Elsevier

Gynecologic Oncology

Volume 122, Issue 2, August 2011, Pages 246-250
Gynecologic Oncology

Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: A report from the International Pleuropulmonary Blastoma Registry

https://doi.org/10.1016/j.ygyno.2011.03.024Get rights and content

Abstract

Objective

Pleuropulmonary blastoma (PPB) is a childhood cancer arising from pleuropulmonary mesenchyme. This neoplasm is a sentinel disease in a familial tumor syndrome recently found to be associated with germline mutations in DICER1. Observations of ovarian sex cord-stromal tumors (OSCST) in PPB kindreds led to further study. We sought to characterize ovarian tumors seen in probands and families with PPB and PPB-related conditions and define germline DICER1 status.

Methods

Patient and family records of pathology-reviewed PPB cases enrolled in the International PPB Registry (IPPBR) were searched for ovarian tumors. Ovarian tumor pathology specimens were obtained and centrally reviewed. Germline DNA from patients with ovarian tumors was tested for DICER1 mutations. Three additional OSCST patients registered in the IPPBR were also tested for mutations in DICER1.

Results

Among 296 kindreds including 325 children with PPB, we observed three children with both PPB and Sertoli–Leydig cell tumors (SLCT)/Sertoli cell tumors. Among family members of PPB patients, we identified six OSCST (three SLCT, one Sertoli cell tumor, one juvenile granulosa cell tumor, one gynandroblastoma). Age at ovarian tumor diagnosis was youngest in PPB probands and younger in family members than in OSCST in general. Germline DICER1 mutations were identified in four of six patients with OSCST from PPB kindreds and in two of three children with OSCST and no personal or family history of PPB.

Conclusions

Primary ovarian neoplasms, particularly OSCST, are a manifestation of the familial PPB syndrome and may be the initial clinical presentation of DICER1 mutations within a family.

Research highlights

► Ovarian sex cord-stromal tumors are associated with a childhood lung tumor, pleuropulmonary blastoma. ► This association may be mediated by germline DICER1 mutations. ► Ovarian stromal tumors may be the presenting feature of DICER1 mutations within a family.

Section snippets

Background

Pleuropulmonary blastoma (PPB) is the most common primary lung cancer of childhood [1]. It is the pulmonary analog of other dysontogenetic or embryonal neoplasms in this age group such as Wilms' tumor, neuroblastoma, retinoblastoma and others. PPB is genetically determined in approximately 70% of cases [2], [3] and is associated with a distinctive inherited tumor predisposition syndrome. Approximately 30–35% of kindreds in which a child has been diagnosed with PPB have findings consistent with

Human subjects sample collection

The records of families enrolled in the International PPB Registry (IPPBR, http://www.ppbregistry.org) were reviewed for proband and/or family member history of ovarian neoplasms. Central review of PPB pathology (LPD, DAH) was required for IPPBR enrollment. Ovarian tumor histopathology was centrally reviewed (MCP, LPD, DAH). All study protocols were approved by participating institutional human subjects committees. All participants providing germline samples for DICER1 sequencing provided

Clinical characteristics

Among 325 patients from 296 families with PPB enrolled in the IPPBR, we identified nine patients or close relatives with an OSCST(Table 1). These included seven Sertoli–Leydig tumors, one juvenile granulosa cell tumor and one gynandroblastoma. In three families, the proband with PPB was also diagnosed with an ovarian Sertoli–Leydig tumor (ages at diagnosis: 6, 8 and 13 years). These three children had received chemotherapy and surgery for PPB 5, 6 and 11 years prior to ovarian tumor diagnosis

Discussion

We identified nine individuals with OSCST among PPB probands and their relatives in the IPPBR. Germline DICER1 mutations were seen in six of eight patients in this report.

Because the precise incidence of OSCST and PPB are difficult to ascertain, we cannot determine the expected incidence of these conditions together in a single patient or in a family kindred. Both conditions are inadequately tabulated in national registries such as Surveillance, Epidemiology and End Results (SEER) [14]. Between

Conclusions

We have shown that germline DICER1 mutations may be found in PPB-associated OSCST cases. DICER1 mutations may also be found in other OSCST patients, including those with SLCT, juvenile granulosa cell tumor and gynandroblastoma whose clinical presentation suggests genetic predisposition. With this insight, we seek to gain a better understanding of tumor pathogenesis, thus leading to improved treatments and outcome for women with sporadic OSCST, which continue to have significant morbidity.

Conflict of Interest Statement

All authors report that they have no conflict of interest.

Acknowledgements

The authors thank the physicians and data managers who supply information and the many patients and families who participate in the International PPB Registry. We thank Leo Twiggs, MD for the critical reading of the manuscript. The Pine Tree Apple Tennis Classic and the Theodora H. Lang Charitable Trust support the International PPB Registry and its staff. Additional support is also provided by NIH 1R01CA143167-01 (Hill P.I.).

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