Endometrial Hyperplasia

Simple endometrial hyperplasia - low mag[1]

Endometrial hyperplasia refers to the abnormal proliferation of glandular and stromal components of the endometrium. This growth is much more than the normal proliferation of the endometrium during menstrual periods.


Presentation

Abnormal vaginal bleeding is one of the most common manifestations of this condition. This may be in the form of intermenstrual bleeding, polymenorrhea, or postmenopausal bleeding. Endometrial hyperplasia may also be found associated with polyps with non-polypoid endometrium [4]. The symptoms are mostly encountered at the time of menarche or postmenopause, as the hormones are slightly out of balance in both tempo and amount. It may also be found in young women who have anovulatory cycles [5]. With the progress of endometrial proliferation, abnormal bleeding may become more frequent. It may also become a continuous feature in some. Abnormal vaginal discharge and glandular abnormalities in the Pap smear are other common features of this hyperplasia [6].

Workup

A complete medical history and a thorough physical examination is recommended when abnormal bleeding is present. Source of bleeding, size of endometrium, and presence of any kind of pelvic mass also should be noted. Pelvic ultrasonography is suggested for obese patients. Endometrial biopsy is the most common diagnostic procedure for endometrial hyperplasia. This can be done in the clinic or in the operating room by dilatation and curettage (D&C). Tissue sampling is suggested for women who present with symptoms like abnormal vaginal bleeding or discharge, and also have risk factors for the condition. Thus biopsy is opted for women with

  • Abnormal bleeding and is older than 35 years
  • Abnormal bleeding and major risk factors, but is younger than 35 years
  • Persistent bleeding
  • Unopposed estrogen therapy 
  • Tamoxifen therapy 

Biopsy is also recommended in women with atypical glandular cells, as revealed by Pap smear [7].
Those on tamoxifen therapy and hereditary nonpolyposis colorectal cancer syndrome should have routine screening. If biopsy cannot be recommended, endovaginal ultrasonography is used to assess the thickness of endometrium and also to evaluate vaginal bleeding. Transvaginal ultrasound has more than 96% sensitivity in identifying the risk of endometrial cancer in women with postmenopausal bleeding. Chances of cancer increase with increase in the thickness of endometrium. Risk of cancer is 7.3% when the thickness is more than 5 mm [8]. If clinical suspicion is high for a person, both hysteroscopy and biopsy are recommended [9]. Confirmatory diagnosis of endometrial hyperplasia is done by biopsy. MRI is used in cases where transvaginal ultrasound scan is not possible or when endometrial carcinoma is suspected.

Treatment

Treatment methods are based on factors like extent of abnormal vaginal bleeding, risks associated with surgery, and the wish to have a child in future. Bleeding can be controlled by progestins and this would also help in controlling progression of the disease. Progestins are also helpful in preventing recurrence, particularly in hyperplasia without atypia. Progestins help to resolve the symptoms within 3-6 months [10]. Progestins can be delivered by levonorgestrel intrauterine system. A study showed that 94% of the patients with atypical hyperplasia showed regression with progestins [11]. About 30% of the patients with oral treatment showed a relapse, while the rate was 14% with intrauterine system. For those who wish to have a child, megestrol acetate is recommended. For hyperplasia with atypia, hysterectomy is recommended due to increased risk of developing endometrial cancer, particularly in surgical candidates.
If the patient wishes to have a child in future, or is not a suitable candidate for surgery, chances of concurrent cancer should be ruled out before treatment. Biopsy is often repeated after 3 months to check for response to therapy. Monitoring is continued every 6-12 months after regression of the disease. This is particularly important if there are risk factors present. Biopsy should be repeated if there is recurrent bleeding or vaginal discharge. Recurrence can be prevented by the use of cyclic or daily progesterone. The two surgical methods in the treatment of endometrial hyperplasia include transcervical resection of the endometrium and hysterectomy.

Prognosis

Primary consideration in the prognosis of this condition is the risk associated with it, particularly the risk of progression to endometrial cancer. Atypia hyperplasia, both simple and complex, have increased risk of developing into cancer. The risk is about 8-10% in simple hyperplasia with atypia, while it is 25-30% with complex hyperplasia with atypia. Rate of spontaneous regression is about 80% in cases without atypia, and 50% with complex hyperplasia with atypia. With good patient compliance, an effective long-term therapy is now available for the control of endometrial hyperplasia. Treatment initiation and maintenance can now be done in an outpatient basis.

Etiology

Imbalance of hormones, particularly estrogen and progesterone, is often implicated in the development of this condition. Chronic anovulation, and estrogen therapy, both of which increase the chance of unopposed estrogen stimulation, are major risk factors of this condition. Unopposed estrogen stimulation increase the risk of endometrial hyperplasia four- to eight-fold. Obesity and nulliparity also increase the risk three times. Other risk factors include diabetes, polycystic ovarian syndrome and use of tamoxifen. Hereditary non-polyposis colorectal carcinoma and estrogen-secreting ovarian tumor are also associated with increased chances of abnormal endometrial proliferation. Atypical hyperplasia have a higher risk of developing into endometrial carcinoma [1]. There is a 30% increase of endometrial carcinoma if there are histological changes. Diagnostic difficulties often pose a challenge in reporting the risk [2].

Epidemiology

Hyperplasia is found to be more prevalent than endometrial cancer, and about 10-25% of the women with postmenopausal bleeding have a chance of developing endometrial hyperplasia. No genetic pattern has been implicated in the development of abnormal endometrial proliferation. It is more prevalent in late reproductive and early menopausal stages of women. About 1-3 percent of the women with this condition may develop endometrial cancer.

Sex distribution
Age distribution

Pathophysiology

The extent of histological changes often indicate the duration and quantity of exposure to unopposed estrogen. Endometrial proliferation is characterized by histological changes, particularly vascular thrombi, stromal breakdown, and scattered cytological changes. Rate of apoptosis of glandular cells in endometrial hyperplasia is similar to that of normal endometrial proliferation. But stromal apoptosis decreases considerably when compared to that of proliferative endometrium. The decrease in stromal apoptosis often results in heavy shedding of cells.
Simple hyperplasia is characterized by increased volume of endometrium. The glandular cells in simple hyperplasia are rounded, and show variation in the cystically dilated forms. Epithelial lining is often pseudostratified and do not have atypia of nucleus. Glandular proliferation is higher in complex hyperplasia. The cells are more crowded and irregular in shape and size. Nuclear atypia is absent in this case too. The cells usually have ‘finger in glove’ appearance because of the presence of side buds and out-pouchings. Atypical hyperplasia affects the glandular cells and not the stromal cells. It is generally localized in nature, but occasionally may be seen as multifocal or diffuse. Epithelium of the gland cells becomes irregularly stratified. Nuclear polarity of the cells are also lost. Stromal cells are relatively reduced in number and present back-to-back arrangement of the gland cells. Epithelial cells show irregular nuclear membrane and has characteristic macronucleoli [3].

Prevention

Endometrial hyperplasia cannot be prevented. Women should ideally do pelvic examinations regularly to detect and treat abnormalities, if any. Estrogen replacement therapy should be accompanied by progestins. Regular monitoring through biopsies and ultrasound assessments is also needed during estrogen therapy. Since obesity is one of the risk factor for the development of the condition, losing weight helps to prevent abnormal proliferation of cells in endometrium. Regular exercise and healthy diet also reduces the risk of this disease.

Summary

Endometrial hyperplasia refers to the abnormal proliferation of glandular and stromal components of the endometrium. This growth is much more than the normal proliferation of the endometrium during menstrual periods. It is characterized by change in histology of the tissues and these alterations differentiate it from normal endometrial proliferation. Endometrial hyperplasia is a major precursor of endometrial cancer. Hyperplasia is of four types – simple, complex, simple atypia, and complex atypia – depending on the risk it presents for progression to cancer. Many of these hyperplasia are benign and may not develop into cancer. Hormonal imbalance like chronic estrogen stimulation increases endometrial proliferation. It mostly affects young women and those nearing menopause. Cases of endometrial hyperplasia respond well to treatment and thus have a good prognosis.

Patient Information

Endometrial hyperplasia refers to the thickening of uterine wall due to an increase in the number of endometrial glands. It is usually seen in young women who is near menarche and older women who are approaching menopause. Most cases of endometrial hyperplasia is not serious and patients respond well to treatment with hormones or surgery. Hormonal imbalance is one of the most common causes of the disease. Unopposed estrogen therapy, taking estrogen without progesterone, is associated with an increased risk of endometrial hyperplasia in menopausal women. Women with irregular menstrual cycle also have increased chances of having this condition. Some other risk factors associated with the disease include age older than 35 years, never having been pregnant, older age at menopause, early age menarche, diabetes mellitus, polycystic ovary syndrome, obesity, and a family history of ovarian, colon or uterine cancer.
Abnormal bleeding between periods or after menopause, heavy vaginal bleeding, absence of menstrual periods, and menstrual periods without ovulation are some of the most common symptoms of hyperplasia in endometrium. Medical history and a thorough physical examination are the first steps in the diagnosis. Biopsy of the uterine tissue is performed after pelvic examination. Tissue samples from the uterine lining can be obtained through D&C. Increase in the thickness of the uterine wall can be assessed using pelvic ultrasound. Hysteroscopy is used to detect abnormal areas in the uterine lining and also to remove tissues for assessment.
In most of the cases, excess uterine tissue is removed during D&C. Postmenopausal women who are on estrogen therapy, but with recurrent endometrial hyperplasia, is recommended to have progestin supplement. Occasionally, it is suggested to stop estrogen therapy. In premenopausal women progestin therapy helps to thin the endometrial lining. Postmenopausal women who have a high risk of endometrial cancer are suggested to have surgical removal of uterus. This is particularly important in women who do not respond to progestin therapy. It may also be used in premenopausal women who no longer wish to have children.
Prevention of endometrial hyperplasia is not possible, but early detection and treatment have a good prognosis. Young women at menarche and women at menopause should have regular pelvic examinations. Losing weight, daily exercise and a healthy diet can be useful in controlling the progression of the disease.

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References

  1. Lacey JV Jr, Sherman ME, Rush BB, et al; Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol. 2010 Feb 10;28(5):788-92. doi: 10.1200/JCO.2009.24.1315. Epub 2010 Jan 11.
  2. Lacey JV Jr, Chia VM; Endometrial hyperplasia and the risk of progression to carcinoma. Maturitas. 2009 May 20;63(1):3 9-44.
  3. Silverberg SG. Problems in differential diagnosis of endometrial hyperplasia and carcinoma. Mod Pathol. 2000;13: 309-327. 
  4. Kelly P, Dobbs SP, McCluggage WG; Endometrial hyperplasia involving endometrial polyps: report of a series and discussion of the significance in an endometrial biopsy specimen. BJOG. 2007 Aug;114(8):944-50. 
  5. Mutter GL. The Endometrial Collaborative Group: Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? Gynecol oncol. 2007;76: 287-290. 
  6. Chiang JW. Premalignant lesions of the endometrium. 2008; eMedicine. Available: http://emedicine.medscape. com/article/269919-overview
  7. Wu HH, Schuetz MJ 3rd, Cramer H. Significance of benign endometrial cells in Pap smears from postmenopausal women. J Reprod Med. 2001;46(9):795-8.
  8. Smith-Bindman R, Weiss E, Feldstein V; How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound Obstet Gynecol. 2004;24(5):558-65.
  9. Litta P, Merlin F, Saccardi C, et al. Role of hysteroscopy with endometrial biopsy to rule out endometrial cancer in postmenopausal women with abnormal uterine bleeding. Maturitas. 2005 Feb 14;50(2):117-23.
  10. Gambrell RD Jr. Progestogens in estrogen-replacement therapy. Clin Obstet Gynecol. Dec 1995;38(4):890-901. 
  11. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA. 1996;275(5):370-5.

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