Pathologic Features of Uterine Cancer
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers.
During child-bearing age, the normal endometrium undergoes a series of sequential changes in the course of the ovulatory cycle that prepare it to receive the ovum. If the ovum is not fertilized, the proliferative endometrium is cast off by menstruation, and the cycle repeats itself. A normal endometrial cycle is associated with changes in both endometrial glands and stroma that allow the pathologist to diagnose microscopically the phase of menstrual cycle. Abnormal uterine bleeding many times is as the result of an identifiable lesion such as endometriosis, submucous myoma, endometrial polyp, or cancer particularly in the postmenopausal patients. In most series, approximately 5% to 15% of the cases of postmenopausal bleeding are due to endometrial carcinoma and a similar proportion to endometrial polyps (1).
The purpose of this document is to enhance the understanding of endometrial hyperplasia and endometrial neoplasia (cancer). Most commonly, the prolonged unremitting estrogen stimulation results in endometrial hyperplasia. All gradations of this phenomenon occur, ranging from one distinguished only with difficulty from a normal exuberant proliferative endometrium (so-called disordered proliferative endometrium) to an atypical one that approaches the appearance of adenocarcinoma.
Classic teaching has been that endometrial hyperplasias represent a continuum of morphologic severity; the most severe form termed atypical adenomatous hyperplasia or carcinoma in situ, was considered the immediate precursor of endometrial carcinoma (2). Since the mid-1980s, this continuum concept has been challenged. Independent studies by Kurman et al. and Ferenczy et al have suggested that there is 1.6% risk of progression to carcinoma in patients devoid of cytologic atypia, compared with a 23% risk in patients with cytologic atypia. This study also found that 29% of women with complex atypical hyperplasia go on to develop endometrial cancer, and the standard recommendation for women with complex atypical hyperplasia is hysterectomy and bilateral salpingo-oopherectomy (3):
In the everyday practice of pathology, the problem of differentiating the four subtypes of hyperplasia is encountered only sporadically, and diagnostic reproducibility is very unsatisfactory. The data suggest that most women with endometrial hyperplasia respond to progestin therapy. Patients who do not respond are at a significantly increased risk of progressing to invasive cancer and should be advised to have a hysterectomy. Patients in whom endometrial carcinoma develops with concomitant hyperplasia are more likely to be younger, to have better-differentiated tumors of lower surgical stage, and to have a better 5-year survival rate. However, the presence of endometrial hyperplasia does not appear to be an independent prognostic factor in multivariate analysis.
World Health Organization Classification of Endometrial Hyperplasia:
Endometrial hyperplasia is most commonly seen during the perimenopausal period. However, it can also be encountered in younger patients, even adolescent ones. Some of these develop as the result of estrogenic stimulation in polycystic ovary syndrome and in estrogen-secreting ovarian neoplasms. The distinction between a case of severe hyperplasia and a well-differentiated adenocarcinoma can be very difficult; largely because of the fact the endometrial hyperplasia and carcinoma represent different points in a disease continuum at the morphologic, ultrastructural, immunocytochemical, and molecular genetic levels. Microscopic features favoring carcinoma include marked pleomorphism with loss of polarity, complex ramification of disorderly arranged glands, extensive papillary formations, confluent glandular pattern with a solid or cribriform appearance, and desmoplastic stroma (4). Whether quantitative morphology (particularly nuclear morphometry), immunohistochemistry, flow cystometry, or other techniques will assist or replace conventional morphology in this difficult problem remains to be seen.
Differential Microscopic Criteria between Endometrial Hyperplasia and Adenocarcinoma:
An endometrium does not necessarily become hyperplastic because it contains a metaplastic change; similarly, a hyperplastic endometrium does not become necessarily malignant because it is accompanied by focal metaplasia because it is accompanied by focal metaplasia of squamous or some other type. Another lesion that is sometimes confused with hyperplasia (and which may actually represent a localized hyperplastic process) is adenomatous polyp, a lesion recognized by its dense its dense fibrotic stoma and thick-walled vessels (5). The term atypical secretory hyperplasia has been applied to a pattern of architectural abnormalities and cellular atypia within a secretory endometrium, with the atypical glands resembling those seen in the 16th to the 17th day of the normal cycle.
Adenomatous Hyperplasia - the microscopic criteria are: Nuclei - smooth and oval, uniform in size, nucleoli small and round, mitosis numerous in stroma and glands, cytoplasm abundant and amphophilic; glands lining epithelium is usually tall columnar, single layered dilated, irregular with out-pouching and infoldings; size of stroma is variable, usually abundant and cellular.
Atypical Hyperplasia - the microscopic criteria are: Nuclei - irregular, large and variable; nucleoli are large and irregular with numerous mitoses; cytoplasm sometimes is scanty, may be very abundant with dense eosinophilia; glands lining epithelium shows stratification, loss of polarity, irregular with intraglandular tufting but no bridging; size of stroma is variable, scant with crowding.
Adenocarcinoma - the microscopic criteria are: Nuclei - irregular, large and variable; nucleoli are large, irregular and speculated; mitoses are variable and scanty cytoplasm, pale and amphophilic; glands show loss of polarity, irregular with cribriform pattern and intraglandular bridging, size of stroma variable and scant.
Endometrial Hyperplasia and Carcinoma Relationship:
The relationship between hyperplasia and carcinoma has been a hotly debated subject (6). On the basis of the considerable collective experience that has accumulated on the subject, the following statements can be safely made:
Although atypical endometrial hyperplasia poses a threat of carcinoma, this can easily be eliminated by either medical (progestogen therapy) or surgical (hysterectomy) means. The great efficacy of hormonal therapy in controlling most cases of endometrial hyperplasia and in avoiding hysterectomy in surgically high-risk postmenopausal patients has been repeatedly demonstrated.
The large majority of endometrial polyps are not true neoplasms but probably represent circumscribed foci of hyperplasia, possibly due to a decreased expression of hormone receptors in the stromal component. Grossly, they protrude into the endometrial cavity and often exhibit secondary changes. The glands usually show some degree of cystic change. They may be lined by an active pseudostratified epithelium containing mitotic figures or in the postmenopausal patient, by a flat, inactive epithelium. The glands and stroma of the polyp are unresponsive to progesterone stimulation and retain their integrity throughout the menstrual cycle. Some polypoid lesions exhibit either simple or complex hyperplasia. Furthermore, endometrial polyps with a typical appearance often coexist with endometrial hyperplasia. All of these observation point to a shared pathogenesis for these two lesions. Exceptionally endometrial polyps contain scattered atypical (bizarre) stromal cells (7).
Endometrial polyps occur with increased frequency after tamoxifen exposure. These are characteristically multiple, large and fibrotic, and may exhibit stromal decidualization and mucinous metaplasia. At the molecular level, they are said to exhibit a higher frequency of k-ras mutations (8). Rarely polyps composed of functional endometrium are encountered. The diagnosis is made on the gross features of the lesion rather than on the microscopic pattern of glands and stroma and is, therefore, difficult or even impossible to make on a D&C specimen. Malignant transformation of endometrial polyps is an exceptional but well documented occurrence. Some of these cases present in the form of in situ or invasive serous carcinomas.
It is currently believed that endometrial carcinoma can be divided in two distinct types on the basis of their pathogenesis: 1) the more common occurring as a result of excess estrogenic stimulation and developing against a background of endometrial hyperplasia, 2) developing de novo. The clinical behavior of endometrioid endometrial carcinoma is dependent largely on the degree of differentiation. High-grade tumors are associated with more advanced-stage disease. Advances in molecular biology have led to the development of targeted biologic therapeutics that may have potential usefulness in endometrial carcinoma. AKT cascade activation in grade 3 endometrioid endometrial cancers and malignant mixed mullerian tumors is a novel finding. Apoptosis and growth arrest that results from AKT inhibition expose opportunities for therapeutic intervention (9). Some cases of endometrial carcinoma, of either endometrioid or papillary serous type, have been seen years after pelvic irradiation for some other condition, but whether these are spontaneous or radiation-induced is not clear. Patients who receive tamoxifen as long-term treatment for breast carcinoma are at an increased risk for the development of endometrial adenocarcinoma, of particular concern is the fact that in two series a significant number of these cases were high-grade tumors associated with a poor prognosis.
Endometrial carcinoma can develop in any anatomic region of the mucosa. Tumors developing in younger women have a greater tendency to involve the lower uterine segment. Grossly, carcinoma of the endometrium may form broad-based polypoid masses or infiltrate diffusely into the myometrium. In general, extensive myometrial invasion is accompanied by clinically detectable uterine enlargement. Microscopically, approximately 80% of endometrial malignant epithelial tumors are conventional adenocarcinomas, which are usually divided into well-differentiated (grade I-50%), moderately-differentiated (grade II-35%), and poorly-differentiated (grade III-15%). The better differentiated tumors closely recapitulate the light and electron microscopic features of the non-neoplastic endometrium, hence the term "endometrioid" that is used for them. Over a quarter of the endometrioid carcinomas have papillary foci, either on the surface or in the invasive areas. These tumors should be sharply separated from the much more aggressive papillary serous carcinomas. It should also be noted that the most superficial portions of endometrial adenocarcinomas can exhibit patterns closely simulating various hyperplastic and metaplastic conditions of the endometrial mucosa.
The frequency and extent of myometrial invasion by carcinoma are directly related to the microscopic grade of the tumor. Care should be exercised to distinguish true myometrial extension by carcinoma from expansion of the endometrial-myometrial junction and from atypical or malignant changes involving pre-existing foci of adenomyosis; the later condition is recognized by the presence of endometrial stroma around the intramyometrial proliferating glandular foci. It has been proposed that CD10 immunostaining can help in this distinction by highlighting the endometrial stroma associated with the adenomyosis when present. However, a warning has been sounded to the effect that CD10 immunoreactivity can also be found around foci of invasive adenocarcinoma (10). Extension of the endometrial carcinoma into the cervix occurs in over 10% if cases, usually by direct invasion, but allegedly also by implantation following D&C. This extension may be grossly evident or become apparent only on microscopic examination; it may involve the surface only, the fibrous stroma, or both. The presence and type of cervical extension; which influences the staging of the tumor is best detected by fractional curettage; care should be exercised in distinguishing bona fide cervical extension from isolated tumor fragments, or else a high-false-positive rate will occur.
Factors of prognostic importance in endometrial adenocarcinoma are the following: tumor stage; level of infiltration; microscopic grade and microscopic type; cervical extension; estrogen dependence; lymph vessel invasion; blood vessel invasion; hormone receptor status; p53 overexpression; HER2/neu expression; epidermal growth factor receptor; DNA ploidy; cell proliferation; Rb gene; and angiogenesis. Tumor relapse may appear in the form of local recurrence (50%), distant metastases (28%), or both (21%); the median interval is between 1 and 2 years. Local recurrences can be treated successfully with aggressive radiation therapy.
Coexistent Uterine and Ovarian Carcinoma:
Approximately 8% of endometrial carcinomas are accompanied by a simultaneous ovarian carcinoma. When they are of similar microscopic types; which are usually the case - it becomes difficult to decide whether there are two independent tumors or whether one of the sites represents a metastasis. Features favoring a metastatic nature for the ovarian tumor include the following: smaller size, bilateral involvement, multinodular pattern of growth, presence of associated surface implants, and prominent lymphatic or vascular invasion within the ovarian stroma. Immuno-histochemical and DNA flow cytometric studies have proved of only limited value in this context. On the other hand, molecular studies done for the evaluation of clonality (loss of heterozygosity, PTEN mutations, microsatellite instability) have provided more pertinent information. The results of these combined evaluations seem to indicate that both situations occur but that at least in the case of endometrioid tumors, there is a greater number of independent primary uterine and ovarian neoplasms than of endometrial tumors metastasizing to the ovary.
Heredity Non-Polyposis Colon Cancer (HNPCC) or Lynch Syndrome and Endometrial Cancer:
HNPCC also known as Lynch syndrome is an autosomal dominantly inherited disease of the DNA mismatch repair system. It results in genetic susceptibility to many types of malignancies, but the two most common are colorectal and endometrial cancers. Nearly all HNPCC-related colorectal cancers and endometrial cancers demonstrate microsatellite instability, whereas this is a much less common finding in sporadic colorectal and endometrial cancers (11). Some centers advocate microsatellite instability testing of all colon and endometrial cancers, especially those occurring in patients under age 50. Genetic testing is recommended when the individual has a personal history or family history suggestive of a cancer susceptibility syndrome, when the test can be adequately interpreted, and when the test results will influence medical management. One must take into account that endometrial cancer is the most common extra-colonic cancer in this syndrome and ovarian cancer risk is elevated as well. The cumulative lifetime risk of endometrial cancer in these patients is between 40% and 60%, and the ovarian cancer risk 12%. If the patient is being explored for another reason, consideration should be given to counseling regarding possible risks and benefits of a total hysterectomy with bilateral salpingo-oophorectomy (12).
Carcinoma of the endometrium is the most common gynecologic malignancy in industrialized countries. The highest incidence rates are in the United States and Canada, but in recent years there has been a decline in incidence and mortality. It typically occurs in elderly individuals, 80% of the patients being postmenopausal at the time of diagnosis. However, it can occur in any age group and has even been reported in association with intrauterine pregnancy. The differentiation between endometrial and endocervical carcinoma is of utmost importance. The distinction between a case of severe hyperplasia and a well-differentiated adenocarcinoma can be very difficult. Persistent hyperplasia poses a threat of carcinoma and should be treated either medically or surgically. Complex atypical hyperplasia patients should be counseled for high risk of finding a concurrent cancer. Women who choose conservative medical management with progesterone due to their wish to retain childbearing potential should be informed of the risks. In addition, very close follow up with serial endometrial biopsies or dilatation and curettage should be considered. When taking a patient with complex hyperplasia to the operating room, an intraoperative frozen section is important. The surgeon should be prepared to perform staging if needed.
The two obvious sites of local spread of endometrial carcinoma are the myometrium and the cervix, both of these having important prognostic connotations. The most common sites of recurrence of endometrial carcinoma are the vaginal vault and pelvis. Distant metastases of endometrial carcinoma are more common in the lung, liver, bone, central nervous system, and skin. The later tend to occur in the head and neck region, particularly the scalp. On occasion, the metastatic breast lobular carcinoma is seen involving a tamoxifen-associated endometrial polyp.