Inflammation
The endometrium and myometrium are relatively resistant to infections, primarily because the endocervix normally forms a barrier to ascending infection. Thus, although chronic inflammation in the cervix is an expected and frequently insignificant finding, it is a concern in the endometrium, excluding the menstrual phase.
Acute endometritis is uncommon and limited to bacterial infections that arise after delivery or miscarriage. Retained products of conception are the usual predisposing influence, causative agents including group A hemolytic streptococci, staphylococci, and other bacteria.
The inflammatory response is chiefly limited to the interstitium and is entirely non-specific. Removal of the retained gestational fragments by curettage is promptly followed by remission of the infection.
CHRONIC ENDOMETRITIS
Chronic inflammation of the endometrium occurs in the following settings:
(1) in patients suffering from chronic PID.
(2) in patients with postpartal or postabortal endometrial cavities, usually due to retained gestational tissue.
(3) in patients with intrauterine contraceptive devices.
(4) in patients with tuberculosis, either from miliary spread or, more commonly, from drainage of tuberculous salpingitis. The last is distinctly rare in Western countries. The chronic endometritis in all these cases represents a secondary disease, and under these circumstances there is a plausible cause.
Endometriosis and Adenomyosis
Endometriosis is the term used to describe the presence of endometrial glands or stroma in abnormal locations outside the uterus.
It occurs in the following sites, in descending order of frequency:
(1) ovaries; (2) uterine ligaments; (3) rectovaginal septum; (4) pelvic peritoneum; (5) laparotomy scars; and (6) rarely in the umbilicus, vagina, vulva, or appendix.
A closely related disorder, adenomyosis, is defined as the presence of endometrial tissue in the uterine wall (myometrium). Adenomyosis remains in continuity with the endometrium, presumably signifying downgrowth of endometrial tissue into and between the smooth muscle fascicles of the myometrium. Adenomyosis occurs in up to 20% of uteri. On microscopic examination, irregular nests of endometrial stroma, with or without glands, are arranged within the myometrium, separated from the basalis by at least 2 to 3 mm.
In some patients, the most important consequence of adenomyosis is shedding of the endometrium during the menstrual cycle . Hemorrhage within these small adenomyotic nests results in menorrhagia, colicky dysmenorrhea, dyspareunia, and pelvic pain, particularly during the premenstrual period.
Theory of edometriosis:
The regurgitation/implantation theory. Retrograde menstruation through the fallopian tubes occurs regularly even in normal women and could mediate spread of endometrial tissue to the peritoneal cavity. Endometriosis is common in the cervical mucosa, particularly following surgical procedures, supporting implantation from above.
The metaplastic theory. Endometrium could arise directly from coelomic epithelium, from which the müllerian ducts and ultimately the endometrium itself originate during embryonic development.
The vascular or lymphatic dissemination theory. Dissemination through pelvic veins and lymphatics would explain the presence of endometriotic lesions in the lungs or lymph nodes, a phenomenon not readily explainable by the first two theories.
Morphology:
The foci of endometrium respond to both extrinsic cyclic (ovarian) and intrinsic hormonal stimulation with periodic bleeding.
This produces nodules with a red-blue to yellow-brown appearance on or just beneath the serosal surfaces in the site of involvement. When the disease is extensive, organizing hemorrhage causes extensive fibrous adhesions between tubes, ovaries, and other structures and obliteration of the pouch of Douglas. The ovaries may become markedly distorted by large cystic masses (3 to 5 cm in diameter) filled with brown blood debris (chocolate cysts).
The histologic diagnosis of endometriosis is usually straightforward but may be difficult in long-standing cases in which the endometrial tissue is obscured by the fibro-obliterative response. A histologic diagnosis of endometriosis is satisfied if endometrial stroma is present, or in its absence, müllerian epithelium with subjacent hemosiderin pigment.
Clinical Course:
Clinical signs and symptoms usually consist of severe dysmenorrhea, dyspareunia, and pelvic pain due to the intrapelvic bleeding and periuterine adhesions.
Pain on defecation indicates rectal wall involvement, and dysuria reflects involvement of the serosa of the bladder.
Intestinal disturbances may appear when the small intestine is affected. Menstrual irregularities are common, and infertility is the presenting complaint in 30% to 40% of women. Malignancies may develop in endometriotic lesions at any site, prompting theories that endometriosis is an "at-risk" epithelium.
Endometrial Polyps
Endometrial polyps are sessile masses of variable size that project into the endometrial cavity. They may be single or multiple and are usually 0.5 to 3 cm in diameter but occasionally large and pedunculated.
Polyps may be asymptomatic or may cause abnormal bleeding if they ulcerate or undergo necrosis. They are generally of two histologic types, made up of (1) functional endometrium, paralleling the adjacent cycling endometrium, or (2) more commonly, hyperplastic endometrium, mostly of the cystic variety. Such polyps may develop in association with generalized endometrial hyperplasia and are responsive to the growth effect of estrogen but exhibit no progesterone response.
Rarely, adenocarcinomas may arise within endometrial polyps.
Endometrial polyps have been observed in association with the administration of tamoxifen, an antiestrogen frequently used in the therapy of breast cancer.
Cytogenetic studies indicate that the stromal cells in endometrial polyps are clonal, with chromosome (6p21) rearrangements, indicating that genetic alterations may play a role in their development.
Endometrial Hyperplasia
(Endometrial Intraepithelial Neoplasia)
Endometrial hyperplasia—recently termed endometrial intraepithelial neoplasia—is another cause of abnormal bleeding that differs from typical anovulation by an increased gland to stroma ratio and abnormalities in epithleial growth relative to normal endometrium.
Endometrial hyperplasia deserves special attention because of its relationship with endometrial carcinoma.
Numerous studies have largely confirmed the malignant potential of certain endometrial hyperplasias and the concept of a continuum of glandular atypia culminating, in some cases, in carcinoma.
Endometrial hyperplasia is linked to prolonged estrogen stimulation of the endometrium by anovulation or increased estrogen production. Conditions promoting hyperplasia include menopause, polycystic ovarian disease (including Stein-Leventhal syndrome), functioning granulosa cell tumors of the ovary, excessive cortical function (cortical stroma hyperplasia), and prolonged administration of estrogenic substances (estrogen replacement therapy). These are the same influences postulated to be of pathogenetic significance in some endometrial carcinomas, discussed later.
A key factor in the development of endometrial hyperplasia and related cancers is inactivation of the PTEN tumor suppressor gene through deletion and/or inactivation.
It encodes a phosphatase with dual lipid and protein specificity Its most important function is as a lipid phosphatase blocking Akt phosphorylation in the P13K pathway.
Unopposed estrogens normally increase native endometrial gland PTEN protein production, which is constantly expressed during the proliferative phase but is absent during the secretory phase. In the absence of PTEN endometrial cells become more sensitive to stimulation by estrogens, and this may be integral to the development of hyperplasias and subsequent cancer PTEN inactivation is seen in 63% of premalignant endometrial hyperplasias and 50% to 80% of endometrial carcinomas. It should also be noted that PTEN loss has been documented in some normal-appearing endometrial glands of 43% of premenopausal women.
The latter observation suggests that loss of PTEN expression may be an early step in endometrial carcinogenesis.
Morphology.
Endometrial hyperplasia has traditionally been subdivided into lower grade (simple) and higher grade (atypical) subgroups. Currently the lower-grade hyperplasias include both anovulatory epithelium and, less commonly, subtle endometrial intraepithelial neoplasms (EIN). In contrast, higher-grade hyperplasias, also termed atypical hyperplasias, typically have the morphologic features (gland crowding and cytologic atypia) and genetic characteristics (PTEN mutations) of intraepithelial neoplasia.
Simple non-atypical hyperplasias:
also known as cystic or mild hyperplasias, are characterized by architectural changes in glands of various sizes, producing irregularity in gland shape, with cystic alterations. The epithelial growth pattern and cytology are similar to those of proliferative endometrium, although mitoses are not as prominent .
These lesions uncommonly progress to adenocarcinoma and largely reflect a response to persistent estrogen stimulation. These simple cystic "hyperplasias" frequently evolve into cystic atrophy in which both the epithelium and stroma become atrophic.
Complex atypical hyperplasias (endometrial intraepithelial neoplasias)
exhibit an increase in the number and size of endometrial glands, with gland crowding, enlargement, and irregular shape. The latter is principally a manifestation of increased cell stratification and nuclear enlargement and may demonstrate complexity of the lining epithelium with scalloped or tufted surface. The glands remain distinct and non-confluent, characteristic of an intraepithelial neoplasm Mitotic figures are common. Predictably, in the most severe forms, cytologic and architectural atypia may border on adenocarcinoma, and an accurate distinction between atypical hyperplasia and cancer may not be made without hysterectomy.
Malignant Tumors of the Endometrium
CARCINOMA OF THE ENDOMETRIUM
Endometrial carcinoma is the most common invasive cancer of the female genital tract and accounts for 7% of all invasive cancer in women, excluding skin cancer. At one time, it was far less common than cancer of the cervix, but earlier detection and eradication of CIN and an increase in endometrial carcinomas in younger age groups have reversed this ratio.
Despite their high frequency, endometrial cancers arise mainly in postmenopausal women, causing abnormal (postmenopausal) bleeding. This permits early detection and cure at an early stage.
Incidence and Pathogenesis.
Carcinoma of the endometrium is uncommon in women younger than 40 years of age. The peak incidence is in the 55- to 65-year-old woman. A higher frequency of this form of neoplasia is seen with (1) obesity, (2) diabetes (abnormal glucose tolerance is found in more than 60%), (3) hypertension, and (4) infertility (women who develop cancer of the endometrium tend to be single and nulliparous and to have a history of functional menstrual irregularities consistent with anovulatory cycles). Infrequently, both endometrial and breast carcinomas arise in the same patient.
In terms of potential pathogenesis, two general groups of endometrial cancer can be identified. The first develops on a background of prolonged estrogen stimulation and endometrial hyperplasia.
The close relationship between hyperplasia and cancer of the endometrium in this setting is supported by the following: