Uterine disorders: Pathology review

Definitions & Key takeaways

Uterine disorders are conditions that affect the uterus, the female reproductive organ that is responsible for gestating a fertilized egg. Common uterine disorders endometritis, asherman syndrome, endometrial hyperplasia, endometrial polyps, endometriosis, and leiomyomas.

Endometritis refers to the acute or chronic inflammation of the endometrium due to invasion by bacteria normally found in the lower genital tract. Asherman syndrome involves intrauterine adhesions following procedures like dilation and curettage and can result in amenorrhea, infertility, or recurrent pregnancy loss. Endometrial hyperplasia is the excessive growth of the endometrial glands, most commonly caused by long-standing increased exposure to estrogen without the counteracting effect of progesterone.

There is also endometrial cancer, which is a type of cancer that begins in the lining of the uterus, called the endometrium. There can also be endometrial polyps, which are benign growths of the endometrial glands and stroma that protrude into the uterine cavity. Next, there is endometriosis in which there is the presence of endometrial tissue outside the endometrial cavity, usually on the ovaries, causing pelvic pain and bleeding that gets worse during menstruation. Finally, there are leiomyomas or uterine fibroids, which are extremely common benign smooth muscle tumors that usually develop in premenopausal women, in response to estrogen. Leiomyomas can present with abnormal uterine bleeding, pain, iron deficiency anemia, or fertility issues.

Chapters:

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Case Study 0:00–0:51

29-year-old Carmen presents to the physician’s office complaining of severe lower abdominal pain during her menstrual periods as well as pain during intercourse.
She has been trying unsuccessfully to get pregnant for the first time for the past 2 years. Pelvic examination shows a normal sized uterus.
Later that day, 44-year-old Susanna comes to her physician reporting heavy menstrual periods that last about 10 days. This has been occurring for the past 6 months and is accompanied with a feeling of “fullness” in the lower abdomen as well as fatigue.
On further history, she has never been pregnant. Physical examination shows an enlarged uterus with multiple round masses.
Laboratory studies reveal iron deficiency anemia.Based on the initial presentation, Carmen and Susanna both have some form of uterine disorder.

Embryology0:51–1:29

Let’s first review physiology real quick. The uterus consists of 3 layers, an outer layer called the perimetrium or the serosa, a middle smooth muscle layer called the myometrium, and the innermost layer, the endometrium.
The endometrium has two layers, an inner functional layer made up mainly of glands and supporting connective tissue, called stroma, and an outer thin basal layer which regenerates the overlying functional layer after each menstrual cycle.

Endometritis1:29–3:50

Okay, now, the first uterine disorder is endometritis or inflammation of the endometrium. This is usually caused by normal bacterial flora of the lower genital tract, meaning the cervix, vagina or external genital organs, that travel upwards into the endometrium.
A high yield risk factor to remember is the retention of products of conception, like parts of the placental or fetal tissues, following delivery or abortion.
Another risk factor is the presence of a foreign body, like an intrauterine contraceptive device. Both can provide a good environment for bacteria to grow and cause an infection in the uterus.
Less commonly, endometritis can be caused by outside bacteria such as Chlamydia trachomatis or Neisseria gonorrhoeae, which are transmitted sexually, or Mycobacterium tuberculosis, which spreads from the lungs into the blood and travels to other organs such as the uterus.
Now, endometritis can be acute or chronic. On your test, an individual with acute endometritis, typically presents with symptoms like fever, abnormal uterine bleeding, lower abdominal pain, dysuria, which is painful urination, or dyspareunia, which means pain during sexual intercourse.
In contrast, in chronic endometritis, people often have no symptoms and normal physical examination, however, some may experience similar symptoms to those of acute endometritis, although milder.
Diagnosis of is usually based on clinical findings. An endometrial biopsy can help make the diagnosis, although it’s not routinely done.
What you absolutely have to remember is that microscopic examination of acute endometritis shows neutrophils in the endometrium, which are the hallmark of acute inflammation, while in chronic endometritis, the presence of lymphocytes, especially plasma cells, in the endometrium is diagnostic.
When endometritis is caused by tuberculosis, an additional finding is the presence of granulomas in the endometrium, which is why it’s also called chronic granulomatous endometritis.
Treatment of endometritis is based on antibiotics. Next, there is Asherman syndrome.

Asherman Syndrome3:50–4:39

This occurs when the basal layer of the endometrium undergoes fibrosis so it’s unable to regenerate the functional layer.
Sections of the normal tissue in the uterus is replaced by multiple bands of collagen which leads to intrauterine adhesions where the bands make the uterine walls stick to each other.
This whole process causes the endometrium to fail to respond to hormonal stimulation, leading to amenorrhea, or the absence of menstrual bleeding.
In severe cases, these fibrous bands can cover the whole uterus, causing infertility or recurrent pregnancy loss. Now, for your exams, it’s important to remember that this typically occurs in a female who has undergone uterine instrumentation in the past, like dilation and curettage.

Endometrial Hyperplasia4:39–6:53

Another uterine disorder that’s high yield is endometrial hyperplasia. This is hyperplasia or excessive growth of the endometrial glands.
What drives this process, in most cases, is long- standing increased exposure to estrogen without the counteracting effect of progesterone.
For your exams, it’s important to remember that this can be caused by a variety of conditions such as obesity, where the extra adipose tissue converts androgens to estrogen.
It could also be caused by estrogen secreting tumors, such as granulosa cell tumors of the ovaries. People with polycystic ovarian syndrome are also at risk of endometrial hyperplasia.
In this condition, the ovary is full of cystic follicles that secrete estrogen. To make things even worse, these follicles don’t ovulate most of the time, a condition known as chronic anovulation, so there’s no luteal body to secrete progesterone.
Now, a person could have normal estrogen production throughout their life, but the number of years the endometrium is exposed to estrogen is also a risk factor for developing endometrial hyperplasia.
Estrogen exposure is increased in people who have an early menarche, which is the age of the first menses, or those that have a late menopause.
This is because these people have experienced a greater number of menstrual cycles, where more follicles have grown, and more estrogen were secreted by these follicles.
The same goes for females who have never given birth, also called nulliparous, who are at a higher risk than those who have been pregnant.
That’s because, during pregnancy, there’s more estrogen and progesterone production, but the balance shifts towards more progesterone, which is protective against endometrial hyperplasia.
Also, we have medications that can cause endometrial hyperplasia, such as estrogen-only hormone replacement therapy, usually taken by postmenopausal females to relieve menopause symptoms, such as hot flashes and vaginal dryness.
In some cases, endometrial hyperplasia can also be caused by tamoxifen, a breast cancer medication which blocks estrogen receptors on the breast, but at the same time, stimulates those on the endometrium.
The number one concerning problem with endometrial hyperplasia is that it increases the risk for endometrial cancer, which is the most common cancer arising from the female reproductive system.

Endometrial Cancer6:53–12:18

The risk of developing endometrial cancer depends on the histological features of the cells undergoing hyperplasia. So, zooming into a section of the endometrium, hyperplasia can be simple, where there’s a lot of dilated glands and stroma, but their ratio is similar to normal tissue.In complex hyperplasia there are way more glands and less stroma, meaning a high gland-to-stroma-ratio, and this type of hyperplasia is more at risk of progression to endometrial cancer.
If we zoom in even more, we can see the nuclei inside these glandular cells.Αbnormal nuclear features, like larger and hyperchromatic or darker nuclei, are called nuclear atypia, which, for your test, is the most important factor in terms of progression to endometrial cancer.
Now, there are two main types of endometrial cancer. The most common one, accounting for about 75% of all cases, is Type 1 endometrial carcinoma, which is also called endometrioid carcinoma.
That’s because the classic histology is “endometrioid”, meaning that the cancer cell looks very much like the normal endometrial cells.
And this is the one that can arise from endometrial hyperplasia and is linked to prolonged unopposed estrogen exposure. Now, another risk factor is age, since this type of endometrial cancer typically presents in postmenopausal individuals, around 55 to 65 years of age.
In addition, a family history of ovarian cancer, colon cancer, or other gastrointestinal cancers can be a hint for an autosomal dominant disorder known as hereditary nonpolyposis colorectal cancer or Lynch syndrome, where you are also at a higher risk for developing endometrial cancer.
Another high-yield fact is that type 1 endometrial cancer usually involves several genetic mutations in endometrial cells, including loss of PTEN, a tumor suppressor gene.
This promotes growth and replication of endometrial cells or enhance the expression of genes which are linked to estrogen receptors.
Type 2 makes up the remaining 25% of endometrial carcinoma and it has a number of subtypes. The most common subtype is serous carcinoma.
Under the microscope, serous carcinomas often form papillary or finger-like structures. On biopsy, they often contain psammoma bodies, which are circular plaques of calcium deposits around necrotic or dead cells.
What you need to remember is that type 2 carcinomas don’t appear to be linked with estrogen levels. In contrast, these cancers typically affect females with endometrial atrophy.
Another important distinction is that they also tend to develop later in life than Type 1, usually around the age of 70.
However, they are more aggressive. For your exams, it’s also important to know that the genetic mutations found most often in serous carcinoma involve the TP53 gene, another tumor suppressor, and aneuploidy, or an abnormal number of chromosomes after cell division.
Alright, let’s talk about symptoms! Both endometrial hyperplasia and endometrial carcinoma typically present with menorrhagia, which means heavy or prolonged menstrual bleeding, metrorrhagia, bleeding between menstrual cycles, or a combination of both known as menometrorrhagia.
Both of these are usually painless. So, a high yield concept is that any painless vaginal bleeding in a postmenopausal female could be a sign of endometrial hyperplasia or cancer!
If we’re dealing with a more advanced endometrial cancer, there might be enlargement of the whole uterus and if the tumor or tumors are large enough, this can cause abdominal pain and cramping.Diagnosing endometrial hyperplasia or cancer usually involves doing a transvaginal ultrasound to determine the thickness of the endometrium.
Afterwards, then a biopsy is used to confirm the diagnosis.Treatment for endometrial hyperplasia includes eliminating the underlying cause of excess estrogen, such as weight loss in cases of obesity, stopping unopposed estrogen therapy and correcting the problem of anovulation in cases of polycystic ovarian syndrome.
Also, progesterone containing medications can be used, which help in counteracting the proliferative effect of estrogen.
For endometrial cancer, treatment is based on surgery. This typically means the removal of the uterus, both ovaries, and both fallopian tubes, also called a hysterectomy with bilateral salpingo-oophorectomy, combined with the removal of pelvic and para-aortic lymph nodes.
In some cases where the cancer is more advanced or is likely to spread, radiation therapy and/or chemotherapy can be also done after surgery.Okay, next, endometrial polyps are benign growths of the endometrial glands and stroma that protrude into the uterine cavity.

Endometrial Polyps12:18–12:59

What’s especially high-yield is that they are more frequent in females who are on tamoxifen therapy. So, in your test question, the typical individual with endometrial polyp will also have a history of breast cancer treatment.
Now, endometrial polyps may be asymptomatic or present with abnormal uterine bleeding. Diagnosis involves a transvaginal ultrasound which can help identify the polyp, and then treatment requires a hysteroscopy, which is done to remove it.

Endometriosis12:59–17:13

Moving on to endometriosis. This when endometrial tissue migrates outside the endometrial cavity and implants themselves in other parts of the body.
Although we are unsure of why this happens, the most common theory is retrograde menstruation. This suggests that during menstruation, some blood carrying endometrial cells will flow backwards into the fallopian tubes and implant into nearby tissue.
Alternatively, the metaplastic theory suggests that cells of the peritoneum, which come from the same cell line as endometrial cells, can transform spontaneously into endometrial tissue.
And then there’s also the benign metastases theory, which says that endometrial cells can travel to distant organs through the lymph and blood.
In any case, once there, endometrial cells will set up camp and start growing to form a mass of endometrial tissue. For your exams, it’s important to know that most often, this affects the ovaries bilaterally, which classically results in formation of a blood- filled 'chocolate' cyst.
But it can also affect other structures in the pelvis and abdomen like the fallopian tubes, the uterine ligaments, the rectouterine pouch, also called the pouch of Douglas, and even the bladder or the intestines!
Another high-yield fact is that these implants classically appear grossly as yellow-brown 'gun- powder' nodules. Now, symptoms of endometriosis are related to the location of the endometrial cells.
Most commonly, endometriosis on the reproductive organs will cause pelvic pain, bleeding, dysmenorrhea, or painful menstruation, and dyspareunia, or painful sexual intercourse.
If it involves the pouch of Douglas, it can cause dyschezia, or pain with defecation. It can also cause urgent, frequent and sometimes painful urination if it involves the bladder, and abdominal pain if involves the intestines.
The most important thing to keep in mind is that all of these symptoms will often vary with the hormone changes throughout the menstrual cycle, and often gets worse during menstrual periods.
Another high-yield fact is that fertility problems are especially common in individuals with endometriosis. The exact link is unclear but it’s believed that the inflammation that comes with endometriosis can damage or scar the ovaries or fallopian tubes thus inhibiting the release of the egg or its movement during ovulation.
Damage to the uterus can also make the implantation of the gamete more difficult. Okay, now, diagnosis starts with pelvic examination, where it’s important to remember that the uterus will be normal sized.
This is followed by laparoscopy, and confirmed with a biopsy. Treatment is focused on managing pain, trying to limit the progression of the implants, and addressing the associated subfertility.
Common medications that are used to treat pain include: combined estrogen- progesterone oral contraceptive pills, which relieve pain through ovarian suppression; progesterone analogs like medroxyprogesterone and levonorgestrel, which inhibit growth of the endometrium; danazol, which is a steroid that inhibits mid-cycle surges of follicular stimulating hormone and luteinizing hormone; and gonadotropin releasing hormone modulators, which causes a decrease in estrogen levels.
Surgical options are available for severe cases. If the woman still wants to have children, the surgery involves only excision of endometrial implants, endometriomas, and adhesions.
If the person has completed their childbearing or if the pain is too debilitating, a hysterectomy and oophorectomy, which is removal of the uterus and ovaries, along with excision of any other endometrial implants is done.
Whatever the treatment, it’s also important to remember that, once menopause hits and hormone levels fall, the symptoms generally go away.
Adenomyosis is a specific form of endometriosis, in which endometrial tissue develops ectopically in the myometrium. Once again, this ectopic endometrial tissue responds to hormonal changes throughout the menstrual cycle just like the endometrium inside the uterine cavity.

Adenomyosis17:13–18:18

So with adenomyosis, there’s typically dysmenorrhea, or painful menstruation. Heavy menstrual bleeding and chronic pain may also be present.
Unlike other forms of endometriosis, remember that, on physical examination, the uterus will be uniformly enlarged, globular and boggy, meaning soft on palpation.
Another tricky thing is that the only definitive diagnosis for adenomyosis is histopathological analysis of the uterus after hysterectomy.
However, hysterectomy is only recommended in individuals who have completed childbearing. If the individual wishes to have children in the future, symptoms are usually managed with hormonal medication, like combined oral contraceptives and gonadotropin releasing hormone modulators.

Leiomyomas18:18–19:46

Okay, next, leiomyomas, also known as uterine fibroids, are benign tumors of smooth muscle. In fact, they are the most common gynecological tumor.
They can be classified based on where they are located in the uterus. For your exams, remember that they are the most common type are intramural fibroids, and they develop within the wall of the uterus.
Subserosal fibroids come from smooth muscle cells at the perimetrium. Submucosal fibroids come from smooth muscle cells just below the endometrium and they can grow into the cavity of the uterus and change the shape of it.
When that happens, they’re called pedunculated fibroids. Fibroids most commonly affect individuals of African descent.
They are related to estrogen exposure, so, the more estrogen available, the more a fibroid is likely to grow. This is why fibroids typically affect premenopausal females, between the ages of 20 and 40, and why they grow rapidly during pregnancy, when there’s a lot of estrogen around, and shrink with menopause.
Another risk factor for developing a fibroid is being nulliparous, early menarche and late menopause, just like the risk factors for endometrial hyperplasia.
Now, a high-yield fact is that fibroids most commonly develop in groups, although they can sometimes be solitary. Fibroids are usually small and asymptomatic, but large or numerous fibroids can cause symptoms like abnormal uterine bleeding, in the form of meno- or metrorrhagia.

Fibroids19:46–21:25

Over time this can lead to iron deficiency anemia in a premenopausal female. Fibroids can also cause abdominal pain or a feeling of “fullness”, by putting pressure on pelvic organs.
Submucosal and intramural fibroids, in particular, are also associated with infertility and a higher risk of miscarriage.
In pregnancy, fibroids can also cause issues such as fetal malpresentation, preterm labor, and postpartum hemorrhage. Diagnosis starts with a pelvic exam, which usually reveals an enlarged uterus with multiple palpable round masses, followed by an ultrasound.
Rarely, a biopsy of the mass is done. On gross examination, these are round, firm, and grayish-white in color, usually without any necrosis or hemorrhage.
And a high- yield fact for your test is that microscopic examination will classically show a whorled pattern of smooth muscle bundles, like a wave in the ocean, with well defined borders.
Treatment of uterine fibroids varies: asymptomatic uterine fibroids are usually left untreated, while symptomatic fibroids can be treated with surgery, either a myomectomy or a hysterectomy or uterine artery embolization, where a catheter is used to reduce blood flow to the fibroids and causes them to shrink.

Leiomyosarcoma21:25–22:42

Finally, the last type of uterine disorder is leiomyosarcoma, which is a very rare, malignant tumor of smooth muscle arising from the myometrium.
The most important thing to remember here is that it arises de novo, or on its own, meaning that leiomyomas do not progress into leiomyosarcomas.
Another key fact is that, unlike leiomyomas, which most commonly affect premenopausal individuals and go away after menopause, leiomyosarcomas usually develop in postmenopausal individuals.
Symptoms are typically similar and may include abnormal uterine bleeding and abdominal or pelvic pain or pressure. Diagnosis includes an ultrasound and a biopsy of the mass.
What’s high-yield here is that unlike leiomyomas, which are usually multiple and gross examination shows no necrosis or hemorrhage, leiomyosarcoma is classically a single lesion with necrosis and hemorrhage.
Microscopic examination of a leiomyosarcoma reveals increased mitotic activity, and cellular atypia. Treatment is surgical and may be combined with chemotherapy or radiotherapy.##SummaryAlright, as a quick recap, endometritis refers to the acute or chronic inflammation of the endometrium due to invasion by bacteria normally found in the lower genital tract.

Review22:42–24:54

Asherman syndrome involves intrauterine adhesions following procedures like dilation and curettage and can result in amenorrhea, infertility or recurrent pregnancy loss.
Endometrial hyperplasia is the excessive growth of the endometrial glands, most commonly caused by long-standing increased exposure to estrogen without the counteracting effect of progesterone.
Endometrial hyperplasia carries a risk of progression into endometrial cancer depending on the histological findings. Endometrial carcinoma has two types.
Type 1 is usually preceded by endometrial hyperplasia. Type 2 isn’t linked with estrogen levels, is usually associated with endometrial atrophy, and is more aggressive than type 1.
The most common symptom of both endometrial hyperplasia and cancer is abnormal vaginal bleeding after menopause. Endometrial polyps are benign growths of the endometrial glands and stroma that protrude into the uterine cavity and are commonly associated with tamoxifen therapy.
Endometriosis refers to the presence of endometrial tissue outside the endometrial cavity, usually on the ovaries, causing pelvic pain and bleeding that gets worse during menstruation.
A specific form of endometriosis is adenomyosis, in which there is endometrial tissue inside the myometrium. Leiomyomas or uterine fibroids, are extremely common benign smooth muscle tumors that usually develop in premenopausal individuals, in response to estrogen and can present with abnormal uterine bleeding, pain, iron deficiency anemia or fertility issues.
Leiomyosarcomas, on the other hand, are malignant tumors of the smooth muscle that develop de novo in postmenopausal individuals.Okay, let’s not forget about our cases.

Summary24:54–25:58

Carmen came in with dysmenorrhea and dyspareunia that get worse during menstruation, as well as fertility issues and a normal-sized uterus on pelvic examination.
This is a classic presentation of endometriosis. Indeed, laparoscopy showed bilateral “chocolate-cysts” in the ovaries, which were biopsied, to confirm the diagnosis.
On the other hand, Susanna presented with menometrorrhagia, a feeling of abdominal “fullness, an enlarged uterus with multiple round masses, and iron deficiency anemia, which are all characteristic for leiomyomas.
Other clues include that she’s premenopausal and nulliparous, which are both related risk factors. This was confirmed by ultrasound and biopsy, where gross examination showed round, firm, and grayish-white lesions, without any necrosis or hemorrhage, and microscopic examination revealed a whorled pattern of smooth muscle bundles with well- defined borders.
And microscopic examination revealed a