Multifocal intrafollicular granulosa cell tumor of the ovary associated with an unusual germline p53 mutation

Abstract

A 23-year-old woman presented with a 7 cm right multicystic mass in the ovary, which corresponded microscopically to an unusual lesion consisting of a multifocal granulosa cell tumor with intrafollicular ('in situ') growth involving two-thirds of mature follicles. Stromal invasion was found in only one area where neoplastic follicles coalesced. Granulosa cells had atypical, bizarre TP53 positive nuclei with hyperchromatism, abundant mitoses and numerous hyaline globules. The contralateral ovary was normal. From the age of 10 years, the patient had a complex medical history of multiple tumors, including telangiectatic osteosarcoma, typical and malignant phyllodes tumor, reticulohistiocytoma of skin, carcinomas of the breast and lipo-and leiomyosarcoma. The female genital tract also harbored myometrial leiomyomas and an early endometrial carcinoma. Retrospective histologic study of all mesenchymal neoplasms in this patient showed, the conspicuous presence of similar bizarre TP53 positive cells with hyaline globules in all the mesenchymal neoplasms. In the genetic study, a germline p53 gene mutation was detected in exon 10, codon 336, generating a stop codon in the oligomerization domain of the protein (E336X). A further p53 mutation was found in exon 7 in the granulosa cell tumor. Mutation occurred de novo since there was no history of tumors in any family members, all of whom had a wild-type p53. Although this patient shows a typical tumor phenotype of Li Fraumeni syndrome, the germline mutation corresponded to a highly unusual mutated domain, which is similar to the one found in childhood malignant adrenocortical tumor; also a rare neoplasm that originates in adrenocortical cells; which are closely related, both functionally and embryologically, to granulosa cells.

High frequency of de novo mutations in Li-Fraumeni syndrome

“…Among a total of seven papers6 7 8 13 14 15 16 which report these “new mutations,” only two papers6 7 report confirmed de novo mutations (in which both the mother and the father are tested and paternity testing is performed) (tables 3 and 4). …”

De novo germline TP53 mutation presenting with synchronous malignancies of the central nervous system

“…Occasionally, germline TP53 mutations present in patients with no family history of malignancy. In reported cases of apparent de novo germline TP53 mutations, patients have presented with neuroblastoma 6, ovarian granulosa cell tumor 7, and synchronous adrenal cortical carcinoma and RMS 8.…”

Li–Fraumeni syndrome: a role for surgical pathologists?

“…59,61,63 It has been suggested that unusual histologic subtypes of osteosarcoma are enriched in genetic cancer syndromes, and that histologic subtyping may represent a diagnostic tool in identifying patients with LFS. 64 There are reports of osteoblastic, 65e67 chondroblastic (Figure 3), 68 small cell, 66 and telangiectatic 69 variants arising with germ-line TP53 mutations. The IARC Figure 2 Photomicrograph of breast invasive ductal carcinoma, no special type, in a patient with a germ-line TP53 mutation (Haematoxylin and Eosin, Â200).…”