We identified nine individuals with OSCST among PPB probands and their relatives in the IPPBR. Germline DICER1 mutations were seen in 6 of 8 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 25 and 50 children are diagnosed with PPB annually in the United States. SLCT comprise less than 1% of ovarian tumors seen in children and adults. It is a reasonable presumption that these two rare cancers occurring in individuals or relatives have a related pathogenesis. Also, the ovarian tumors seen are predominantly limited to the otherwise rare specific histologic subtype of OSCST with a predominance of SLCT. The ages at diagnosis of SLCT/Sertoli cell tumors for PPB patients (6, 8 and 13 years) and family members (4, 7, 15 and 32 years) are generally younger than the age of diagnosis of “sporadic” SLCT (mean 25 years) [15
]. Although our numbers are small, these data suggest that SLCTs associated with PPB occur at a younger age than sporadic examples, as is typical of hereditary tumor predisposition. All of the patients described are alive without evidence of disease, including one patient who relapsed and underwent surgery, although the numbers are too small to draw conclusions regarding prognosis.
In addition to the PPB-associated cases, we identified three children with OSCST for whom there was no personal or family history of PPB, however clinical findings were suggestive of a genetic tumor predisposition. Two were sisters with OSCST (one with a lung cyst); the third patient had ovarian sarcoma with contralateral OSCST. DICER1 mutations were also seen in this group.
In general, the pathogenesis of OSCST is unknown, in part because of the tumor’s rarity. Genetic analyses of tumor tissue have generally shown balanced karyotypes, with chromosomal imbalances in up to 25%, occasionally gain of chromosome 12 [16
]. Trisomy 8 was seen in one case of metastasizing SLCT [17
]. Sex cord-stromal tumors have been described in other genetic syndromes, suggesting that genetic predisposition is important. Sex cord-stromal tumor with annular tubules are associated with Peutz Jeghers syndrome characterized by the STK11 gene mutation but STK11 gene mutations have not been observed in sporadic OSCST [18
]. Juvenile granulosa cell tumors have been described in association with Ollier enchondromatosis and Maffucci syndrome [19
Four OSCST patients we report had nodular thyroid hyperplasia (NTH) (). The association of NTH with SLCT has recently been shown to be related to germline mutations in DICER1
] lending further support to the association described here. Our research expands these findings to include cases of juvenile granulosa cell tumor and gynandroblastoma and defines a link between PPB, OSCST and germline DICER1
Germ-cell tumors are a separate entity from OSCST. We observed one case of ovarian dysgerminoma in a third-degree relative of a PPB patient. Three seminomas have also been observed in relatives of PPB patients. Germline mutations results were available for one patient with seminoma; we did not find DICER1
mutation. Of 71 patients with seminoma, Slade et al. identified one DICER1
] It is currently unclear whether the dysgerminoma/seminoma group of gonadal tumors is part of the PPB-related spectrum of diseases.
Our sequence analysis identified heterozygous germline loss of function DICER1
mutations in 4 of 6 patients with PPB-associated OSCST. We also identified a DICER1
mutation in two young sisters with OSCST and no known family or personal history of PPB. On staging chest CT one sister was also found to have a lung cyst (), likely an occult manifestation of the cystic variant of PPB. [23
]. The finding of a lung cyst or one of the PPB-related tumors in a patient or close family member with OSCST should suggest the possibility of germline DICER1
mutations were first identified in PPB patients [9
] and have subsequently been seen in other conditions seen in familial PPB cases [3
]. Clinical testing for DICER1
mutation status is available.
Mutations in DICER1
are hypothesized to alter production of mature miRNAs leading to dysregulated gene expression [9
]. Because miRNAs are important in controlling many biological functions, the effects of reduced DICER1
expression in different tissues at different stages of growth, development or homeostasis may be expected to lead to pleiotropic effects. DICER1
may function as a haploinsufficient tumor suppressor [25
]. Decreased DICER1
expression in tumor tissue has recently been shown to be associated with poorer prognosis in adults with epithelial ovarian cancer [13
]. The role of germline DICER1
mutations and downstream implications for miRNA expression in presumed sporadic OSCST is not yet clear. DICER1
mutations are not found in all cases of PPB or OSCST and many carriers of DICER1
mutations are phenotypically normal, thus other genetic factors are also likely to be important in these conditions.
The PPB Family Tumor and Dysplasia Syndrome phenotype includes PPB, lung cysts, cystic nephroma, OSCST (especially SLCT) as described here, thyroid nodular hyperplasia (NTH) and differentiated carcinomas, nasal chondomesenchymal hamartoma, ciliary body medulloepitheioma and sarcoma botryoides of the uterine cervix as well as more familiar childhood cancers and dysplasias [3
]. The importance of detailed family histories is thus apparent, and co-occurrence in a child or family of any of the PPB-associated illnesses raises the possibility of genetically-determined disease. DICER1
sequencing may be indicated and if such a genetic marker is found, the at-risk family members can be identified. Because PPB-related diseases affect many organs over the first 20–30 years of life and because disease penetrance is low, disease screening must be very carefully considered. On the other hand, families and medical professionals should be aware of familial diseases associated with OSCST. Obtaining detailed family histories from patients with OSCST may lead to timely diagnosis of a familial cancer syndrome with important implications for young children within the family. For very young children who carry DICER1 gene mutations, screening with chest CT scan may be most helpful in early identification of PPB, which is by far the most lethal tumor seen within this familial tumor syndrome and a tumor in which early detection provides the best opportunity for cure. [26
] Clinicians and family members should be alert for signs of an abdominal mass, pain or signs of hormone production such as precocity or virilization that may herald the presence of an ovarian sex cord-stromal tumor.
From this group of patients we cannot determine the prevalence of germline DICER1 mutations in patients with OSCST in general. Medical or family history of lung cysts, lung tumors diagnosed at a young age (especially PPB), hyperplastic thyroid disease, gonadal tumors, cystic nephroma, intestinal hamartomas, childhood benign or malignant tumors or SLCT/OSCST diagnosed at a younger than expected age strongly suggest the need for genetic counseling and consideration of DICER1 testing. Studies underway and in development will offer further insights into these important questions.