Elsevier

Human Pathology

Volume 35, Issue 6, June 2004, Pages 649-662
Human Pathology

Current topic
Prognostic parameters of endometrial carcinoma

https://doi.org/10.1016/j.humpath.2004.02.007Get rights and content

Abstract

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the Western world. Approximately 80% of cases are well- to moderately differentiated (endometrioid) adenocarcinomas, which are confined to the uterine corpus at diagnosis, and thus most can be cured. Conversely, high-grade (ie, clear cell and serous) carcinomas account for only 15% to 20% of cases and show marked nuclear atypia. These tumors usually invade the myometrium and may extend beyond the uterus at the time of hysterectomy. In addition to clinical and morphological differences, these 2 groups of endometrial carcinomas differ in their pathogenesis. Whereas prognosis in the latter group is generally poor, the pathologist’s role in establishing the outcome in the former group is crucial. Furthermore, it has become progressively apparent that both groups overlap to some extent, making the dualistic model a guideline at best. Over the last 2 decades, several studies have demonstrated the prognostic importance of various key surgical and pathological parameters, including histological type, histological grade, surgical-pathological stage, depth of myometrial invasion, vascular invasion, and cervical involvement. This review presents the most important prognostic factors of endometrial carcinomas from the pathologist’s viewpoint, and attempts to clarify existing conflicts in the classification and diagnosis of these tumors.

Section snippets

Histological type

Cell type has consistently been recognized as an important predictor of the biological behavior of endometrial carcinoma. Over the last 15 years, based on Bokhman’s clinical model for explaining the pathogenesis of endometrial carcinomas,7 these tumors have been classified into 2 types. Type I tumors (about 80%) are endometrioid carcinomas (Fig 1), frequently preceded by complex atypical hyperplasia and associated with estrogenic stimulation. Type I tumors occur predominantly in premenopausal

Histological grade

Whereas nonendometrioid carcinomas are considered high-grade tumors by definition and thus need not be graded, the grading of endometrioid carcinomas is prognostically important. These tumors span the spectrum from very well differentiated to almost completely undifferentiated, and probably merge at the higher end of the spectrum with undifferentiated carcinomas.31 The prognostic value of grading endometrial adenocarcinomas has been recognized for many years.6, 32 The 1988 International

FIGO stage

Although not perfect, FIGO stage is the single strongest prognostic parameter for women with endometrial carcinoma.37, 38, 39, 40 The 1971 FIGO clinical staging system (based on sounding of the uterus, fractional curettage, and pelvic examination) proved to be less accurate than histological evaluation of the hysterectomy specimen.37, 38, 39 Determination of the spread of tumor to the cervix (stage II) based on fractional curettage had an error rate of approximately 50%.37, 39 A decrease in

Intraendometrial carcinoma (stage IA)

Endometrial stromal invasion is manifested by various architectural and cytological features, some of which may be absent in individual cases, leaving the final decision to the overall evaluation of the lesion. In most cases, there is confluent arrangement of clearly malignant glands that may result in either a cribriform pattern or extensive papillary growth into the glandular lumina. Rarely, however, the invasive glands lack significant nuclear atypia, and the diagnosis of stromal invasion

Myometrial invasion

In low-stage endometrial carcinomas, myometrial invasion is an independent predictor of outcome.3, 4, 32, 36, 44, 45, 46 Recognition of myometrial invasion is straightforward when glands that are irregularly shaped, randomly distributed, and surrounded by a desmoplastic stroma infiltrate the myometrium (Fig 8). Occasionally, however, a carcinoma that has not invaded the myometrium exhibits an irregular endomyometrial junction in which rounded nests of tumor seem to protrude into the inner

Vascular invasion

The presence of tumor cells within endothelial-lined spaces is a strong predictor of recurrence and death from tumor, independent of histological grade or depth of myometrial invasion.57, 58, 59 As stated earlier, stromal retraction is a frequent artifact that may simulate vascular invasion. Immunoperoxidase staining of endothelial cells (factor VIII or CD31) may facilitate recognition of vascular channels.46 In addition, a perivascular lymphocytic infiltrate is often associated with vascular

Endometrial hyperplasia

Endometrioid carcinomas that are accompanied by atypical endometrial hyperplasia and exhibit various metaplasias, particularly ciliated and eosinophilic metaplasia, are associated with a favorable prognosis. These tumors are frequently low-grade carcinomas and lack myometrial invasion.60, 61 Alternatively, high-grade tumors are often accompanied by an atrophic endometrium.

Cervical involvement (stage II)

Cervical involvement in endometrial carcinoma, a finding present in 6% to 20% of cases, usually results from direct surface or stromal extension, although it may be secondary to implantation or lymphatic spread.39, 62, 63, 64 Implantation occurs in the denuded endocervix after fractional curettage in about 5% of cases.62, 64 As stated earlier, histological diagnosis of cervical involvement on the basis of the findings from endocervical curettage can be difficult.37, 39, 64 The diagnosis of

Serosal invasion, peritoneal cytology, and adnexal involvement (stage IIIA)

In the view of many gynecologic oncologists, the criteria used for classifying an endometrial carcinoma as stage III tumor (6% of cases) are somewhat artificial.65 The adverse prognostic significance of stage IIIA tumors (based on tumor involvement of the uterine serosa or positive peritoneal cytology) (Fig 15) has not been universally confirmed.69 Serosal invasion represents the extreme of deep myometrial invasion of stage I disease. It is quite different from adnexal spread, and according to

Lymph node metastasis (stage IIIC)

Endometrial carcinomas associated with pelvic and/or paraaortic lymph node metastasis are classified as stage IIIC tumors33 (Fig 16). Almost 33% of patients with positive pelvic lymph nodes have positive para-aortic nodes as well. Prognosis with positive pelvic lymph nodes seems more favorable than that with positive para-aortic lymph nodes.4 In fact, in a Gynecologic Oncology Group study, only 36% of patients with positive aortic nodes were free of tumor at 5 years, compared with 85% of those

Ploidy

Approximately 67% of endometrioid carcinomas are diploid, as evaluated by flow or static cytometry. In contrast, 55% of the nonendometrioid carcinomas (ie, serous, clear cell, or undifferentiated carcinomas) exhibit nondiploid DNA patterns. Diploid tumors are usually low-grade endometrioid carcinomas with only superficial invasion, and are associated with longer survival than aneuploid carcinomas.72, 73, 74, 75 Differences in disease-free survival for stage I tumors have been as significant as

Steroid receptors

Most endometrioid carcinomas contain cells with both ERs and progesterone receptors (PRs) as a sign of differentiation. Currently, assessment of ERs and PRs is done mainly by immunohistochemistry. Characteristically, endometrioid carcinomas exhibit marked heterogeneity in ER and PR distribution. The presence and quantity of steroid receptors correlate with FIGO stage, histological grade, and survival.79, 80, 81, 82 There is also correlation between ER and PR and bcl-2, absence of mutant p53,

bcl-2

bcl-2 is a proto-oncogene that inhibits programmed cell death or apoptosis. The immunohistochemical expression of Bcl-2 protein varies during the menstrual cycle; it is highly expressed in the proliferative phase, with down-regulation during the secretory phase. High levels of Bcl-2 are found in endometrial hyperplasia, with decreased expression in adenocarcinoma. Loss of Bcl-2 has been associated with poorer prognosis, increased depth of invasion, higher FIGO stage, and aggressive cell types,83

c-erb-B2 (HER2/neu) and p53

Amplification or overexpression of the c-erb-B2 (HER2/neu) oncogene occurs in about 20% to 40% of endometrial carcinomas (Fig 17) and has been associated with other adverse prognostic factors, including advanced stage, higher grade, and worse overall survival.86, 87 However, some studies have found that c-erb-B2 is not independently associated with adverse prognostic factors, although it does seem to have an influence on overall survival.88, 89 Currently, c-erb-B2 is thought to be a parameter

Markers of proliferation

Mitotic count, S-phase fraction by flow cytometry, and proportion of proliferating cells by immunohistochemistry (PCNA, Ki-67, MIB-1) are the most commonly used methods of quantifying proliferation. Ki-67 and MIB-1 identify cells in most of the G1, S, G2, and M phases of the cell cycle.91, 92, 93 PCNA and Ki-67 expression in stage I endometrial carcinoma correlate with histological grade, depth of myometrial invasion, and risk of recurrence. Most endometrioid carcinomas express a low Ki-67

Microsatellite instability

Microsatellites are repetitive DNA sequences distributed widely throughout the genome. Because of their repetitive structure, microsatellites are particularly susceptible to replication errors, resulting in insertion or deletion mutations (ie, MSI).94 The genes responsible for MSI encode proteins involved in DNA mismatch repair, including MLH1, MLH6, MSH2, MSH3, and PMS2. Mutations of these genes alter the ability of the cells to repair replication errors. Although MSI was initially found in

PTEN

The tumor-suppressor gene PTEN (phosphatase and tensin homolog deleted from chromosome 10), also called MMAC1 (mutated in multiple advanced cancers) is mutated in 30% to 60% of endometrial carcinomas.98, 99 PTEN is located on chromosome 10q23.3 and encodes a phosphatidylinositol phosphatase. The product induces apoptosis and G1 cell cycle arrest through antagonizing the phosphatidylinositol 3′-kinase/Akt-mediated cell growth pathway.100 PTEN mutation occurs almost exclusively in endometrioid

Beta-catenin

Beta-catenin is involved in the maintenance of tissue architecture and cell polarity and also plays a role in transcriptional activation. Cytoplasmic levels of beta-catenin are regulated by the opposing actions of Wnt-1 and APC. An increase in Wnt-1 stimulation or a decrease in beta-catenin degradation results in nuclear accumulation of beta-catenin and transcriptional activation. Beta-catenin gene (CTNNB1) mutations have been reported in approximately 15% to 40% of low-grade endometrioid

K-ras

Mutations in codon 12 of K-ras occur in approximately 20% of endometrial carcinomas, mostly of the endometrioid type with MSI. In most series, the ras mutations have not been related to stage, grade, depth of myometrial invasion, or survival.110

Acknowledgements

The author thanks Alberto Gallardo, MD for providing clinicopathologic data and Julie A. Irving, MD for her assistance in preparing the manuscript.

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