Endometrial Precancers: A Model

horizontal rule

Precancers and endometrial tumorigenesis.
Endometrioid endometrial adenocarcinoma, the most common form of endometrial cancer in the United States, is often preceded by a physical precursor lesion which mediates subsequent cancer risk. These precancers are initiated from a polyclonal normal field by mutations conferring marginal increases in growth potential that under the mitogenic stimulus of unopposed estrogen successfully proliferate as a clone (indicated by expanding arrows). The monoclonal precancer develops internal heterogeneity through mutation, and advantageous events selected by local conditions result in hierarchical subclones (left to right) of varying success. Some premalignant clones involute.  Others progress by additional mutation and selection, eventually reaching a stage where hormonal support is no longer required for survival. Malignant transformation to Cancer (red irregular clones)  is defined by accumulation of sufficient genetic damage to permit invasion of adjacent stromal tissues. 

     Endometrial precancers have been usually diagnosed as atypical endometrial hyperplasias, but may be designated in functional terms as Endometrial Intraepithelial Neoplasia (EIN). Precancers are the targets of, and effectors for, hormonally mediated tumor risk.  The PTEN gene is a hormonally responsive tumor suppressor gene mutated at the time of initiation in many endometrial neoplasms which may be an informative biomarker for premalignant and malignant clones.  These and other documented features of the model are presented in  Precancer Postulates Fulfilled.

PE Mutant Model.gif (5030 bytes) Summary Model of endometrial cancer pathways. Endometrioid endometrial adenocarcinoma (excluding papillary serous and non-endometrioid cancers) can arise through a PTEN dependent (left) or independent (right) pathway. Three stages of EIN-mediated endometrial carcinogenesis are shown, top to bottom, as tissue compartments proportionately shaded to show that fraction (% PTEN defect) of endometrial glands at each stage  which have PTEN mutation and/or deletion (black) or normal PTEN (white). Normal proliferative endometria contains a small fraction (42% of women have 2-3% PTEN mutated/deleted glands, for overall PTEN null rate estimated here as 1%) of PTEN-defective cells. EIN and cancer (CA) are usually homogenous regarding PTEN expression, so defective and non-defective fractions are reported as published PTEN mutation/deletion rates for these diagnoses in cases with a documented premalignant phase. Latent PTEN mutant clones within proliferative endometria are, individually, at least 50 times more susceptible to EIN conversion than glands with normal PTEN genotype.

horizontal rule

Reference List

(1) Faquin WC, Fitzgerald JT, Lin MC, Boynton KA, Muto MG, Mutter GL. Sporadic microsatellite instability is specific to neoplastic and preneoplastic endometrial tissues. Am J Clin Pathol 2000; 113(4):576-582.

(2) Faquin WC, Fitzgerald JT, Boynton KA, Mutter GL. Intratumoral genetic heterogeneity and progression of endometrioid type endometrial adenocarcinomas. Gynecol Oncol 2000; 78:152-157.

(3) Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecological Pathology 2000; 19:301-309.

(4) Mutter GL, Baak JPA, Crum CP, Richart RM, Ferenczy A, Faquin WC. Endometrial precancer diagnosis by histopathology, clonal analysis, and computerized morphometry. J Pathol 2000; 190:462-469.

(5) Mutter GL. Clonal analysis of gynecologic tumors. CME Journal of Gynecologic Oncology 2000; 5:171-176.

(6) Jovanovic AS, Boynton KA, Mutter GL. Uteri of women with endometrial carcinoma contain a histopathologic spectrum of monoclonal putative precancers, some with microsatellite instability. Cancer Res 1996; 56:1917-1921.

(7) Mutter GL, Boynton KA, Faquin WC, Ruiz RE, Jovanovic AS. Allelotype mapping of unstable microsatellites establishes direct lineage continuity between endometrial precancers and cancer. Cancer Res 1996; 56:4483-4486.

(8) Mutter GL, Chaponot M, Fletcher J. A PCR assay for non-random X chromosome inactivation identifies monoclonal endometrial cancers and precancers. Am J Pathol 1995; 146:501-508.

 

horizontal rule

Copyright 1998-2015 by George L. Mutter, MD.  All Rights Reserved