Endometrial adenocarcinoma is the most common invasive malignant neoplasm of the female genital tract, with an estimated 40,000 diagnosed cases and 6600 deaths in 2002 in the United States (1). Fortunately, surgery alone provides effective therapy for about 80% of these women, but very few of those with advanced or metastatic disease are cured by radiation, hormonal or chemotherapy. Significant future improvements in survival most likely will result from a better understanding of the pathways involved in carcinogenesis and metastasis, with concomitant clarification of the specific precursor lesions and identification of molecular targets for preinvasive and advanced disease.
Endometrial adenocarcinoma rarely occurs before the age of 40 (2,3), but the incidence rises dramatically between the ages of 45 and 65, following which it plateaus (4). Estrogens stimulate the proliferation of the normal endometrial glands and stroma, so it should not be surprising to find that most of the risk factors for endometrial hyperplasia and carcinoma reflect either exogenous or endogenous states of hyperestrinism. Risk factors for endometrial carcinoma include long-term unopposed estrogen therapy,
From: Current Clinical Oncology: Molecular Pathology of Gynecologic Cancer Edited by: A. Giordano, A. Bovicelli, and R. Kurman © Humana Press Inc., Totowa, NJ
tamoxifen therapy, polycystic ovarian syndrome, estrogen-producing tumors, a history of nulliparity or infertility, irregular menstrual cycles, early age at menarche, late age at menopause, obesity, diabetes mellitus, and hypertension (4-9).
Case-control studies have shown a relative risk of about 4 (range of 2-10) for women who have used long-term unopposed estrogen. In general, the tumors arising in users of estrogen are of endometrioid cell type, of low stage, and low grade, and these women are more likely to be younger, white, and nonobese. The endometrial carcinoma survival rate is higher for the women who have a history of estrogen use, which in part may be explained by the prognostic factors already delineated. However, after adjustment for the common prognostic factors, the probability of survival remains significantly less for the estrogen nonusers. A detection bias has been suggested as a possible explanation, because women being treated with estrogens are monitored more closely than the general population. In addition, it is possible that some endometrial carcinomas only achieve clinical detection when stimulated by estrogen. This hypothesis is supported by the observation of Horwitz et al. (10) of a fourfold increase in the rate of endometrial cancer in an autopsy-based study compared with the population-based incidence.
Carcinomas which occur in women under the age of 40 years are almost invariably associated with endogenous hyperestrinism, including obesity, anovulation, nulliparity, and polycystic ovary syndrome.
Tamoxifen, a nonsteroidal selective estrogen receptor modulator, has estrogen agonistic and antagonistic activities that are site specific. It has been extensively used in the last decade as adjuvant therapy following surgical treatment of breast cancer, for the treatment of metastatic breast carcinoma, and for prophylaxis against the breast carcinoma in high-risk populations. Fornander et al. (11) in a study of tamoxifen use as adjuvant therapy in more than 1800 menopausal women with breast carcinoma observed a sixfold increase in the relative risk of endometrial carcinoma. In a similar study, Fisher et al. (12) found a relative risk of 15 in the randomized tamoxifen treated group compared with the placebo group from the National Surgical Adjuvant Breast and Bowel Project. Although Magriples et al. (13) found the tamoxifen associated cancers to be of more aggressive cell type and have worse prognosis than those occurring in the general population, this observation has not been confirmed (14).
Obesity, diabetes mellitus, late menopause (i.e., after age 55), and nulliparity are each associated with about a twofold increase risk of developing endometrial adenocar-cinoma. Although, often cited as a risk factor, the significance of hypertension is lost when adjusted for obesity.
One risk factor unassociated with estrogen is hereditary, nonpolyposis colon carcinoma, with affected individuals having a 50-40-fold relative risk of developing endometrial carcinoma. The lifetime absolute probability approaches 50% for those who carry the germ-line mutation (15). It is this population for whom it is reasonable to consider annual screening or prophylactic hysterectomy.
About 20 years back, Bokhman (16) suggested that there were two pathogenetic forms of endometrial adenocarcinoma, the first arising in women with obesity, hyper-lipidemia, and signs of hyperestrogenism, such as anovulatory bleeding, infertility, late onset of menopause, hyperplasia of the ovarian stroma, and endometrial hyperplasia;
the second arising in women without such signs. The first, more common type, was found to be more often well differentiated, only superficially invasive, sensitive to progestin therapy, and with a favorable prognosis. In contrast, the second type was more often poorly differentiated, deeply invasive, more often associated with nodal metastasis, less often sensitive to progestins, and with a less favorable prognosis (16). This division has been supported and refined by subsequent investigators (17,18). Pathologists recognize that endometrial adenocarcinoma may have any of the variety of histologically defined cell types, each of which falls into one of the two pathogenetic types. Most endometrioid adenocarcinomas, with or without squamous differentiation, mucinous adenocarcinomas, and villoglandular adenocarcinomas are of the first type. Whereas uterine papillary serous carcinomas (UPSC), clear cell carcinomas, and some poorly differentiated endometrioid adenocarcinomas fall into the second group. Although all of the first types display similar biological behavior, among the second type, the patterns of spread and preinvasive disease differ according to the cell type.
1.3. The Histological Classification of Endometrial Adenocarcinoma
The current classification of endometrial adenocarcinomas by the International Society of Gynecological Pathologists and the World Health Organization (WHO) (19) divides neoplasms according to histologically defined features that describe the appearances of individual neoplastic cells. Pathologists recognize that the cell types in themselves do not imply any particular biological behavior, but these features probably represent reasonably good surrogates for molecular changes that have yet to be defined.
Endometrioid adenocarcinoma is the prototypical endometrial adenocarcinoma and retains the basic architectural arrangement of endometrial glands of varying complexity with a lining of stratified, columnar, epithelial cells (Fig. 1). Decreasing differentiation is characterized by an increasing proportion of tumor made up of solid masses of epithelial cells. Intraglandular papillae formed exclusively of neoplastic cells without a supporting stroma may be present, and a cribriform growth is common in well-differentiated tumors, which are confined to the endometrium. The glands of endometrioid adenocarcinoma are formed of tall columnar cells that share a common apical border, resulting in a smoothly delineated, round or oval luminal contour. With decreasing differentiation, there is a preponderance of solid growth rather than gland formation. About 60% of endometrioid adenocarcinomas contain inactivating mutations in the tumor suppressor gene PTEN.
Secretory adenocarcinoma is an uncommon variant of typical endometrioid adeno-carcinoma in which well-formed tubular glands are lined by a columnar epithelium in which there is prominent subnuclear, and sometimes supranuclear, vacuolization. This change sometimes reflects a response to progestin exposure either from ovulation or rarely exogenous progestin therapy.
Villoglandular adenocarcinoma is another subtype of endometrioid adenocarcinoma and is characterized by papillae formed of tall, thin, occasionally branching fibrovascu-lar cores, covered by columnar cells with a straight apical border and generally low-grade nuclei (Fig. 2). The arrangement of neoplastic cells on the connective tissue cores is analogous to the arrangement of the cells that line glands in a typical endometrial adenocarcinoma, with the formation of a smooth apical border. About half of villoglandular carcinomas are admixed with endometrioid adenocarcinomas.
Adenocarcinomas with foci of squamous differentiation represent about 20% of endometrial cancers (20-23) (Fig. 3). Usually, the squamous differentiation in an endometrial adenocarcinoma is easy to recognize. Sheets of keratin, isolated cell kera-tinization, or intercellular bridges are often conspicuous. However, in order to distinguish foci of squamous differentiation from the poorly differentiated solid portions of adenocarcinoma, more subtle features should also be sought, including the presence of distinct cell membranes accompanied by more abundant eosinophilic cytoplasm than other cells in the same tumor (19). The squamous component may appear histologically benign, atypical, or overtly malignant.
Mucinous adenocarcinoma may be entirely tubular or cribriform, but more often has a papillary architecture. The covering epithelium is made up of multiple layers of columnar cells, with intracytoplasmic mucin variably filling the apical portion of the cells, resembling the arrangement of endocervical type epithelium (Fig. 4). Occasionally, an endometrial adenocarcinoma might contain cells with the distended, discrete, apical vacuole characteristic of a goblet cell. Usually intracytoplasmic mucin is easy to identify as finely granular compared with diffuse pale basophilia, but in questionable cases, the reaction with mucicarmine or alcian blue stain within neo-plastic cells can confirm its presence. The stroma may not be clearly of endometrial type, and often contains spindled cells, thin walled blood vessels, and variably dense
infiltrates of acute inflammatory cells. It is a relatively rare form of endometrial adenocarcinoma (24-26), with a mean age at diagnosis of about 60 years, and with a generally good prognosis.
Serous adenocarcinoma or UPSC of the endometrium is histologically similar to its counterpart in the ovary. It is characterized by branching complex papillae, formed of fibrovascular cores, covered by one or more layers of cuboidal cells with high-grade nuclei and a scalloped apical border (Fig. 5). Usually, the fibrovascular cores are blunt and hyalinized, but occasionally they are thin and delicate. Detached tufts of epithelial cells and psammoma bodies are often present. Whereas papillae typically forms the superficial portion of the tumor, irregularly dilated or gaping glands made up of cells with similar cytological atypia, commonly constitute the deeper aspect of these neoplasms. The neoplastic cell cytoplasm is often eosinophilic and finely granular. Large nucleoli and aberrant mitotic figures are common.
Serous carcinomas sometimes arise within endometrial polyps or in a background of atrophy. Most UPSC have inactivating mutations that result in histological overexpression of p53. The overall 5-year survival rate has varied from less than 40% to about 60% (27-37). The patients are often of advanced age, and most have either clinically advanced disease or unsuspected metastases discovered at surgery (32,38-43).
Clear cell adenocarcinoma of the endometrium is generally recognized by the distinctive, clear cytoplasm of neoplastic cells growing in any combination of solid, glandular,
tubulocystic, or papillary configurations (Fig. 6). The solid pattern consists of masses of large neoplastic cells of polygonal shape, with clear to faintly eosinophilic cytoplasm, and distinct cell membranes. The glandular pattern is reminiscent of the tubular glands of endometrioid adenocarcinoma, whereas the tubulocystic pattern is formed of dilated spherical appearing glands. The papillary pattern is architecturally identical to that of serous carcinoma, with generally short, branching fibrovascular cores, often hyalinized, covered by neoplastic cells. The last three patterns often have lining cells with a hobnail appearance, resulting from the scalloped apex of individual neoplastic cells, which project along the surface. Many tumors contain scattered densely eosinophilic intracytoplasmic inclusions, which are periodic acid-schiff reaction (PAS) positive, and resistant to diastase digestion. About 4% of endometrial adenocarcinomas are of clear cell type (20,44-48). The mean age at diagnosis is about 68 years, which is similar to that of serous adenocarcinoma and about 6 years older than that of typical endometrial adenocarcinoma. It is a biologically aggressive neoplasm, with a 5-year survival rate varying from only about 20-65% (46-49).
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