Gynecologic Tumors and Precursor Lesions, Including p53-Aberrant Atypical Hyperplasia-like Endometrial Lesions, in Li-Fraumeni Syndrome.

Abstract

Li-Fraumeni syndrome (LFS), caused by germline TP53 (g-TP53) mutation, predisposes to a wide range of early-onset malignancies, but gynecologic tumors are relatively uncommon. We sought to define the spectrum of neoplasms and atypical lesions of the female reproductive tract in LFS patients. A histomorphologic review was performed on tumors and gynecologic tissues from biopsy or resection specimens from 20 female patients with g-TP53 mutations. Gynecologic cancers (n = 7) comprised high-grade serous carcinomas of tubo-ovarian/primary peritoneal origin (n = 3), high-grade endometrioid ovarian carcinoma (n = 1), endometrial serous carcinoma (n = 1), and leiomyosarcomas (uterine, n = 1; and ovarian, n = 1). Morphologic features were indistinguishable from sporadic cases. With exception of 1 case, somatic inactivation of the remaining TP53 allele was identified by loss of heterozygosity or deep deletion. Other abnormal lesions, which exhibited aberrant p53 expression by immunohistochemistry, included serous tubal intraepithelial carcinomas (n = 2), a uterine smooth muscle tumor of uncertain malignant potential (n = 1), and endometrial glandular lesions, morphologically resembling atypical hyperplasia (n = 4; median age, 33 years). Immunohistochemistry on p53-aberrant atypical hyperplasia-like lesions revealed PAX2 loss (3/4), nuclear β-catenin (1/3), and decreased PTEN (2/3); molecular analysis on 2 cases revealed TP53 loss of heterozygosity, with concomitant KRAS or PTEN mutation. These lesions resolved with progestin therapy (n = 2) or did not recur following hysterectomy (n = 2). In morphologically benign tissues, p53 immunohistochemistry revealed variable staining patterns, including wild-type only, discrete foci of aberrant expression, or diffuse p53 overexpression in nearly all cells (associated with the g-TP53 p.Arg337His founder variant). Our findings demonstrate that g-TP53 mutations can drive the pathogenesis of gynecologic tumors that are usually defined by somatic TP53 mutations. A novel p53-aberrant endometrial glandular lesion, occurring in young patients with LFS, likely represents an unusual form of endometrial atypical hyperplasia rather than serous carcinoma. In morphologically benign tissues, aberrant p53 expression in numerous discrete foci or diffusely across nearly all cells should prompt consideration of an underlying g-TP53 mutation.