10 Endometrial Carcinoma Important Issues in Interpretation of The tumors are often associated with hyper- Biopsies . 209 plasia and atypical hyperplasia, conditions that Criteria for the Diagnosis of result from unopposed estrogenic stimulation Well-Differentiated Endometrial such as anovulatory cycles that normally occur Adenocarcinoma . 209 at the time of menopause or in younger women Benign Changes that Mimic with the Stein–Leventhal syndrome (polycystic Carcinoma . 214 ovarian disease). Unopposed exogenous estro- Malignant Neoplasms—Classification, gen use as hormone replacement therapy in Grading, and Staging of the Tumor . 216 older women also predisposes to endometrial Classification . 216 carcinoma that tends to be low-grade. In hys- Grading . 216 Clinically Important Histologic terectomy specimens these low-grade tumors Subtypes . 221 generally show minimal myometrial invasion, Staging . 236 although deep invasion can occur in some Endometrial Versus Endocervical cases.5;6 The prognosis is generally good, with a Carcinoma . 237 5-year survival of 80% or better.3 Metastatic Carcinoma . 238 Type II neoplasms represent another, very Clinical Queries and Reporting . 239 different, form of endometrial carcinoma. They are high-grade neoplasms that do not appear to be related to sustained estrogen stimulation.1;2;4 Endometrial adenocarcinoma is the most com- Tumors in this group account for 15% to 20% mon malignant tumor of the female genital of all endometrial carcinomas. The prototypical tract in the United States. This neoplasm rep- type II neoplasm is serous carcinoma, but other resents a biologically and morphologically histologic subtypes include clear cell carcino- diverse group of tumors, with differing patho- mas and other carcinomas that show high-grade genesis.1–4 These tumors have two basic clinico- nuclear features. They tend to occur in older pathologic forms, type I and type II. These two postmenopausal women, are not associated forms of endometrial carcinoma display differ- with atypical hyperplasia, and often occur in ent clinicopathologic, immunohistochemical, atrophic endometrium. Endometrial intra- and molecular biologic features suggesting two epithelial carcinoma (EIC), the putative pre- pathways of carcinogenesis. cursor lesion, is frequently associated with Type I carcinomas are generally well to mod- serous carcinoma (see Chapter 9). Serous erately differentiated and account for 80% to carcinoma usually invades the myometrium 85% of all endometrial carcinomas. The typical deeply, permeates lymphatic and vascular chan- patient is an obese, hypertensive, and diabetic nels, and not infrequently has spread beyond perimenopausal or postmenopausal woman. the uterus at the time of hysterectomy. 208 Important Issues in Interpretation of Biopsies 209 Although most endometrial carcinomas tend Important Issues in to be either type I or type II, there are cases that do not fall neatly into either category. For Interpretation of Biopsies instance, some endometrioid carcinomas are There are two major concerns in the evaluation very high grade. Also, some endometrioid car- of endometrial biopsies from the standpoint of cinomas can show foci of serous or clear cell a diagnosis of carcinoma. First, is the lesion carcinoma. benign or malignant? Second, if the biopsy con- Clinicopathologic studies over the past tains a malignant tumor, what is the grade, his- several years have shown the importance of tologic subtype, and is it a primary endometrial recognizing specific histologic subtypes and or an endocervical carcinoma? accurately grading carcinomas to help pre- dict outcome and direct treatment.7–26 Most endometrial tumors diagnosed on a biopsy Criteria for the Diagnosis of are subsequently treated by extrafascial total Well-Differentiated Endometrial abdominal hysterectomy and bilateral salp- Adenocarcinoma ingo-oophorectomy that allows precise surgical–pathologic staging.27 Nonetheless, Because a diagnosis of carcinoma will have an identification of more aggressive tumors is important impact on clinical management, it is important at the time of biopsy, as these necessary for the pathologist to be familiar with neoplasms have greater potential for metasta- the minimal histologic criteria for that diagno- tic spread, including involvement of the peri- sis. One of the most problematic areas is the dis- toneal surfaces. The aggressive neoplasms are tinction of atypical hyperplasia (see Chapter 9) high-grade carcinomas that merit surgical from well-differentiated adenocarcinoma.30–33 staging. The clinical relevance of the histologic Separation of these entities is based on identi- classification and grading of endometrial carci- fication of specific morphologic criteria that noma is reflected in the revised World Health establish the diagnosis of low-grade carcinoma. Organization (WHO) Histologic Classifica- Hyperplasia without atypia generally is not a tion28;28a and the International Federation of problem in the differential diagnosis, as these Gynecology and Obstetrics (FIGO) staging forms of hyperplasia do not have nuclear system.29 atypia. It is important, however, to accurately The morphologic diversity of endometrial separate carcinoma from other, benign changes carcinoma can lead to problems in the diagno- that mimic neoplasia, including tissue artifacts sis of carcinoma in biopsies and curettings. For and pregnancy-related changes. low-grade carcinoma, distinction from atypical Diagnosis of low-grade adenocarcinoma can hyperplasia and other benign lesions that be difficult at times,because these tumors do not mimic carcinoma is an important issue. Identi- always show clear-cut destructive stromal inva- fying and properly classifying aggressive, sion. Furthermore, invasion into myometrium clinically significant histologic subtypes of is rarely, if ever, demonstrated in biopsies. endometrial carcinoma is a second important Nonetheless, invasion is a logical criterion for area of biopsy interpretation. Another problem separating frank adenocarcinoma from atypical in biopsy interpretation is ascertaining whether hyperplasia or other lesions that mimic the tumor originates in the endometrium or the adenocarcinoma. endocervix. This chapter addresses the general For practical application, specific patterns of classification, staging, and grading of endome- stromal and epithelial alterations have been trial carcinoma, the differential diagnosis of defined that reflect “endometrial stromal inva- benign lesions versus low-grade carcinoma, and sion” and identify carcinoma.31;34 There are the classification of different types of carci- three separate features, any of which indicates noma once the diagnosis of carcinoma has been stromal invasion in low-grade glandular established. proliferations: 210 10. Endometrial Carcinoma 1. A confluent glandular pattern in which evident, a diagnosis of carcinoma should be individual glands, uninterrupted by stroma, made even if the diagnostic area does not merge and create a cribriform arrangement; occupy one-half of a low-power field. 2. An irregular infiltration of glands associated with an altered fibroblastic stroma (desmo- Confluent Gland Pattern plastic response); and This pattern reflects invasion by showing a 3. An extensive papillary pattern. complete absence of stroma between glands.At Although quantitative features have limited times a cribriform bridging pattern with true usefulness in endometrial biopsy diagnosis, “gland in gland” formation is present. With these specific and objective criteria for invasion cribriform growth, trabeculae of columnar cells also should be quantitatively significant. There- bridge the lumen, subdividing the lumen into fore, the glandular proliferation that fulfills smaller glandular spaces (Figs. 10.1 and 10.2). criteria for well-differentiated adenocarcinoma No stroma supports the bridging cells. A con- should be sufficiently extensive to involve at fluent gland pattern also is represented by large, least one half of a low-power (¥4) field, a dis- irregular glands that interconnect continuously tance of 2.0mm. This guideline helps mainly to throughout the field, exceeding the outline of avoid the problem of tangential sectioning or any acceptable non-neoplastic gland (Fig. 10.3). other artifacts in establishing the diagnosis of Confluent gland patterns should be identified in carcinoma. This general rule should not be too areas free of squamous differentiation, as squa- rigidly applied, particularly in scant specimens. mous morules may bridge gland lumens, but If the features of “stromal invasion” are clearly these do not reflect stromal invasion. Figure 10.1. Adenocarcinoma, FIGO grade 1. The grade 1 with minimal pleomorphism, small nucleoli, neoplasm shows well-formed glands with a confluent and low mitotic rate. pattern. The stroma is desmoplastic. The nuclei are Figure 10.2. Adenocarcinoma, FIGO grade 1. Confluent gland pattern. Confluent glands with a cribriform bridging arrangement. There is no stromal support to the epithelium that bridges the glandular lumens. Figure 10.3. Adenocarcinoma, FIGO grade 1. Confluent gland pattern. Large irregular and branching glands interconnect continuously throughout the field. 212 10. Endometrial Carcinoma Altered Fibrous or Desmoplastic Stroma in establishing an unequivocal diagnosis of malignancy. With this change, atypical glands are dispersed in a reactive fibroblastic mesenchyme rather Extensive Papillary Pattern than in endometrial stromal cells (Fig. 10.4). These fibrous stromal cells are different from The extensive papillary