminating PPB other therapies are often tried. Research is ongoing to find more effective therapies for PPB
Children, adults and families with PPB or other DICER1-related conditions are invited to participate in the International PPB/DICER1 Registry. The goal of the Registry is to optimize surveillance strategies to determine the best way to detect these tumors in their earliest and most curable forms and to find more effective and less toxic ways to treat these DICER1-related cancers.
Research into the inheritance patterns in PPB patients and their families has already led to the understanding that the DICER1 gene mutation is the reason why some families have a tendency to develop PPB or other problems. DICER1 specific surveillance guidelines are available for anyone with PPB, another DICER1-related condition or variation in the DICER1 gene. This research is ongoing. Please contact the International PPB/DICER1 Registry for more information about this study:
The International Pleuropulmonary Blastoma/DICER1 Registry
Email contact: [email protected]
Anne Harris, MPH, CCRP or Kris Ann Schultz, MD
Children’s Hospital and Clinics of Minnesota
910 East 26th ST.
Minneapolis, MN 55404
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
SELECT JOURNAL ARTICLES
Bauer AJ, Stewart DR, Kamihara J, Harris AK, Turner J, Shah R, Schneider KW, Schneider K, Carr AG, Harney LA, Frazier AL, Orbach D, Schneider DT, Malkin D, Dehner LP, Messinger YH, Hill DA, Schultz KAP. DICER1 and associated conditions: identification of at-risk individuals and recommended surveillance strategies-response. Clin Cancer Res. 2019 Mar 1;25(5):1689-1690. doi: 10.1158/1078-0432.CCR-18-3495. PubMed PMID: 30824630.
Stewart DR, Best AF, Williams GM, Harney LA, Carr AG, Harris AK, Kratz CP, Dehner LP, Messinger YH, Rosenberg PS, Hill DA, Schultz KAP. Neoplasm risk among individuals with a pathogenic germline variant in DICER1. J Clin Oncol. 2019 Mar 10;37(8):668-676. doi: 10.1200/JCO.2018.78.4678. Epub 2019 Feb 4. PubMed PMID: 30715996.
Khan NE, Ling A, Raske ME, Harney LA, Carr AG, Field A, Harris AK, Williams GM, Dehner LP, Messinger YH, Hill DA, Schultz KAP, Stewart DR. Structural renal abnormalities in the DICER1 syndrome: a family-based cohort study. Pediatr Nephrol. 2018 Dec;33(12):2281-2288. doi: 10.1007/s00467-018-4040-1. Epub 2018 Sep 3. PubMed PMID: 30178239; PubMed Central PMCID: PMC6203641.
Schultz KAP, Williams GM, Kamihara J, Stewart DR, Harris AK, Bauer AJ, Turner J, Shah R, Schneider K, Schneider KW, Carr AG, Harney LA, Baldinger S, Frazier AL, Orbach D, Schneider DT, Malkin D, Dehner LP, Messinger YH, Hill A. DICER1 and associated conditions: Identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res. 2018 May 15;24(10):2251-2261. doi: 10.1158/1078-0432.CCR-17-3089. Epub 2018 Jan 17. Review. PubMed PMID: 29343557; PubMed Central PMCID: PMC6260592.
Khan NE, Bauer AJ, Schultz KAP, Doros L, Decastro RM, Ling A, Lodish M, Harney LA, Kase RG, Carr AG, Harris AK, Williams GM, Dehner LP, Messinger YH, Hill DA, Stewart DR. Increased risks of multi-nodular goiter and thyroid cancer in a cohort with DICER1 syndrome. J Clin Endocrinol Metab 2017;102(5):1614-22. doi: 10.1210/jc.2016-2954. PubMed PMID: 28323992; PubMed Central PMCID: PMC5443331.
Schultz KAP, Harris AK, Finch M, Dehner LP, Brown JB, Gershenson DM, Young RH, Field A, Yu W, Turner J, Cost NG, Schneider DT, Stewart DR, Frazier AL, Messinger Y, Hill DA. DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry Gynecol Oncol. 2017 Dec;147(3):521-527. doi: 10.1016/j.ygyno.2017.09.034. Epub 2017 Oct 14. PubMed PMID: 29037807; PubMed Central PMCID: PMC5716477.
Brenneman M, Field A, Yang J et al. 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. F1000Research 2015;4:214.
Dehner LP, Messinger YH, Schultz KAP, Williams GM, Wikenheiser-Brokamp K, Hill DA. Pleuropulmonary blastoma: the evolution of an entity as an entry into a familial tumor predisposition syndrome. Pediatr Dev Pathol 2015;18:504-11.
Messinger YH, Stewart DR, Priest JR, Williams GM, Harris A, Schultz KAP, Yang J, Doros L, Rosenberg PS, Hill DA, Dehner LP. Pleuropulmonary blastoma: a report on 350 central pathology confirmed PPB cases by the International PPB Registry. Cancer 2015;121(2):276–85.
Pappo AS, Furman WL, Schultz KA, Ferrari A, Helman L, Krailo MD. Rare tumors in children: progress through collaboration. J Clin Oncol 2015: 33(27):3047-54.
Pashankar F, Bisogno G, Ribeiro R, Messinger Y, Schultz KA, Rodriguez-Galindo C. The role of registries and tumor banking in rare pediatric tumors. Curr Pediatr Rep 2015;3(2):128-36.
Sabapathy DG, Guillerman RP, Orth RC, Zhang W, Messinger Y, Foulkes W, Priest JR, Annapragada AV. Radiographic screening of infants and young children with genetic predisposition for rare malignancies: the case of DICER1 mutations and pleuropulmonary blastoma. Am J Roentgenol 2015;204(4):W475-82.
Wagh PK, Gardner MA, Ma X, Callahan M, Shannon JM, Wert SE, Messinger YH, Dehner LP, Hill DA, Wikenheiser-Brokamp KA. Cell-and developmental stage-specific DICER1 ablation in the lung epithelium models of cystic pleuropulmonary blastoma. J Pathol 2015; 236(1):41-52.
Yin Y, Castro AM, Hoekstra M, Yan TJ, Kanakamedala AC, Dehner LP, Hill DA, Ornitz D. Fibroblast growth factor 9 regulation by MicroRNAs controls lung development and links DICER1 loss to the pathogenesis of pleuropulmonary blastoma. PLoS Genet. 2015 May 15;11(5):e1005242.
Pugh TJ, Yu W, Yang J, Field A, Ambrogio L, Carter SL, Cibulskis K, Giannikopoulos P, Kiezun A, Kim J, McKenna A, Nickerson E, Getz G, Hoffher S, Messinger YH, Dehner LP, Roberts CWM, Rodriguez-Galindo C, Williams GM, Rossi CT, Meyerson M, Hill DA. Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two-hit DICER1 loss resulting in retention of 5p-derived miRNA hairpins. Oncogene 2014;33:5295-5302.
Schultz KAP, Harris A, Williams GM, Baldinger S, Doros L, Valusek P, Frazier AL, Dehner LP, Messinger Y, Hill DA. Judicious DICER1 testing and surveillance imaging facilitates early diagnosis and cure of pleuropulmonary blastoma. Pediatr Blood Cancer 2014;61(9):1695-7.
Schultz KA, Yang J, Doros L, Williams GM, Harris A, Stewart DR, Messinger Y, Field A, Dehner LP Hill DA. DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions Pathol Case Rev 2014;19(2):90–100.
Slade I, Bacchelli C, Davies H, Murray A, Abbaszadeh F, Hanks S, Barfoot R, Burke A, Chisholm J, Hewitt M, Jenkinson H, King D, Morland B, Pizer B, Prescott K, Saggar A, Side L, Traunecker H, Vaidya S, Ward P, Futreal PA, Vujanic G, Nicholson AG, Sebire N, Priest JR, Pritchard-Jones K, Houlston R, Turnbull C, Stiller C, Stratton MR, Douglas J, Rahman N. DICER1 syndrome – clarifying the diagnosis, clinical features and management implications of a pleiotropic tumor predisposition syndrome. J Med Genet 2011;48:273-78.
Schultz KAP, Pacheco MC, Yang J, Williams GM, Messinger Y, Hill DA, Dehner LP, Priest JR. Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: A report from the International Pleuropulmonary blastoma Registry. Gynecol Oncol 2011;122(2):246-50.
Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ. DICER1 mutations in familial pleuropulmonary blastoma. Science 2009;325:965.
Priest JR, Williams GM, Hill AD, Dehner LP, Jaff? A. Pulmonary Cysts in Early Childhood and the Risk of Malignancy. Pediatr Pulmonol 2009;44(1):14-30.
Hill DA, Jarzembowski JA, Lennerz JK, Priest JR, Williams G, Schoettler P, Dehner LP. Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the International Pleuropulmonary Blastoma Registry. Am J Surg Pathol 2008;32(2):282-295.
Pai S, Eng HL, Lee SY, Hsaio CC, Huang WT, Huang SC, Hill DA, Dehner LP, Priest JR. Correction: Pleuropulmonary blastoma, not rhabdomyosarcoma in a congenital lung cyst [Letter to the Editor]. Pediatr Blood Cancer 2007;48(3):370-371.
Priest JR, Magnuson J, Williams GM, Abromowitch M, Byrd R, Sprinz P, Finkelstein M, Moertel CL, Hill DA. Cerebral metastasis and other central nervous system complications of pleuropulmonary blastoma. Pediatr Blood Cancer 2007;49(3):266-273.
Priest JR, Hill DA, Williams GM, Moertel CM, Messinger Y, Finkelstein MJ, Dehner LP. Type I pleuropulmonary blastoma: A report from the International Pleuropulmonary Blastoma Registry. J Clin Oncol 2006;24:4492-4498.
Dehner LP. Beware of “degenerating” congenital pulmonary cysts [Letter to the Editor]. Pediatr Surg Int 2005;21:123-124.
Hill DA. USCAP Specialty Conference, case 1: Type I Pleuropulmonary blastoma. Pediatr Dev Pathol 2005;8:77-84.
Priest JR, McDermott MB, Bhatia S, Watterson J, Manivel JC, Dehner LP. Pleuropulmonary blastoma. A clinicopathologic study of 50 cases. Cancer 1997;80:147-61.
Priest JR, Watterson J, Strong L, Huff V, Woods WG, Byrd RL, Friend SH, Newsham I, Amylon MD, Pappo A, Mahoney DH, Langston C, Heyn R, Kohut G, Freyer DR, Bostrom B, Richardson MS, Barredo J, Dehner LP. Pleuropulmonary blastoma: a marker for familial disease. J Pediatr 1996;128(2):220-4.
McDermott MB, Dehner LP, Priest JR. Reply to Lopez-Andreu JA et al. Pleuropulmonary blastoma and congenital cystic malformations. J Pediatr 1996;129(5):772-5.
Dehner LP, Watterson J, Priest JR. Pleuropulmonary blastoma. A unique intrathoracic-pulmonary neoplasm of childhood. Perspectives in Pediatric Pathology 1995;18:214-226.
Dehner LP. Pleuropulmonary blastoma is THE pulmonary blastoma of childhood. Semin Diagn Pathol 1994;11(2):144-51.
Manivel JC, Priest JR, Watterson J, et al. Pleuropulmonary blastoma. The so-called pulmonary blastoma of childhood. Cancer 1988;62:1516-1526.
Schultz KAP, Stewart DR, Kamihara J, Bauer AJ, Merideth MA, Stratton P, Huryn LA, Harris AK, Doros L, Field A, Carr AG, Dehner LP, Messinger Y, Hill DA.DICER1 Tumor Predisposition. 2014 Apr 24 [Updated 2020 Apr 30]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK196157/ Accessed June 8, 2020.
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