Uterus (myometrium & endometrium)

Menstrual cycle and the endometrium

Endometrium

The endometrium is divided into the basalis and functionalis. The basalis is a thin layer of endometrium attached to the underlying myometrium and stays constant over the menstrual cycle. The functionalis lies ontop of the basalis and changes in response to estrogen levels, it sheds during menstration when estrogen levels fall, and grows when estrogen levels increase.

Proliferation phase

At the end of menstration the endometrium is lined by a thin basal endometrium and a thin functionalis endometrium. At the start of the proliferative phase, the functional endometrium starts to thicken and there is glandular, stromal and vascular growth. During this time the glands are unifrom and with regular wide space in between them.
Histology

1. Wide and regular space between glands
2. Glands are uniform
   Tubular glands, can be mildly dilated
   The glands are lined with cuboidal or low-columnar epithelium / cells which is pseudostratified
   The nuclei is oval to rounded and basally placed. Small nucleoli might be seen.
   Mitotic figures are found in the glands
   Some epithelial cells might be ciliated apically.
   After the 8th day, the epithelium becomes more stratified and more mitotic figures are apparent. In the last days of the proliferative phase the glands might start to become more irregular, and subnuclear vacuoles might appear.
3. Stroma is densely cellular
   Stromal cells are small with oval and hyperchromatic nuclei
   Cell borders cannot be seen
   Mitotic figures might be seen (though not as many as in the glands)
   A few thin-walled vessel are seen
   Lymphoid aggrigates might be seen
   In the last days of the proliferative phase, you start to see edema in the stroma.

Secretory phase

During the secretory phase the endometrium continues to thicken and develop. The secretory phase is divided into:

1. The early secretory phase (day 16-18)
   Glands still have a tubular appearance and some mitotic activity. Subnuclear vacuoles start to appear, most often first in the midzone of the functionalis. In the end of this phase, subnuclear vacuoles are seen in almost all glandular cells. One can assume that ovulation has occurred if >50% of the glands have at least 50% of the cells with subnuclear vacuoles.
   Stroma is identical to late-proliferative phase stroma.
2. The mid-secretory phase (day 19-23)
   Glandular secreation increases during this phase, seen in the glandular lumina, and cytoplasmic vacules move to become supranuclear.
   Glands become angular
   Mitotic activity disappears
   Stromal edema increases, and will be most prominant in the mid-zone
   Spiral arteries appear, and stromal cells surrounding them have eosinophilic cytoplasm. these cells later become predecidual cells.
3. The late secretory phase (day 24-28)
   Now glands become serrated and tightly packed and predecidual stroma changes are more evident. Sometimes the precidual cells have a spindle cell appearance or even signet-ring cell morphology. Lymphocytes are seen infiltrating the stroma and even neutrophils may be seen.

Menstrual phase

1. Endometrial glands are serrated and start to collaps
2. Endometrial stroma is compact and starts to collaps into tighty aggregated balls with hyperchromatic nuclei, called "blue balls"
3. Other features: Necrotic debris, neutrophils, interstitial hemorrhage, fibrin, apoptotic debris.
The glands become tightly packed as the stroma breaks down, even assuming micropapillary morphology (called papillary syncytial metaplasia).

Endometrial polyps

Endometrial polyps are localized overgrowths of endometrial tissue that protrude into the uterine cavity. They can be sessile or pedunculated and vary in size from a few millimeters to several centimeters. They are most commonly found in women aged 40-50 years and are often associated with abnormal uterine bleeding, such as menorrhagia (heavy menstrual bleeding) or metrorrhagia (bleeding between periods). The exact cause of endometrial polyps is not well understood, but they are thought to be related to hormonal imbalances, particularly an excess of estrogen relative to progesterone. Risk factors for developing endometrial polyps include obesity, hypertension, and the use of tamoxifen (a medication used to treat breast cancer). While most endometrial polyps are benign, there is a small risk of malignancy, especially in postmenopausal women. Thus, polyps are often removed and examined histologically to rule out cancer.
Histology

1. Glands
   dilated and irregular, even focal crowding
   might see epithelial metaplasia
   often with proliferative activity (even in postmenopausal women)
2. Stroma
   more fibrous than the normal endometrium
   collections of thick-walled vessels
   you might see hyperplastic areas, but they should only be confined to a few areas of the polyp

Postmenopausal endometrium / Atrophic inactive endometrium

Lack of hormone production from the ovaries, leads to atrophic endometrium as the functionalis layer of the endometrium is no longer stimulated and only a thin layer of basalis endometrium remains. The histological appearance varies, but the endometrium is usually thin with glands that show no proliferative activity. Glands can vary, from being small atrophic tubules (often more prevalent in the immediate years following menopause) and widely spaced to cystically dilated (more often older women), or a combination of both. The glandular cells have small, round to ovoid, dark nuclei and can even be flat in cystic glands. You might see some degree of nuclear pseudostratification, but with no mitotic activity. Though, sometimes, a few mitotic figures can be seen, in women where menopause appears gradually and with uterine prolapse. The surrounding stroma can be densely cellular, but tends to become more fibrous and hypocellular with age. Lymphoid aggregates are often prominent.

Disordered proliferative endometrium

Is a benign endometrial change that occurs in response to prolonged estrogen stimulation without the counterbalancing effect of progesterone. This condition is often seen in women with anovulatory cycles, such as those with polycystic ovary syndrome (PCOS) or during perimenopause. In disordered proliferative endometrium, the endometrial glands exhibit irregularities in size, shape, and distribution, leading to a chaotic architectural pattern. The glands may be cystically dilated and show focal crowding and branching. The glandular epithelium typically displays proliferative morphology, but without secretions in the lumen. Tubal metaplasia, characterized by the presence of ciliated cells, is often observed in the glands. The surrounding stroma may show condensation, but lacks the cellular atypia seen in hyperplasia. It is important to distinguish disordered proliferative endometrium from simple endometrial hyperplasia, as the latter carries a risk of progression to endometrial carcinoma. The key differentiating feature is the extent of glandular dilatation; in disordered proliferative endometrium, the dilated glands are focal, whereas in simple hyperplasia, they are more extensive.
Histology

1. normal to gland stroma ratio is most often normal, but focal glandular crowding and branching may be seen.
2. Proliferative morphology but with cystically dilated and irregular glands focally and without secretions in the lumen. These glands often have tubal metaplasia.
3. You might see stromal condensation

If you see a significant number of dilated glands, it is more likely to be simple hyperplasia. In disordered proliferative endometrium the dilated gland are a focal in nature, while simple hyperplasia is more extensive.

Endometrial hyperplasia

With unopposed estrogen stimulation there is a risk for endometrial hyperplasia. Endometrial hyperplasia is characterized by an increased gland-to-stroma ratio compared to normal proliferative endometrium. The glands may vary in size and shape, and can be cystically dilated. Based on the architectural complexity and the presence or absence of nuclear atypia, endometrial hyperplasia is classified into three main types:
Simple endometrial hyperplasia without atypia Responds well to therapy with progestins (oral pills, injections or with intrauterine device). Has a low risk of progression to endometrial carcinoma.

1. Increased gland/stroma ratio
2. Glands most often vary in size and shape and cystically dilated
3. Only focal crowding of the glands
4. Glands are stratified and columnar with light-blue/amphophilic cytoplasm. Nuclei are elongated
5. Mitotic activity varies
6. Stroma is cellular, more cellular than found in normal proliferative endometrium

Complex endometrial hyperplasia without atypia Treated similarly to simple endometrial hyperplasia without atypia, with progestins. Has a slightly higher risk of progression to endometrial carcinoma compared to simple hyperplasia without atypia. Control biopsies are often performed to ensure regression of the hyperplasia.

1. Increased gland/stroma ratio
2. Glands can be tubular with or without dilated and more complexed with branching and irreglar outlines
3. Glands are more crowded, and even back to back, with little stroma in between
4. Glands are stratified, up to four layers
5. Mitotic activity varies
6. Nuclei are oval and resemble those found in normal glands, mitotic activity can be increased
7. Stroma is cellular and cells are spindle in shape as the stroma is compressed between glands
8. you might see foamy lipid-laden macrophages

Atypical hyperplasia Here you will find endometrial hyperplasia, like in simple and complex endometrial hyperplasia, but you will also find glands with nuclear atypia. One should not confuse metaplastic glands with atypia. For example in tubal metaplasia you might find nuclear enlargement and round nuclei, that can even be vesicular. Treatment is often hysterectomy, especially in women who have completed their family planning. In women who wish to preserve fertility, high-dose progestins can be tried, but with close follow-up with endometrial biopsies as the risk of progression to endometrial carcinoma is high.

1. Nuclear atypia: Cells are stratified with loss of polarity. The nucleus is enlarged, with irregular contours and with coarse or vesicular chromatin. Sometimes with obvious nucleoli

Atypical polypoid adenomyoma

1. Glands with variable architectural complexity
2. Some nuclear atypia
3. Squamous morules is a constant feature
4. Glands surrounded by smooth muscle (not cytogenic stroma, like in hyperplasia)

Endometrial metaplasia

Is a response to estrogen or progesteron stimulation. Metaplasia can be diffuse when accompanied by hyperplasia. Metaplasia is often seen in anovulation, polyps, endometritis and trauma.

1. Papillary Syncytial metaplasia
2. Eosinophilic and ciliated cell metaplasia
3. Mucinous metaplasia
4. Hobnail metaplasia
5. Squamous metaplasia

Carcinom in the endometrium

How to identify carcinoma in the endometrium?

1. Stroma shows desmoplastic reaction => the stroma is more fibrous with spindle shaped cells and elongated nuclei with eosinophilic cytoplasm. However, do not forget that the stroma of a endometrial polyp is often fibrous.
2. Glands are confluent and form a complex labyrinth, sometimes even cribiform or forming complex papillary patterns.
3. Extensive squamous epithelium with minimal atypia, is only considered a sign of invasion if the stroma around shows desmoplastic reacion
4. Intraglandular fibrovascular cores in papillary formation is a sign of papillary hyperplasia, and not cancer.

Gestational trophoblastic disease

Hydatidiform mole

There are two forms of hydatidiform moles depending on the number of chromosomes; complete where the cells are diploid (have 46 chromosomes, all paternal) and partial where the cells are triploid (contain 69 chromosomes; 23 maternal and 46 paternal)

Complete hydatidiform mole

hydrophic swelling of most villi (edema), from a few mm in diameter to 3 cm. Some have central cistern formation, a central acellular space
trophoblastic proliferation around the villi with atypia, and outgrowths of cells (syncytiotrophoblasts and cyncytiotrophoblasts). This proliferation can be diffuse or only focal
usually no fetal tissue
the villous stroma has a pale-blue color with widely separated spindle cells and many blood vessels
Implantation site contains intermediate trophoblastic cells that have more atypical features with higher proliferative activity

Partial hydatidiform mole

There is a mixture of two different villi; normal-sized and enlarged edematous villi occationally with central cisterns (acellular space) and irregular contours. The small villi often show fibrosis
focal trophoblastic hyperplasia is seen, but in lesser extend than in complete hydatidiform mole, and with minimal atypia
invaginations or inclusions in the stroma
embryo/fetus may be seen often abnormal features