Endometrial diseases

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Morphological changes reflecting endocrine defects are commonly seen in the endometrium.

Histological examination of the endometrium is frequently undertaken as part of the investigation of disordered menstruation or infertility. The histological pattern of endometrium is correlated with the stated last date of menstrual period and with any relevant drug therapy. 

Among the most common abnormalities encountered in clinical practice is senile atrophy, seen after the menopause. Glands are simple, lined by inactive cuboidal cells and may form large cystic spaces. There is no evidence of mitotic activity, reflecting lack of oestrogenic stimulation.

Anovulatory cycles are common at the start and end of reproductive life. They are associated with irregular menstruation. The effects of excessive oestrogen stimulation are manifest in the endometrium as proliferation of glands.

Luteal-phase defect or irregular ripening is associated with infertility. This may be caused by failure of production of progesterone by the corpus luteum, or by defective receptors for progesterone within endometrium. Examination of the endometrium in the second half of the menstrual cycle shows inadequate or absent development of secretory changes in the endometrium.
Persistence of the corpus luteum at the end of the normal menstrual cycle causes failure of normal endometrial shedding, leading to abnormal uterine bleeding. Examination of the endometrium reveals a mixed pattern of menstrual-phase, secretory-phase and proliferative-phase patterns.
Oral contraceptive pills cause changes in the structure of the endometrium, which is greatly reduced in bulk. Glands become small and inactive, with poor development of the stroma.

Intrauterine contraceptive devices (IUCDs) are sometimes associated with chronic endometritis and Actinomyces infection.

Metaplasia of the endometrium is usually seen in post-menopausal women, arising less commonly in normal cycling endometrium. The main types are squamous metaplasia and metaplasia to epithelial patterns resembling tubal or endocervical epithelium. 

Acute endometritis is usually encountered as a complication of pregnancy

Chronic endometritis is usually associated with recent gestation, pelvic inflammatory disease, or IUCDs

Chronic endometritis may be associated with menstrual irregularities, but is also found in women who are being investigated for infertility. Histologically the endometrium shows lymphoid infiltration, with formation of plasma cells. The majority of cases are associated with a definite clinical risk factor for developing inflammation. The condition has occurred after recent pregnancy, miscarriage or instrumentation in 50% of cases, in association with pelvic inflammatory disease (e.g. salpingitis) in 25% of cases, and in association with previous use of IUCDs in about 20% of cases. In the remaining 5% of cases without a defined risk factor, chronic endometritis may be caused by gonococcal or chlamydial infection, or TB.

In tuberculous endometritis, because granulomas form only in secretory endometrium, they may not be seen in samples taken from early in the cycle. The condition is commonly part of more widespread infection involving fallopian tubes.

In adenomyosis, endometrium burrows deep within the wall of the uterus

Adenomyosis is a condition in which endometrium grows down to develop deep within the myometrium. The condition may cause enlargement of the uterus and is sometimes associated with menstrual abnormalities and dysmenorrhoea.

Macroscopically, small, irregular, pink areas, some with small cysts, are seen in the affected myometrium. Histologically, islands of endometrium are seen deep within muscle. If traced, these deep islands are found to be in continuity with surface endometrium. This process may affect the myometrium diffusely or may occur focally, producing apparently circumscribed nodules of hypertrophied muscle and deep endometrium (nodular adenomyosis).

Pathogenesis of endometriosis

Ectopic growth of endometrium outside the uterus is termed endometriosis

Endometriosis is a condition in which ectopic endometrium develops outside the uterine cavity. It affects 1 in 15 (7%) women of reproductive age, with associated infertility in about 30% of cases. The pathogenesis is discussed in the adjacent pink box.

The common sites for ectopic endometrial growth are ovaries, fallopian tubes, round ligaments, and pelvic peritoneum. Less common sites are intestinal wall, bladder, umbilicus, and laparotomy scars. Rarely, involvement of lymph nodes, lung and pleura is seen.

The ectopic endometrium still responds to cyclical hormonal stimulation, with phases of proliferation and breakdown with bleeding. The bleeding and breakdown stimulate the formation of fibrous adhesions and accumulation of haemosiderin pigment. 

Macroscopically, foci of endometriosis appear as cystic and solid masses, which are characteristically dark brown from iron pigment accumulated as a result of repeated bleeding. Histologically, endometrial glands and stroma are seen, together with fibrosis and macrophages containing iron pigment. 
Endometrial tissue growing in abnormal sites stimulates fibrosis and may cause fibrous adhesions between adjacent organs. When peritoneum is involved, adhesions may cause bowel obstruction.

The condition usually presents with cyclical pelvic pain, dysmenorrhoea, and infertility. When it affects the fallopian tubes and ovaries, the whole of the fallopian tube and ovary may be converted to a cystic mass containing brown, semi-liquid material (chocolate cyst).

Treatment by endocrine manipulation of endometrial growth is usually effective.

Endometrial polyps are localized overgrowths of endometrial glands and stroma

Endometrial polyps are very common and are usually seen in the peri-menopausal age range.

They are thought to be caused by over-proliferation of glands in response to oestrogenic stimuli.

Macroscopically they vary in size but are usually 1-3 cm in diameter and are usually sited in the uterine fundus. They appear as firm smooth nodules within the endometrial cavity, occasionally prolapsing through the cervical os.

Histologically they are made up of cystically dilated endometrial glands in a vascular stroma. They are clinically associated with menstrual abnormalities and dysmenorrhoea, but may develop ulceration or undergo torsion.

Endometrial hyperplasia is seen in response to oestrogenic stimulation. An endogenous response may be seen with successive anovulatory cycles or oestrogen-secreting tumours, and an exogenous response with oestrogen-containing drugs.

The importance of endometrial hyperplasia is that it is associated with an increased risk of development of adenocarcinoma of the endometrium. There are several histological types, simple hyperplasia being the most common pattern, diffusely affecting the whole endometrium. Proliferation of glands can be seen, with evident mitoses and stratification of cells. Glands grow in a regular tubular pattern, but are often dilated; however, there is no cytological atypia of the nuclei. This type is associated with a very slightly increased risk of malignancy after a long period of time, typically over 10 years.

Complex hyperplasia is almost always seen focally within the endometrium. There is obvious proliferation of epithelium, evident by mitotic figures, but the glands grow in an irregular pattern, with branched irregular contours and little intervening stroma. The cells forming the glands do not show cytological atypia. This type is associated with a slightly increased risk of development of malignancy.

Complex atypical hyperplasia is commonly seen only focally within the endometrium. Like complex hyperplasia, there is proliferation of epithelium, evident by mitotic figures, and the glands grow in an irregular pattern, with branched irregular contours. However, the cells forming the glands show cytological atypia, with pleomorphism and hyperchromatism. About 30% of cases with this pattern of hyperplasia will develop a carcinoma of the endometrium, usually within 5 years of diagnosis.

Endometrial carcinoma is the most common cancer of the female genital tract
Carcinomas of the endometrium are nearly all adenocarcinomas, with several histological subtypes. This type of carcinoma is the most frequent invasive malignancy in the female genital tract, accounting for about 7% of all tumours in women. Endometrial carcinoma can be divided into two main groups:
Tumours that occur at a time close to menopause, associated with endometrial hyperplasia and abnormal oestrogenic stimulation of the endometrium. This is the largest group and is associated with a generally good prognosis.

Tumours that occur in older, post-menopausal women, not associated with oestrogenic stimulation or endometrial hyperplasia. Tumours in this group are more often associated with a poor prognosis.
Macroscopically, small tumours appear as diffuse, solid areas or polypoid lesions in the endometrium, whereas larger tumours fill and distend the endometrial cavity with soft, white, friable tissue. Necrosis of tumour is common and leads to a frequent presenting feature of post-menopausal bleeding.

Most tumours associated with oestrogenic excess are endometrioid adenocarcinomas (60% of all cases). These can be graded (I-III) according to the amount of glandular and solid pattern with tumour. A high grade is associated with worse prognosis. In some cases, areas of squamous metaplasia or true squamous carcinoma (adenosquamous carcinoma) are also present.

Two other main types of tumour are seen, mostly in the non-oestrogen-related post-menopausal group. Uterine papillary serous carcinoma is a highly aggressive tumour. 

Even in the absence of significant myometrial or vascular invasion, recurrence, widespread metastasis and death may occur. Uterine clear-cell carcinoma also behaves in a highly malignant fashion.

Spread of carcinoma of the uterus is mainly by local invasion. In cases of direct invasion a factor that has a close correlation with prognosis is invasion into the myometrium. Tumours with a small depth of invasion have a better prognosis than those showing involvement of most of the thickness of the myometrium. Progressive local invasion leads to parametrial involvement and later spread to bladder and rectum.

Spread along lumen of fallopian tubes leads to frequent involvement of ovaries, and with venous and lymphatic invasion there may be involvement of the vagina and para-aortic nodes. Widespread haematogenous metastasis is uncommon, except with papillary serous carcinomas and clear-cell carcinomas.

Tumours of endometrial stroma may be pure or seen as part of mixed tumours

Under 2% of all uterine tumours involve neoplastic proliferation of the stromal element of the endometrium. These tumours are thought to be derived from primitive Mnllerian cells that can variably differentiate into endometrial stroma, epithelium, or support tissues. Tumours present as expansile masses within the uterine cavity, causing post-menopausal bleeding; with the more malignant tumours, there is evidence of dissemination.

Endometrial stromal sarcoma is composed of malignant stromal spindle cells and can be graded from low to high.

Adenosarcoma contains malignant stroma and a histologically benign epithelial component. Tumours commonly recur after hysterectomy.

Carcinosarcoma (malignant mixed Mnllerian tumour)} has both malignant stromal and epithelial components. Often the stromal component contains tissues not normally seen in the uterus, e.g. cartilage, fat and skeletal muscle. This typically occurs in elderly women and has an extremely poor prognosis.
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