A family with Sertoli-Leydig cell tumour, multinodular goiter, and DICER1 mutation.

FAMILY WITH SLCT, MULTINODULAR GOITER, AND DICER1 MUTATION, Haley et al. CASE REPORT A family with Sertoli–Leydig cell tumour, multinodular goiter, and DICER1 mutation M. Haley do,* P. Bindal mbbs,* A. McAuliffe do,* and J. Vredenburgh md† ABSTRACT Background DICER1 syndrome is an autosomal dominant tumour predisposition syndrome associated with a wide variety of cancerous and noncancerous conditions, including ovarian sex cord–stromal tumours and thyroid conditions, including multinodular goiter. The most common ovarian sex cord–stromal tumour associated with DICER1 syndrome is Sertoli–Leydig cell tumour, with germline DICER1 mutations present in more than 50% of cases. We present a case in which a patient in her late 30s was diagnosed with a Sertoli–Leydig cell tumour in the background of a strong family history of multinodular goiter and Sertoli–Leydig cell tumour with a germline mutation in DICER1. Case Presentation A 38-year-old woman with history of multinodular goiter was found to have stage iiic ovarian Sertoli–Leydig cell cancer after presenting with abdominal pain. She underwent multiple surgeries and chemotherapy. The patient developed rapid disease progression and died 7 months after diagnosis. Seven years earlier, a daughter had experienced the same disease and was found to have a germline DICER1 mutation. The mother had not undergone testing before her own diagnosis. Summary The co-occurrence of Sertoli–Leydig cell tumour and multinodular goiter is highly suggestive of DICER1 syndrome. The recognition of DICER1 syndrome within a family is essential for increased awareness and potential early recognition of complications. Most conditions associated with DICER1 syndrome occur in childhood, and most of the current screening recommendations are specific for childhood and young adulthood. Cancer risks and findings for the adult population are not as well defined. Clinicians who encounter DICER1 syndrome should review recommendations for genetic testing and surveillance and enrol patients in the DICER1 registry. Key Words DICER1, microrna, sex cord–stromal tumour, Sertoli–Leydig, multinodular goiter, genetic mutation Curr Oncol. 2019 June;26(3):183-185 BACKGROUND Ovarian tumours are classified into 3 main types, the most common being epithelial, followed by germ-cell and sex cord–stromal tumours. Sex cord–stromal tumours represent 8% of all ovarian tumours and include Sertoli–Leydig cell tumours (slcts)1. Sertoli–Leydig cell tumours are very rare, accounting for fewer than 0.5% of all ovarian tumours. They contain Sertoli and Leydig cells, which are somatic cells in male gonads, presenting a pseudo-male gonadal genesis in the ovary. Sertoli–Leydig cell tumours can therefore present with androgenic symptoms2. They are typically unilateral and large in size. Less than 20% display malignant behaviour3,4. In DICER1 syndrome, slcts are the most commonly observed sex cord–stromal tumour. The mortality rate with slcts is low, representing fewer than 5% of the recorded deaths associated with DICER1 syndrome5. www.current-oncology.com Sertoli–Leydig cell tumours can be well, moderately, or poorly differentiated. Well-differentiated slcts are often DICER1-independent, while the moderately and poorly differentiated types often co-exist with one another and typically have a DICER1 mutation3. The international Ovarian and Testicular Stromal Tumour Registry has shown that a germline DICER1 mutation is present in more than 50% of female patients with slct6. Individuals with DICER1 syndrome have an increased risk of multinodular goiter (mng) and differentiated thyroid cancer7,8. Multinodular goiter is a frequent manifestation of DICER1 syndrome8,9. The overall incidence of mng or thyroidectomy by 20 years of age is 32% in female patients and 13% in male patients with DICER1 syndrome, compared with 0% in male and female control subjects7. Individuals with a DICER1 mutation have a risk of developing thyroid cancer 16–24 times that in the general population7. Correspondence to: Meredith Haley, University of Connecticut Health, 263 Farmington Avenue, Farmington, Connecticut 06030 U.S.A.. E-mail: n DOI: https://doi.org/10.3747/co.26.4727 Current Oncology, Vol. 26, No. 3, June 2019 © 2019 Multimed Inc. 183 FAMILY WITH SLCT, MULTINODULAR GOITER, AND DICER1 MUTATION, Haley et al. Thyroid cancer associated with DICER1 syndrome is usually differentiated, of follicular or papillary origin, and typically behaviourally indolent7. Dicer1 is a rnase iii endonuclease involved in the generation of double-stranded microrna [mirna (non-coding rna)] that affects gene expression post-transcriptionally5. It has 2 functional enzymatic domains: rnaseiiia and rnaseiiib. Most DICER1 syndrome tumours have one allele with a germline nonsense or frameshift mutation resulting in loss of function; the other allele has a somatic missense mutation within 5 known hotspots within rnaseiiib2,6,10. Of all ovarian slcts, 50%–60% occur in carriers of germline DICER1 mutations. Nearly all moderately or poorly differentiated slcts harbour a somatic mutation in 1 of the 5 hotspots2,3. Those mutations result in improperly cleaved 5p mirnas from pre-mirna hairpin structures, which result in an abnormal ratio of 5p to 3p mirnas, ultimately affecting downstream target expression6. The situation is similar to a 2-hit tumour suppressive model; however, the 2nd somatic “hit” creates a partially functional allele with a mirna biogenesis bias. Systemic loss of 5p mirnas can cause pseudodifferentiation of testicular elements and oncogenic transformation in the ovary2. Current data suggest that about 80% of people with a DICER1 mutation inherit the mutation from a parent; in the remaining 20% of cases, the mutation likely appears de novo11. We present a patient with a history of mng who was diagnosed with a slct in the background of a strong family history of slct and mng in her daughters. CASE PRESENTATION A 38-year-old woman with history of mng, gastric bypass surgery, and iron and vitamin B12 deficiencies presented to the emergency department with sharp left-sided abdominal pain. The patient otherwise felt well and had not noted any other changes. Computed tomography imaging of her abdomen and pelvis showed a massive, complex, solid and cystic mass occupying most of the right side of the abdomen. The mass was 25 cm in its largest dimension, consistent with a complex ovarian neoplasm without evidence for metastatic disease to the chest, abdomen, or pelvis. The patient was referred to gynecology, where transvaginal and pelvic ultrasonography confirmed the findings. Serum cancer antigen 125 was elevated at 122.3 U/mL. The patient subsequently underwent cystoscopy and bilateral ureteral stenting, followed by an exploratory laparotomy with lysis of adhesions, right salpingooophorectomy, tumour debulking, and appendectomy. Pathology examination of the tumour revealed a malignant moderately-to-poorly differentiated Se (...truncated)