Resident Program - Case of the Month

Discussion

Ovarian fibromas constitute 5% of ovarian neoplasms, with an average age of onset of 48 years. More than 90% of cases are unilateral.  Approximately 8% are bilateral and primarily associated with nevoid basal cell carcinoma syndrome (NBCCS, also known as Gorlin syndrome), a rare autosomal dominant disease estimated to affect 1 in 30,000 individuals. It is caused by germline mutations in sonic hedgehog pathway genes PTCH1, PTCH2, or SUFU.  Patients present with multiple, early onset, cutaneous basal cell carcinomas, as well as predisposition to additional malignancy such as medulloblastoma. NBCCS patients often present with developmental defects such as bifid ribs, macrocephaly, bossing of the forehead, coarse facial features, odontogenic keratocysts, calcifications. However, the patient has no personal or family history of benign findings or neoplasms to suggest NBCCS. 

Approximately 20% of NBCCS patients develop bilateral fibromas, typically in their 30s, and most NBCCS patients have already been diagnosed with the syndrome at this age. But the patient’s tumors lacked the characteristic heavy calcifications that are present in fibromas associated with NBCCS.  Bilateral fibromas have been reported in rare cases of Meigs syndrome; however, the patient did not have ascites and pleural effusion, the other components of the clinical triad that defines this syndrome. Approximately 10–15% of women with ovarian fibroma develop ascites, and 1% develop pleural effusions. Meigs' syndrome occurs in approximately 1% patients with ovarian fibroma.  

The patient and her daughter underwent genetic testing and were both positive for the identical germline mutation in MUTYH.  

MUTYH-associated polyposis (MAP) is a rare autosomal recessive cancer syndrome caused by biallelic germline mutations in MUTYH. MUTYH encodes MYH glycosylase, a protein involved in base excision repair.  The frequency of heterozygote carriers in the general population is 1-2% and the frequency of biallelic mutation carriers is 1 per 10,000-40,000 individuals. Biallelic mutations predispose individuals to hundreds of adenomatous colorectal polyps and high risk for colorectal cancer, as seen in the patient’s daughter.  Extraintestinal manifestations include osteomas, epidermoid cysts, central nervous system tumors, thyroid cancer, and congenital hypertrophy of the retinal pigment epithelium, ovarian cancer, endometrial cancer, breast cancer among other findings.

In contrast to her daughter, this patient has none of the characteristic findings of MAP. This suggests her germline mutation may be monoallelic/heterozygous, which is not thought to confer significant risk of colorectal cancer or other features of MAP. The extreme rarity of bilateral fibromas that are not associated with NBCCS raises the possibility that this may be the first example of bilateral ovarian fibromas associated with a germline MUTYH mutation.  Sequencing the tumor DNA will determine whether there is loss of the patient’s putative wild-type MUTYH allele. 

References

Evans DG, Farndon PA. Nevoid Basal Cell Carcinoma Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. 2002 Jun 20 [Updated 2018 Mar 29].

Garg K, Karnezis AN, Rabban JT. Uncommon hereditary gynaecological tumour syndromes: pathological features in tumours that may predict risk for a germline mutation. Pathology. 2018 50(2):238-256.

Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997;69:299-308.

Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med. 2004;6:530-539.

Sampson JR, Dolwani S, Jones S et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet. 2003;362 (9377):39-41.

Nielsen M, Lynch H, Infante E, et al. MUTYH-Associated Polyposis. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. 2012 Oct 4 [Updated 2015 Sep 24].

Vogt S, Jones N, Christian D et al. Expanded Extracolonic Tumor Spectrum in MUTYH-Associated Polyposis. Gastroenterology. 2009 137(6):1976-1985.

Sánchez-Torres DA, Díaz-Murillo R, Kazlauskas S et al. Meigs' syndrome caused by bilateral ovarian fibroma mimicking ovarian cancer. Abstract. Ginecol Obstet Mex. 2016 84(2):122-125.

Kohlmann W, Gruber SB. Lynch Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReview. 2004 Feb 5 [Updated 2018 Apr 12].