Problems in the Differential Diagnosis of Endometrial Hyperplasia and Carcinoma Steven G

THE 1999 LONG COURSE ON PATHOLOGY OF THE UTERINE CORPUS AND CERVIX Problems in the Differential Diagnosis of Endometrial Hyperplasia and Carcinoma Steven G. Silverberg, M.D. Department of Pathology, University of Maryland Medical Center, Baltimore, Maryland consider the questions of the progression of endo- The differential diagnosis of endometrial hyperpla- metrial hyperplasia (and specifically its atypical sia and well-differentiated endometrioid adenocar- variant) to carcinoma, as well as the prognostic cinoma is complicated not only by the resemblance effect of the presence of endometrial hyperplasia in of these lesions to each other, but also by their cases of endometrial carcinoma, and the biologic tendency to be overdiagnosed (particularly hyper- significance of carcinoma that arises in the pres- plasia) on the background of polyps, endometritis, ence or absence of hyperplasia. The last of these artifacts, and even normally cycling endometrium. topics, however, is considered in much greater de- Atypical hyperplasia may also be overdiagnosed tail in the article by Sherman (1) in this issue. when epithelial metaplastic changes occur in sim- There are four possible approaches to making the ple or complex hyperplasia without atypia. Low- differential diagnosis between atypical endometrial grade adenocarcinomas are best recognized by ar- hyperplasia and well-differentiated endometrioid chitectural evidence of stromal invasion, usually in adenocarcinoma of the endometrium. These ap- the form of stromal disappearance, desmoplasia, proaches may be summarized briefly as follows: necrosis, or combinations of these findings between (1) adenocarcinoma in situ, (2) endometrial intraepi- adjacent glands. Endometrioid adenocarcinomas thelial neoplasia (EIN), (3) nonhistologic techniques, are usually Type 1 cancers associated with manifes- and (4) so-called “routine” light microscopy. tations of endogenous or exogenous hyperestro- The oldest of these approaches is the first, in genic stimulation and a favorable prognosis. Sub- which it is assumed that there must be an entity, types include adenocarcinomas with squamous conveniently named adenocarcinoma in situ, that differentiation and secretory, ciliated cell and vil- is intermediate between the most severe atypical loglandular variants. Rules and pitfalls in the grad- hyperplasia and the earliest focal change recogniz- ing of endometrioid adenocarcinomas and the esti- able as invasive adenocarcinoma. Probably the mation and reporting of myometrial invasion are most effective rebuttal of this concept for diagnos- presented. tic purposes was made by Professor Harold Fox, who stated, “A true adenocarcinoma in situ of the KEY WORDS: Differential diagnosis, Endometrial endometrium is one in which the glands have un- carcinoma, Endometrial hyperplasia, Grading, dergone neoplastic change but in which there is no Myoinvasion. invasion of the endometrial stroma. It is doubtful if Mod Pathol 2000;13(3):309–327 any adenocarcinoma of this type exists or if it could be recognized even if it did exist” (2). Because of The purpose of this article is to review the relation- this and similar objections, the term “adenocarci- ships between hyperplasia and adenocarcinoma of noma in situ” does not appear in the current Inter- the endometrium, with an emphasis on the differ- national Society of Gynecological Pathologists ential diagnostic problems both between these two (ISGP), International Federation of Gynecology and lesions and between them and other entities that Obstetrics (FIGO), and World Health Organization enter into the differential diagnostic picture. How- (WHO) classifications (which are identical) of en- ever, differential diagnosis is not the only relation- dometrial neoplasia and preneoplasia (3). ship between endometrial hyperplasia and carci- Another approach that has had and continues to noma. During the course of this review, we briefly have its proponents is the use of the term “endometrial intraepithelial neoplasia (EIN)” to encompass le- Copyright © 2000 by The United States and Canadian Academy of sions that span from atypical complex hyperplasia to Pathology, Inc. VOL. 13, NO. 3, P. 309, 2000 Printed in the U.S.A. focal low-grade endometrioid adenocarcinoma (4). Date of acceptance: November 8, 1999. The assumption is that reliable and reproducible cri- Address reprint requests to: Steven G. Silverberg, M.D., Department of Pathology, University of Maryland Medical Center, 22 S. Greene Street, teria for distinguishing these two entities do not exist, Baltimore, MD 21201; fax: 410-328-0081. and that they should therefore be combined under 309 the one rubric of EIN. This approach has much to endometrial hyperplasias are among the most com- recommend it, but the problem is that decisions must monly overdiagnosed lesions in diagnostic surgical still be made by the diagnostic pathologist. Thus, di- pathology. In a classic study, Winkler et al. (19) agnostic problems will still exist at both the lower end analyzed 100 consecutive cases referred to their (complex hyperplasia without atypia versus atypical laboratory with the diagnosis of endometrial hyper- complex hyperplasia) and the upper end (focal low- plasia. Remarkably, they found that the exact diag- grade endometrioid adenocarcinoma versus a more nosis made by the referring pathologist was con- extensive or higher-grade adenocarcinoma) of the firmed in only 24 of these cases; among the others, EIN spectrum. Thus, I assert that the EIN terminology the diagnosis was downgraded in 69, upgraded in does not solve our diagnostic problems but merely only 3, and uncertain in the remaining 4. The most adds a new term that further confuses the clinicians common downgrading was done for polyps (25 cas- who care for patients with these diseases. es), normal cycling endometrium (17 cases), and The third possibility in dealing with these differen- less severe forms of hyperplasia than originally di- tial diagnostic problems is to admit defeat at the light agnosed (16 cases). It was also noted in this study microscopic level and search for various nonhisto- that nine cases had metaplastic changes that might logic techniques that might enable making a distinc- have contributed to the diagnostic difficulty, and tion between an atypical hyperplasia and well- three had endometritis. My own anecdotal experi- differentiated adenocarcinoma. However, to date, this ence has been very similar, both in the frequency of search has proved elusive, as no ploidy, histochemi- overdiagnosed hyperplasia and in the reasons for it. cal, immunohistochemical, or molecular studies have Other studies have also commented on problems yet demonstrated reproducible differences between with reproducibility of diagnostic criteria among these two entities (5–18). If anything, these studies the hyperplasias, with particular emphasis on atyp- have supported the EIN concept, as most abnormal- ical hyperplasia (20, 21). ities found in low-grade endometrioid carcinomas The histologic appearance of simple hyperplasia is can also be demonstrated in more or less equal pro- that of an endometrium that is first increased in vol- portions of atypical hyperplasias. ume and second qualitatively different from normal Finally, we are left with the fourth approach, cycling endometrium. Both the glands and the stroma which is the attempt to distinguish between atypi- participate in this process so that the glands are not cal complex hyperplasia and well-differentiated ad- particularly crowded. The glands are usually uni- enocarcinoma on purely histologic grounds. This formly rounded but may show marked variation in distinction, therefore, forms a major part of the shape, with many cystically dilated forms (Fig. 1). discussion that follows. Their lining epithelium is pseudostratified to mod- estly stratified, contains occasional mitotic figures, and, by definition, lacks nuclear atypia. The stroma is CLASSIFICATION AND DIFFERENTIAL also active, is uniformly cellular, may be mitotically DIAGNOSIS OF ENDOMETRIAL HYPERPLASIAS active, and contains evenly distributed small blood vessels resembling the spiral arterioles seen in late Before proceeding to the discussion of the differ- secretory endometrium or those seen in low-grade ential diagnosis between the most marked forms of endometrial stromal tumors (Figs. 1 and 2). atypical complex hyperplasia and the lowest-grade Because the most prominent feature noted in endometrioid adenocarcinoma, we must first con- simple hyperplasia at low-power examination is of- sider the full spectrum of endometrial hyperplasias. ten the cystically dilated glands, the differential di- The new ISGP, FIGO, and WHO classification diagnosis includes both cystic atrophy and endome- vides the endometrial hyperplasias into those that trial polyps. In the former, the distinction is easily are and those that are not atypical, and each of made because the glands are lined by reduced these classifications is divided into simple and rather than proliferated epithelium and the stroma complex variants (3). It is important to realize that is dense and appears atrophic. Polyps are often each of these forms (simple hyperplasia without more of a problem, unless they present as large, atypia, complex hyperplasia without atypia, atypi- spherical, cohesive masses obviously covered on cal simple hyperplasia, and atypical complex hy- three surfaces by epithelium (Fig. 3). However, the perplasia) must be distinguished not only from the majority of endometrial polyps encountered

Load more