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

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.

Conflict of interest statement

Conflict of Interest Statement: All authors report that they have no conflict of interest.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Fig. 1

Lung cyst discovered at age 16 years in child with juvenile granulosa cell tumor (Case 11). Such cysts discovered after age 8 years in patients with PPB-associated conditions are very likely benign cystic variants of PPB [3].

Fig. 2

(4 panel photomicrographs). A. Sertoli cell tumor of the ovary (case 2) shows the pattern of solid cords of uniform basophilic cells. B. Other patterns in the same tumor (case 2) demonstrate small tubules adjacent to retiform or papillary profiles. C. Sertoli-Leydig cell tumor (case 4) was largely necrotic and hemorrhagic but the viable areas show the presence of small basophilic cells in cord-like structures with intermixed clusters of larger, pale staining cells representing Leydig cells. D. Juvenile granulosa cell tumor (case 8) with a cystic structure resembling a graffian follicle is surrounded by a densely cellular stroma.

Fig. 3

(gross). Sertoli cell tumor of the ovary (case 2) presented with persistent abdominal pain in a 6-year-old female with the previous history of multiple PPBs and a cystic nephroma of the kidney. The hemorrhagic appearance of this 8 cm ovarian mass reflects the torsion with hemorrhagic infarction.