Overview

Endometrial hyperplasia involves the proliferation of endometrial glands that results in a greater than normal gland-to-stroma ratio. This results in varying degrees of architectural complexity and cytologic atypia. The clinical significance of this diagnosis is progression to or concurrent endometrioid endometrial adenocarcinoma.

This article reviews the classification, pathophysiology, clinical features, and treatment of endometrial hyperplasia.

For other information, see Medscape's Ob/Gyn & Women's Health Specialty Center.

Background

Endometrial hyperplasia is believed to produce a continuum of lesions that may be precursor to endometrial carcinoma of endometrioid histology. The classification of endometrial hyperplasia has had numerous terminologies. The classification below is currently the most commonly accepted system and is used by the World Health Organization (WHO) and the International Society of Gynecologic Pathologists. This system characterizes the glandular architectural pattern as simple or complex and describes the presence or absence of nuclear atypia.

Simple hyperplasia - Increased number of glands but regular glandular architecture Complex hyperplasia - Crowded irregular glands

Simple hyperplasia with atypia - Simple hyperplasia with presence of cytologic atypia (prominent nucleoli and nuclear pleomorphism)

Complex hyperplasia with atypia - Complex hyperplasia with cytologic atypia

The original study of 170 patients by Kurman et al found that lesions with varying degrees of complexity and presence of atypia, when left untreated, progressed to adenocarcinoma at different rates. Simple hyperplasia was associated with a 1% rate of progression to cancer, complex hyperplasia 3% rate of progression, simple atypical hyperplasia 8% rate of progression, whereas complex atypical hyperplasia had a 29% rate of progression to cancer.[1]

Not only does the concern exist for atypical hyperplasia progressing to invasive cancer if untreated, but numerous studies found coexisting carcinoma at rates ranging from 17-56%.[2, 3, 4, 5]

[6, 7, 8] A prospective Gynecologic Oncology Group study found that 306 patients with preoperative biopsies that diagnosed atypical endometrial hyperplasia had concurrent invasive adenocarcinoma in 42.6% of hysterectomy specimen.[9] Part of the difficulty in diagnosing concurrent carcinoma is due to lack of reproducibility in diagnosing hyperplasia, especially atypical hyperplasia versus adenocarcinoma among even expert gynecologic pathologists. Studies report only 40-69% interobserver agreement for hyperplasia or cancer.[10, 11, 12, 9]

Due to the poor reproducibility of diagnosis, gynecologic pathologists also proposed a simpler classification of endometrial hyperplasia versus endometrial intraepithelial neoplasia using a computerized morphometric analysis. Endometrial intraepithelial neoplasia is defined as when

the volume of glandular crowding is greater than the stromal volume, the presence of cytologic alterations, a lesion larger than 1 mm, and exclusion of mimics or carcinoma. Classification as complex atypical hyperplasia (WHO system) or as endometrial intraepithelial neoplasia had similar sensitivities and negative predictive values for coexisting endometrial cancer.[13]

Pathophysiology

Endometrial hyperplasia results from continuous estrogen stimulation that is unopposed by progesterone. This can be due to endogenous estrogen or exogenous estrogenic sources. Endogenous estrogen may be caused by chronic anovulation associated with polycystic ovary syndrome (PCOS) or perimenopause. Obesity also contributes to unopposed estrogen exposure due to chronic high levels of estradiol that result from aromatization of androgens in adipose tissue and conversion of androstenedione to estrone. Endometrial hyperplasia and cancer can also result from estradiol-secreting ovarian tumors such as granulosa cell tumors.

Exogenous estrogen without progesterone has been associated with increased endometrial hyperplasia and adenocarcinoma.[14] The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial found that unopposed estrogen exposure with 0.625 mg of conjugated equine estrogens increased the risk of complex hyperplasia by 22.7% and atypical hyperplasia by 11.8% over 3 years of use compared with a less than 1% increase in placebo controls. [15] The risk of endometrial cancer was not increased when 2.5 mg of medroxyprogesterone acetate was used in combination with 0.625 mg of conjugated equine estrogens in 8506 women in the Women's Health Initiative (WHI) study.[16] Tamoxifen, with its estrogenic effect on the endometrium, increases the risk of endometrial hyperplasia and endometrial cancer. The risk of progression to cancer is associated with an increased duration of use.[17]

The exact mechanism of estrogen's role in the transformation of normal endometrium to hyperplasia and cancer is unknown. Genetic alterations are known to be associated with hyperplasia and type I endometrial cancers. Lesions with hyperplasia are associated with microsatellite instability and defects in DNA mismatch repair genes. PTEN tumor suppressor gene mutations have also been found in 55% of hyperplasia cases and 83% of hyperplasia cases once it has progressed to endometrial cancer.[18]

Mortality/Morbidity

Endometrial carcinoma is the most common gynecologic malignancy and the fourth most common cancer in women in the United States. In 2013, the number of projected cases is 49,560 cases, leading to 8190 deaths.[19] Significant morbidity or mortality can occur if endometrial hyperplasia is untreated or concurrent malignancy is present.

Endometrial hyperplasia is often associated with irregular or heavy vaginal bleeding, which can lead to disruptions with quality of life. Occasionally, uterine hemorrhage occurs, which may necessitate medical or surgical intervention, loss of fertility, and blood transfusion therapy.

Sex

Endometrial hyperplasia only affects females.

Age

Endometrial hyperplasia is most frequently diagnosed in postmenopausal women, but women of any age can be at risk if they are exposed to a source of unopposed estrogen. Endometrial hyperplasia can frequently be seen in young women with chronic anovulation due to PCOS or obesity.

Clinical Features

Other risk factors for endometrial hyperplasia are the same as those for type I endometrial adenocarcinoma, including obesity, nulliparity, early menarche, and late menopause. While unopposed estrogen in oral contraceptive pills or estrogen replacement therapy increases the risk of hyperplasia and cancer, combination oral contraceptive pills and combination hormone replacement therapy does not increase and may decrease the risk of hyperplasia and cancer. The independent risk factors for predicting when endometrial hyperplasia coexists with cancer include age older than 53 years, postmenopausal status, diabetes, abnormal bleeding, body mass index (BMI) of 27 or more, and atypical hyperplasia.[6]

The most common clinical presentation of patients with endometrial hyperplasia is abnormal uterine bleeding, whether in the form of menorrhagia, metrorrhagia, or postmenopausal bleeding. Others present with abnormal vaginal discharge or Pap smear results showing glandular abnormalities. The abnormal Pap smear result may be atypical glandular cells or presence of atypical endometrial cells.

When abnormal bleeding is present, a full history and physical examination is warranted with careful examination of the lower genital tract for lesions of the vulva, vagina, cervix, and palpation of uterus and ovaries. The source of vaginal discharge or bleeding, the size of the uterus and endometrial cavity, and any pelvic masses should be noted. If the patient is obese and a pelvic examination is inadequate, pelvic ultrasonography may be helpful. A diagnostic procedure is needed to rule out hyperplasia or cancer if the patient is symptomatic or has abnormal cytology.

Diagnosis of endometrial hyperplasia is usually made by sampling the endometrial cavity with an endometrial biopsy in the office or dilation and curettage in the operating room. Tissue sampling should be performed in women with risk factors who present with symptoms of abnormal vaginal bleeding or discharge. This includes women older than 35 years with abnormal bleeding, women younger than 35 years with bleeding and risk factors, women with persistent bleeding, and women with unopposed estrogen replacement or tamoxifen therapy.

In addition, a biopsy should be performed in women with atypical glandular cells (AGC) Pap smear or endometrial cells in Pap smears of women older than 40 years when out of synch with menstrual cycle.[20, 21] While no evidence of improved survival has been documented, some also advocate routine screening by endometrial biopsy in asymptomatic women with hereditary

nonpolyposis colorectal cancer (HNPCC) syndrome or those on tamoxifen therapy. However, most of this high-risk population present with abnormal vaginal bleeding; thus, other experts recommend work-up when symptoms are present.

If a patient does not tolerate an office biopsy or has cervical stenosis, endovaginal ultrasonography is an effective method to assess thickness of the endometrial echo complex and to evaluate uterine bleeding. Endovaginal ultrasonography has a sensitivity of greater than 96% for ruling out endometrial carcinoma if the endometrial echo complex is less than 5 mm. Persistent bleeding, despite a thin stripe, still warrants tissue biopsy because of the risk of missing a type 2 cancer that is not associated with hyperplasia and thickening of the endometrial echo complex.[22] If hyperplasia is diagnosed by office biopsy, one should consider D&C hysteroscopy to rule out atypia or cancer prior to conservative medical management.

Treatment & Management

Once a tissue diagnosis of endometrial hyperplasia is made, treatment depends on the patient's symptoms such as degree of bleeding, presence of cytologic atypia, patient's surgical risks, and wish for future childbearing. Progestins can effectively treat endometrial hyperplasia to control bleeding and prevent progression to cancer. They can serve as prevention of recurrence in those with continued risk factors. Hyperplasia without atypia responds well to progestins. More than 98% of women with hyperplasia treated with cyclic progestins experienced regression of the disease in 3-6 months.[23]

The PEPI trial showed a 94% normalization of complex or atypical hyperplasia in 45 women treated with progestins.[15] One cohort study found that 115 patients with complex atypical hyperplasia had approximately 30% persistence or progression of disease whether treated with progestins or not. However, of 70 patients with atypical hyperplasia, 67% vs 27% had persistence or progression when not treated with progestins.[24]

Multiple regimens of progestin therapy have been found effective in reversing endometrial hyperplasia, including the following:

Medroxyprogesterone acetate (Provera), 10-20 mg qd, or cyclic 12-14 days per month Micronized vaginal progesterone (Prometrium), 100-200 mg qd or cyclic 12-14 days per

month

Levonorgestrel-containing IUD (Mirena), 1-5 years [25]

Megestrol acetate (Megace), 40-200 mg per day, usually reserved for women with atypical hyperplasia

The authors recommend Megace for atypical hyperplasia, with or without levonorgestrel IUD for patients wishing to preserve fertility or for those too ill for surgical management. Any progestin should be adequate for treatment of hyperplasia without atypia or for maintenance after resolution of atypical hyperplasia. If hyperplasia with atypia is found upon dilation and curettage

(D&C) or endometrial biopsy, definitive treatment with hysterectomy is recommended due to the high rate of concurrent endometrial cancer for surgical candidates.

Consider bilateral salpingo-oophorectomy in perimenopausal or postmenopausal women due to possibility of cancer on permanent section. However, if the patient has not completed childbearing or is not a surgical candidate, then concurrent cancer must first be ruled out by D&C with hysteroscopy prior to medical management.

Because D&C and pipelle biopsy only sample 50-60% of the endometrial lining, focal lesions containing adenocarcinoma may be missed. Biopsy is recommended after 3 months to check for response to medical therapy. Continued surveillance after regression of the lesion is recommended every 6-12 months, if risk factors persist. Repeat biopsy is also indicated for recurrent abnormal bleeding or discharge. Prevention of recurrence include daily or cyclic progesterone, along with weight loss for obese patients.

Due to the large number of young anovulatory women diagnosed with atypical hyperplasia or early endometrial cancer, numerous studies have examined the outcome of fertility-sparing hormonal therapy. A meta-analysis of 24 observational studies that included a total of 151 women with atypical hyperplasia found that those who had fertility-sparing treatments had 86% regression, 26% relapse, and live birth rate of 26%.[26]

Another review of complex atypical hyperplasia patients who underwent progestin therapy found a complete response rate of 66%. Median time to response was 6 months. Recurrence rate after initial response was 23%. During study follow-up time of 39 months, 41% of patients with atypical hyperplasia became pregnant.[27] Interest is increasing in the use of levonorgestrel-releasing intrauterine system (LNG-IUS) as a treatment option for endometrial hyperplasia to deliver local effect with less systemic side-effects. A 15-year study using the LNG-IUS for 34 patients with endometrial hyperplasia found regression to atrophic endometrium in 94%. However, this study had only 4 (12%) patients with atypical hyperplasia.[28]

A meta-analysis of 24 observational studies, including 1,001 cases, indicated that progestins appeared to induce a lower disease regression rate than LNG-IUS in the treatment of complex and atypical endometrial hyperplasia. However, a controlled clinical trial is necessary to confirm the observational findings.[29] The authors feel data using the LNG-IUD as the only treatment modality for atypical hyperplasia or endometrial cancer are limited.

As mentioned above, the Gynecologic Oncology Group pathologic study with biopsy diagnosis of atypical hyperplasia found 42.6% concurrent endometrial carcinoma on hysterectomy specimen; 31% of these had myometrial invasion, including 10.6% with outer half myometrial invasion.[9] Thus, if a hysterectomy is planned for treatment of atypical hyperplasia based on office endometrial biopsy, the authors recommend having a gynecologic oncologist on back-up for surgical staging if needed based on frozen section of uterine specimen.

One review found atypical endometrial hyperplasia was associated with a 44% cancer rate on frozen pathology and 56% cancer rate on permanent pathology. This confirms use of frozen pathology and the need for gynecologic oncology availability for staging or to be primary

surgeon.[8] The authors strongly recommend that the uterine specimen not be morcellated for staging purposes and to prevent metastatic disease if cancer is diagnosed. If a D&C hysteroscopy had been performed to rule out concurrent carcinoma definitively, oncology back-up is likely not needed. However, a study by Suh-Burgmann et al found that D&C may not definitively exclude cancer.[30]

The need for hysterectomy to exclude concurrent myoinvasive endometrioid adenocarcinoma presents a barrier to nonsurgical management of endometrial hyperplasia. A Gynecologic Oncology Group study examined the histomorphometric 4-class rule (4C), which measures epithelial abundance, thickness, and nuclear variation as applied to diagnostic biopsies to predict myoinvasive cancer outcomes at hysterectomy.[31] Women with endometrial biopsies or curettages with a community diagnosis of atypical endometrial hyperplasia were enrolled in a clinical trial in which subsequent hysterectomy was scored for endometrial adenocarcinoma, and 4C rule ability to predict cancer outcomes was measured.

Qualifying biopsies were stratified into high-risk and low-risk histomorphometric subgroups. Assignment to a high-risk category by 4C rule was highly sensitive in predicting any (71%) or deeply (92%) myoinvasive adenocarcinoma at hysterectomy, and assignment to a low-risk group had a high negative predictive value for absence of any (90%) or deeply (99%) myoinvasive disease.

At present, this use of histomorphometry is most suited to a centralized reference laboratory performing histomorphometry for a variety of diagnostic applications. However, in the future, formal histomorphometry of endometrial biopsies using the 4C rule may become a more common method to identify a subset of women with premalignant disease who are unlikely to have concurrent myoinvasive adenocarcinoma and therefore may qualify for nonsurgical therapy.

  From : Medscape Updated: Mar 15, 2013

Jing Wang Chiang, MD  Clinical Assistant Professor of Obstetrics and Gynecology, Stanford University School of Medicine; Chief of Gynecologic Oncology, Department of Obstetrics and Gynecology, Santa Clara Valley Medical Center

Jing Wang Chiang, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists and Society of Gynecologist Oncologist

 

1.  Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer. Jul 15 1985;56(2):403-12. [Medline].

2. Kurman RJ, Norris HJ. Evaluation of criteria for distinguishing atypical endometrial hyperplasia from well-differentiated carcinoma. Cancer. Jun 15 1982;49(12):2547-59. [Medline].

3. Janicek MF, Rosenshein NB. Invasive endometrial cancer in uteri resected for atypical endometrial hyperplasia. Gynecol Oncol. Mar 1994;52(3):373-8. [Medline].

4. Dunton CJ, Baak JP, Palazzo JP, van Diest PJ, McHugh M, Widra EA. Use of computerized morphometric analyses of endometrial hyperplasias in the prediction of coexistent cancer. Am J Obstet Gynecol. May 1996;174(5):1518-21. [Medline].

5. Horn LC, Schnurrbusch U, Bilek K, Hentschel B, Einenkel J. Risk of progression in complex and atypical endometrial hyperplasia: clinicopathologic analysis in cases with and without progestogen treatment. Int J Gynecol Cancer. Mar-Apr 2004;14(2):348-53. [Medline].

6. Chen YL, Wang KL, Chen MY, et al. Risk factor analysis of coexisting endometrial carcinoma in patients with endometrial hyperplasia: a retrospective observational study of Taiwanese Gynecologic Oncology Group. J Gynecol Oncol. Jan 2013;24(1):14-20. [Medline]. [Full Text].

7. Rakha E, Wong SC, Soomro I, et al. Clinical outcome of atypical endometrial hyperplasia diagnosed on an endometrial biopsy: institutional experience and review of literature. Am J Surg Pathol. Nov 2012;36(11):1683-90. [Medline].

8. Morotti M, Menada MV, Moioli M, Sala P, Maffeo I, Abete L. Frozen section pathology at time of hysterectomy accurately predicts endometrial cancer in patients with preoperative diagnosis of atypical endometrial hyperplasia. Gynecol Oncol. Jun 2012;125(3):536-40. [Medline].

9. Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer. Feb 15 2006;106(4):812-9. [Medline].

10. Bergeron C, Nogales FF, Masseroli M, et al. A multicentric European study testing the reproducibility of the WHO classification of endometrial hyperplasia with a proposal of a simplified working classification for biopsy and curettage specimens. Am J Surg Pathol. Sep 1999;23(9):1102-8. [Medline].

11. Kendall BS, Ronnett BM, Isacson C, et al. Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma. Am J Surg Pathol. Aug 1998;22(8):1012-9. [Medline].

12. Zaino RJ, Kauderer J, Trimble CL, et al. Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer. Feb 15 2006;106(4):804-11. [Medline].

13. Salman MC, Usubutun A, Boynukalin K, Yuce K. Comparison of WHO and endometrial intraepithelial neoplasia classifications in predicting the presence of coexistent malignancy in endometrial hyperplasia. J Gynecol Oncol. Jun 2010;21(2):97-101. [Medline]. [Full Text].

14. Lethaby A, Suckling J, Barlow D, Farquhar CM, Jepson RG, Roberts H. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev. 2004;CD000402. [Medline].

15. 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. Feb 7 1996;275(5):370-5. [Medline].

16. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA. Oct 1 2003;290(13):1739-48. [Medline].

17. Cohen I. Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol. Aug 2004;94(2):256-66. [Medline].

18. Sherman ME. Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol. Mar 2000;13(3):295-308. [Medline].

19. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. Jan 2013;63(1):11-30. [Medline].

20. Wu HH, Schuetz MJ 3rd, Cramer H. Significance of benign endometrial cells in Pap smears from postmenopausal women. J Reprod Med. Sep 2001;46(9):795-8. [Medline].

21. Siebers AG, Verbeek AL, Massuger LF, Grefte JM, Bulten J. Normal appearing endometrial cells in cervical smears of asymptomatic postmenopausal women have predictive value for significant endometrial pathology. Int J Gynecol Cancer. May-Jun 2006;16(3):1069-74. [Medline].

22. Wang J, Wieslander C, Hansen G, Cass I, Vasilev S, Holschneider CH. Thin endometrial echo complex on ultrasound does not reliably exclude type 2 endometrial cancers. Gynecol Oncol. Apr 2006;101(1):120-5. [Medline].

23. Gambrell RD Jr. Progestogens in estrogen-replacement therapy. Clin Obstet Gynecol. Dec 1995;38(4):890-901. [Medline].

24. Reed S, Voigt L, Newton K, et al. Progestin therapy of complex endometrial hyperplasia with and without atypia. Obstet Gynecol. March 2009;113:655-662.

25. Buttini MJ, Jordan SJ, Webb PM. The effect of the levonorgestrel releasing intrauterine system on endometrial hyperplasia: an Australian study and systematic review. Aust N Z J Obstet Gynaecol. Jun 2009;49(3):316-22. [Medline].

26. Gallos ID, Yap J, Rajkhowa M, et al. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol. Oct 2012;207(4):266.e1-12. [Medline].

27. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol. May 2012;125(2):477-82. [Medline].

28. Scarselli G, Bargelli G, Taddei GL, et al. Levonorgestrel-releasing intrauterine system (LNG-IUS) as an effective treatment option for endometrial hyperplasia: a 15-year follow-up study. Fertil Steril. Jan 2011;95(1):420-2. [Medline].

29. Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK, Coomarasamy A, Gupta JK. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol. Dec 2010;203(6):547.e1-10. [Medline]. [Full Text].

30. Suh-Burgmann E, Hung YY, Armstrong MA. Complex atypical endometrial hyperplasia: the risk of unrecognized adenocarcinoma and value of preoperative dilation and curettage. Obstet Gynecol. Sep 2009;114(3):523-9. [Medline].

31. Mutter GL, Kauderer J, Baak JP, Alberts D. Biopsy histomorphometry predicts uterine myoinvasion by endometrial carcinoma: a Gynecologic Oncology Group study. Hum Pathol. Jun 2008;39(6):866-74. [Medline]. [Full Text].

 

Precancerous conditions of the uterusPrecancerous conditions of the uterus have the potential to develop into uterine cancer.

Atypical endometrial hyperplasia

Atypical endometrial hyperplasia is an overgrowth of abnormal cells that line the uterus. Sometimes polyps that grow in the uterus will have atypical endometrial hyperplasia. Atypical endometrial hyperplasia can progress from endometrial hyperplasia, which is an overgrowth of normal cells that line the uterus. Approximately one-third of women with atypical endometrial hyperplasia will develop uterine cancer.

Risk factors

The following risk factors may increase a woman's chance of developing atypical endometrial hyperplasia.

growing older hormone replacement therapy with estrogen only

obesity

late menopause

early menarche (first menstruation)

history of menstrual problems

previous pelvic radiation

use of tamoxifen (Nolvadex, Tamofen) for breast cancer

never having children

not ovulating

endometrial hyperplasia

Signs and symptoms

The most common symptom of atypical endometrial hyperplasia is abnormal vaginal bleeding. Women may also present with abnormal vaginal discharge or abnormal Pap test results, but this is less common.

Diagnosis

If a woman has abnormal vaginal bleeding, or if the doctor suspects atypical endometrial hyperplasia, a sample of the endometrium (lining of the uterus) is taken for a biopsy or dilation and curettage (D&C).

Treatment

Treatment for atypical endometrial hyperplasia depends on:

the degree of cell abnormality symptoms, such as amount of bleeding

surgical risks

reproductive wishes of the woman

 

Treatment for post-menopausal women or those who are finished having children may include removal of the uterus (hysterectomy), Fallopian tubes and ovaries.

Treatment for women who want to keep their reproductive organs may include progesterone therapy.

From:

Almadrones L. Endometrial Cancer. Yarbro, C. H., Frogge, M. H. & Goodman, M. (2005). Cancer Nursing: Principles and Practice. (6th Edition). Sudbury, MA: Jones and Bartlett Publishers. 51: pp 1244-1257.

Chiang, J.W. & Wilcox, N.. Premalignant lesions of the endometrium. (2008, September 3). eMedicine.com. Omaha: eMedicine, Inc.

Chu CS, Lin LL & Rubin SC. Cancer of the uterine body. Devita, V. T., Jr., Lawrence, T. S., & Rosenberg, S. A. (2008). Cancer: Principles & Practice of Oncology. (8th Edition). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 42.3: pp. 1543-1563.

Stern JL. Uterus: endometrial carcinoma. Ko, A. H., Dollinger, M., & Rosenbaum, E. (2008). Everyone's Guide to Cancer Therapy: How Cancer is Diagnosed, Treated and Managed Day to Day. (5th Edition). Kansas City: Andrews McMeel Publishing. 5: pp. 881-888.

WIKIPEDIA

Endometrial intraepithelial neoplasia, (EIN) is a premalignant lesion of the uterine lining that predisposes to endometrioid endometrial adenocarcinoma. It is composed of a collection of abnormal endometrial cells, arising from the glands that line the uterus, which have a tendency over time to progress to the most common form of uterine cancer — endometrial adenocarcinoma, endometrioid type.

History

EIN lesions have been discovered by a combination of molecular, histologic, and clinical outcome studies beginning in the 1990s which provide a multifaceted characterization of this disease. They are a subset of a larger mixed group of lesions previously called "endometrial hyperplasia [1] [2] " The EIN diagnostic schema is intended to replace the previous "endometrial hyperplasia" classification as defined by the World Health Organization in 1994, which have been separated into benign (benign endometrial hyperplasia) and premalignant (EIN) classes in accordance with their behavior and clinical management.EIN should not be confused with an unrelated entity, serous intraepithelial carcinoma ("serous EIC"), which is an early stage of a different tumor type known as papillary serous adenocarcinoma that also occurs in the same location within the uterus.

Clinical Aspects

The average age at time of EIN diagnosis is approximately 52 years, compared to approximately 61 years for carcinoma. The timeframe and likelihood of EIN progression to cancer, however, is not constant amongst all women. Some cases of EIN are first detected as residual premalignant disease in women who already have carcinoma, whereas other EIN lesions disappear entirely and never lead to cancer. For this reason, treatment benefits and risks must be individualized for each patient under the guidance of an experienced physician.Risk factors for development of EIN and the endometrioid type of endometrial carcinoma include exposure to estrogens without opposing progestins, obesity, diabetes, and rare hereditary conditions such as hereditary nonpolyposis colorectal cancer. Protective factors include use of combined oral contraceptive pills (low dose estrogen and progestin), and prior use of a contraceptive intrauterine device.

Biology

EIN lesions demonstrate all of the behaviors and characteristics of a premalignant, or precancerous, lesion.

Precancer Features of EIN (Table I). The cells of an EIN lesion are genetically different than normal and malignant tissues, and have a distinctive appearance under the light microscope. EIN cells are already neoplastic, demonstrating a monoclonal growth pattern and clonally distributed mutations. Progression of EIN to carcinoma, effectively a conversion from a benign neoplasm to

a malignant neoplasm, is accomplished through acquisition of additional mutations and accompanied by a change in behavior characterized by the ability to invade local tissues and metastasize to regional and distant sites.

Table I: Precancer Characteristics of EIN

Precancer Characteristics EIN Evidence

Precancers differ from normal tissue

Monoclonal EIN[3][4][5][6] arise from polyclonal normal field.[7]

Mutations are acquired in EIN.[6][8][9][10][11][12][13]

Precancers share some, but not all, features of cancer

EIN-cancer lineage hierarchy[14]

EIN may share PTEN,[11][13][15] K-ras,[9][10][12][16] MLH1[8]

[17] changes with cancer.

Both EIN and cancer are monoclonal.[3][5][6][18][19]

Precancers increase risk for carcinoma

Elevated concurrent cancer rate (39% in first year after EIN diagnosis)[20]

EIN elevates future cancer risk 45-fold.[20]

Precancers can be diagnosed

Morphometric reference standard (D-Score) for EIN diagnosis.[3][21][22][23]

Subjective EIN diagnosis using criteria (Table 2).[24]

Cancer must arise from cells within the precancer

EIN-cancer lineage hierarchy.[14]

EIN may share PTEN,[11][13][15] K-ras,[9][10][12][16] MLH1[8]

[17] changes with resultant cancer.

EIN Biomarkers. (Figure 1). There are no single biomarkers which are completely informative in recognition of EIN. The tumour suppressor gene PTEN is frequently inactivated in EIN, being abnormally turned off in approximately 2/3 of all EIN lesions. This can be seen with special tissue stains applied to histological sections known as PTEN immunohistochemistry, in which the brown PTEN protein is seen to be absent in the crowded tubular glands that make up an EIN lesion.

Diagnosis

Diagnosis of EIN lesions is of clinical importance because of the increased risk of coexisting (39% of women with EIN will be diagnosed with carcinoma within one year) or future (the long term endometrial cancer risk is 45 times greater for a woman with EIN compared to one with only a benign endometrial histology) endometrial cancer. Diagnostic terminology is that used by pathologists, physicians who diagnose human disease by examination of histologic preparations

of excised tissues. Critical distinctions in EIN diagnosis are separation from benign conditions such as benign endometrial hyperplasia (a field effect in endometrial tissue caused by excessive stimulation by the hormone estrogen), and cancer.The spectrum of disease which must be distinguished from EIN (Table II) includes benign endometrial hyperplasia and carcinoma:[2]

Table II: Disease classes that need to be distinguished from EIN.

DiseaseClass

EndometrialTopography

FunctionalCategory

Treatment

Benignendometrialhyperplasia

DiffuseHormone(estrogen)

EffectHormonal therapy

EIN,Endometrial

IntraepithelialNeoplasia

Focalprogressing to

diffuse(clonal)

PrecancerHormonal or

surgical

EndometrialAdenocarcinoma

Focalprogressing to

diffuse(clonal)

CancerSurgical

stage-based

EIN may be diagnosed by a trained pathologist by examination of tissue sections of the endometrium. All of the following diagnostic criteria must be met in a single area of one tissue fragment to make the diagnosis (Table III).

Table III: EIN diagnosis.

EIN Criterion Comments

1 Architecture Gland area exceeds that of stroma, usually in a localized region.

2CytologicalAlterations

Cytology differs between architecturally crowded focus and background.

3Size greater than 1mm

Minimum linear dimension should exceed 1mm. Smaller lesions have unknown natural history.

4 Exclude mimicsBasalis, normal secretory, polyps, repair, lower uterine segment, cystic atrophy, tangential sections, menstrual collapse, disruption artifact, etc.

5 Exclude CancerCarcinoma should be diagnosed if: glands are mazelike and rambling, there are solid areas of epithelial growth, or there are significant bridges or cribriform areas.

References

1.

Mutter GL, Duska L, Crum CP (2005). "Endometrial Intraepithelial Neoplasia". In Crum CP, Lee K. Diagnostic Gynecologic and Obstetric Pathology. Philadelphia PA: Saunders. pp. 493–518. Silverberg SG, Mutter GL, Kurman RJ, Kubik-Huch RA, Nogales F, Tavassoli FA (2003). "Tumors of the uterine corpus: epithelial tumors and related lesions". In Tavassoli FA, Stratton MR. WHO Classification of Tumors: Pathology and Genetics of Tumors of the Breast and Female Genital Organs. Lyon, France: IARC Press. pp. 221–232. Mutter GL, Baak JP, Crum CP, Richart RM, Ferenczy A, Faquin WC (March 2000). "Endometrial precancer diagnosis by histopathology, clonal analysis, and computerized morphometry". J. Pathol. 190 (4): 462–9. doi:10.1002/(SICI)1096-9896(200003)190:4<462::AID-PATH590>3.0.CO;2-D. PMID 10699996. Jovanovic AS, Boynton KA, Mutter GL (April 1996). "Uteri of women with endometrial carcinoma contain a histopathological spectrum of monoclonal putative precancers, some with microsatellite instability". Cancer Res. 56 (8): 1917–21. PMID 8620514

Treatment and Prognosis

ENDOMETRIAL HYPERPLASIA

Treatment of endometrial hyperplasia depends largely on the presence or absence of cellular atypia, as well as the patient's desire for future fertility.

Because of its benign course, endometrial hyperplasia without atypia is usually treated with hormonal intervention. Hyperplasia develops in the presence of unopposed estrogen. Therefore, the administration of a progestin is usually sufficient to counteract the effects of unopposed estrogen. Medroxyprogesterone acetate (Provera), 10 mg daily for 10 to 14 days per month, replicates the natural presence of progesterone in an ovulatory woman. Megestrol (Megace), 40 mg daily on a continuous basis, is also commonly administered.2

Endometrial hyperplasia with cellular atypia is considered a precancerous lesion with a 29 percent risk of developing into endometrial cancer.23 Endometrial cancer is a concurrent condition in 42.6 percent of women who have been diagnosed with atypical endometrial hyperplasia by endometrial biopsy.24 If a woman has completed childbearing, a hysterectomy should be recommended to rule out the presence of adenocarcinoma, as well as to prevent its future development. If the patient desires to retain fertility, a thorough evaluation of the endometrium should be performed to rule out a coexisting cancer. If no cancer is present, the patient may undergo high-dose progesterone therapy in an attempt to reverse the condition. This treatment option has also been described for women with well-differentiated adenocarcinomas.25,26 If treatment is successful, the patient may attempt pregnancy with close follow-up. After the patient has completed childbearing, a hysterectomy must be considered because of possible recurrence of atypical endometrial hyperplasia or endometrial cancer.

MEDIKAHiperplasia endometrium adalah suatu keadaan yang disebabkan oleh pertumbuhan yang berlebihan dari dinding uterus, yaitu endometrium. Hal ini menyebabkan jaringan endometrium menebal. Awalnya, pertumbuhan endometrium normal, tetapi karena beberapa hal, dapat terjadi perubahan yang sewaktu-waktu bisa mengarah ke kanker endometrium.

Hiperplasia endometrium disebabkan oleh ketidakseimbangan hormon estrogen dan progesteron, yang dihasilkan oleh ovarium. Perubahan level kedua hormon ini tiap bulan  mengatur siklus menstruasi. Tetapi, bila efek estrogen berlebihan atau tubuh memproduksi estrogen lebih banyak dari progesteron maka sel-sel endometrium akan terstimulasi untuk bertumbuh dengan sangat cepat.

Sejauh ini belum ada angka pasti ataupun perkiraan jumlah penderita hiperplasia endometrium yang pernah dilaporkan. Pemaparan endometrium terhadap estrogen secara terus menerus tanpa pemberian progesteron (disebut juga unopposed estrogen) adalah penyebab hiperplasia endometrium. Mengingat kelainan ini dapat berkembang menjadi keganasan maka dokter umum

perlu memiliki pengetahuan tentang kelainan ini sehingga dapat melakukan diagnosis dini dan rujukan yang tepat.