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Uterine disorders: Pathology review

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Uterine disorders: Pathology review

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USMLE® Step 1 style questions USMLE

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A 55-year-old woman presents to the office because of vaginal spotting, abdominal distention and constipation for the past 3 months. She is also having difficulty defecating and often has to put her index and middle finger in her vagina to aid in pushing the stools out. Menopause was at age 48. Past history is significant for breast cancer treated by breast-sparing mastectomy and tamoxifen. Vitals are within normal limits. BMI is 33 kg/m2. Physical examination shows an enlarged irregular uterus and normal rectal tone. Transvaginal doppler ultrasound shows mixed echogenic masses with increased vascularity and central necrosis, bulging into the uterine cavity. Hysterectomy is performed which reveals a poorly-demarcated large yellow soft mass with areas of hemorrhage and necrosis. Histology of the specimen is shown.  


Reproduced from: Wikimedia Commons  
Which of the following is the most likely diagnosis in this patient?  

Transcript

Content Reviewers:

Yifan Xiao, MD

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.

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.

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.

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.

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.

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.

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.

Sources
  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Schwartz's Principles of Surgery" F.C. Brunicardi (2018)
  4. "Williams Gynecology, Third Edition" McGraw-Hill Education / Medical (2016)
  5. "Echogenic Endometrial Fluid Collection in Postmenopausal Women Is a Significant Risk Factor for Disease" Journal of Ultrasound in Medicine (2005)
  6. "Invasive implantation and intimate placental associations in a placentotrophic african lizard, Trachylepis ivensi (scincidae)" Journal of Morphology (2011)
  7. "Review: Chronic endometritis and its effect on reproduction" Journal of Obstetrics and Gynaecology Research (2019)