DICER1-related ovarian tumors

DICER1-related ovarian tumors including Sertoli-Leydig cell tumor (SLCT), gynandroblastoma and ovarian sarcoma. Most DICER1-related ovarian tumors are diagnosed in young children, adolescents or young women. More than 90% are diagnosed prior to age 40 with rarer cases diagnosed in individuals up to 62 years of age.

DICER1-related ovarian tumors may present with an isolated pelvic mass or abdominal or pelvic pain. They are often very large when first discovered. Sertoli-Leydig cell tumors and gynandroblastoma may also present with signs of hormone production such as deepening voice, hair growth, early puberty, menstrual irregularities or acne.

Laboratory studies may show elevation of tumor markers such as alpha-fetoprotein (AFP), testosterone, inhibin A or B, estradiol. Tumor marker elevation may occasionally occur in the absence of a mass on imaging, in which case, sampling of the ovarian vein may be considered.

Ultrasound is the initial diagnostic modality for most suspected pelvic masses or unexplained elevation of hormonal markers. If a mass is noted, magnetic resonance imaging (MRI) and/or computed tomography (CT) scans provide additional information.

Surgery is generally required for newly diagnosed ovarian tumors. During surgery, staging should be performed using the International Federation of Gynecology and Obstetrics (FIGO) staging system and should include peritoneal cytology and examination of the contralateral ovary. Care should be taken to avoid rupturing the tumor but if rupture occurs, it is critical to carefully document preoperative vs. intraoperative rupture.

Spread of ovarian stromal tumors to the chest without extensive abdominopelvic disease is unlikely, however baseline evaluation with chest CT or chest x-ray is reasonable given the concern for synchronous conditions.

In addition to stage, ovarian sex cord stromal tumors are also evaluated using a grading system to document the level of differentiation from well to moderate to poorly differentiated tumors.

Level of differentiation and stage influence outcome and are critical to determining whether adjuvant therapy is necessary for ovarian sex cord- stromal tumors. Well differentiated, stage Ia tumors generally behave in a benign fashion. Poorly differentiated or higher stage tumors are associated with a poorer prognosis.

Follow-up monitoring for ovarian sex cord-stromal tumors should include attention to tumor markers and imaging. Imaging with either MRI or ultrasound may be preferred over CT as neither is associated with exposure to ionizing radiation; however, the use of MRI in very young children is limited by the need for sedation. If MRI is chosen, the radiologist should be notified of the clinical concern for ovarian tumor so that the appropriate imaging protocols may be utilized. Similar strategies are utilized for ovarian sarcoma. It should be noted that recurrent ovarian tumors can be very difficult to detect with imaging alone.

The Registry is actively working to develop novel diagnostics to improve the ability to detect recurrent disease. Please contact the Registry for additional information about these research initiatives.

In addition to risk for recurrence, individuals with DICER1 variation are at risk of developing a contralateral ovarian tumor. It is critical to distinguish this situation from the situation of relapse as the prognosis is more favorable. These metachronous tumors are generally identified as stage Ia and are often treated with surgery alone.

Individual and health care provider education regarding symptoms (hormonal symptoms including virilization, recurrent abdominal pain, and abdominal mass) is recommended so that imaging evaluation may be performed urgently if clinically indicated. For girls, we recommend pelvic US be performed in conjunction with abdominal US every 6 to 12 months until age 12 years and that every 6-12 month pelvic US continue throughout adulthood. Alternatively, adult women and their health care providers may choose a surveillance strategy based on physical examination. In that instance, US should be obtained if any clinical findings suggest gynecologic tumor. The optimal timing of US and/or pelvic examinations and relative sensitivity of these varying surveillance strategies are not yet known.

Surgical resection with staging procedures is usually the initial treatment regimen. Fertility sparing surgery is recommended for most girls and young women.

Most patients undergo unilateral salpingo-oophorectomy with sampling of peritoneal fluid and cytologic examination of peritoneal washings. Lymph nodes should be carefully examined intraoperatively and removed if clinically concerning. Level of differentiation and stage influence outcome and are critical to determining whether adjuvant therapy is necessary. Effort must be made to avoid rupture of the tumor as this would result in an increased stage for some patients. If rupture occurs, the timing of rupture (preoperative vs. intraoperative rupture) must be carefully documented as this may influence the need for adjuvant therapy.

From a pathology perspective, SLCT comprises uniform small tubules and trabecular profiles (Sertoli component) accompanied by solid collections of eosinophilic polygonal cells (Leydig cells). Gynandroblastoma is a mixed neoplasm with features of SLCT and Juvenile granulosa cell tumor.

Ovarian small cell carcinoma of the hypercalcemic type may mimic an ovarian stromal tumor but the distinction is usually clear when the calcium level is evaluated. DICER1-related ovarian sarcoma typically has features of a classical DICER1-related sarcoma with rhabdomyoblastic and chondrosarcomatous elements.