Diagnosis and management of an endometrial cancer patient with Cowden syndrome

Abstract

Somatic PTEN alterations are common in endometrial carcinoma (EC), but in rare cases PTEN mutations are associated with inherited syndromes. Here, we present a case of Cowden syndrome-associated EC. We discuss clinical, pathologic and molecular features of her tumor and PTEN-mutated EC, inherited syndromes predisposing to EC and PTEN-targeted therapies.

Keywords: Cowden syndrome; Germline; PTEN mutation; Pathology; Targeted therapy.

Figure 1.. Pre-therapy imaging studies of the abdomen and pelvis.

A, Axial T2 weighted magnetic resonance (MR) image shows endometrial tumor with extension into the cervix (white arrow) and heterogeneous left ovarian mass with solid and cystic components (black arrow). B, Sagittal T1 weighted sagittal MR image demonstrates deep myometrial invasion (black arrow): the endometrial tumor is hypointense relative to the hyperintense enhancing myometrium with invasion of the outer half of the myometrium.

Figure 2.. Pathology of the endometrial carcinoma.

A, Gross appearance of the uterus showing a 4 cm mass protruding into endometrial cavity (right) and ovarian metastasis (left). Reprinted from WHO Classification of Tumours Editorial Board. Female Genital Tumours. Lyon (France), IARC 2020 [2]. B, Representative hematoxylin and eosin-stained section showing a grade 1 endometrial endometrioid carcinoma with complex cribriform glands and marked squamous and morular differentiation (20x). C, PTEN immunohistochemical expression of endometrial carcinoma (DAB 20X; Clone 6H2,1; Agilent/Dako). Tumor cells show loss of expression of PTEN in the presence of internal controls. Scale bars, A, 100μm, B, 50μm.

Figure 3.. Somatic genetic alterations of the Cowden syndrome-related endometrial and ovarian carcinoma.

A, Repertoire of somatic mutations of the Cowden syndrome patient’s primary endometrial (EC) and synchronous ovarian carcinoma (OC) subjected to whole-exome sequencing [1, 25]. Mutation types are color-coded according to the legend. Both the EC and the OC arising in this PTEN germline mutation carrier share somatic mutations, including a CTNNB1 hotspot mutation and a PIK3R1 mutation, suggesting that these two lesions are related rather than being two independent primary tumors. B, Mutational signatures provide information about the mutational processes, such as specific DNA repair deficiencies or DNA damage, that have occurred throughout tumor development [58]. Mutational signatures of the EC (left) and the synchronous OC (right) defined by DeconstructSigs [59] are shown. Akin to sporadic copy-number low (CN-L) ECs, which we have shown previously to harbor a dominant mutational signature 1 related to aging in the majority of cases [26], both the EC and OC of this Cowden syndrome patient display a dominant aging-related mutational signature (signature 1) [1, 25], color-coded according to the legend. C, Copy number plots of the EC (top) and the OC (bottom) with the Log₂-ratios plotted on the y-axis and the genomic positions on the x-axis [1]. Both the EC and OC occurring in this Cowden syndrome patient share the same copy number gains and losses, including a 1q gain. D, Hierarchical cluster analysis of somatic mutations identified in 505 cancer-related genes [27] using complete linkage and Euclidian distance metric, including the Cowden syndrome patient’s EC from this study (Cowden_EC), which harbors a PTEN germline mutation and is of CN-L molecular subtype, and 77 sporadic PTEN-mutant ECs of CN-L molecular subtype from The Cancer Genome Atlas [23]. This Cowden syndrome-related EC intermingles with the sporadic PTEN-mutant ECs, rather than forming a distinct cluster, suggesting that their somatic mutational profiles are similar.

Figure 4.. Pre-operative imaging of the posterior cranial fossa

A, Axial T2 weighted magnetic resonance (MR) image shows a hyperintense lesion with folial thickening in the right cerebellum, a characteristic finding of dysplastic cerebellar ganglioytoma (Lhermitte-Duclos disease). B, Representative hematoxylin and eosin-stained section (20x) showing the histologic features of the dysplastic gangliocytoma of the cerebellum with dysplastic ganglion cells. Scale bar, 50μm.