Endometrial intraepithelial neoplasia
Jump to navigation
Jump to search
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]
Synonyms and keywords: Atypical endometrial hyperplasia; Minimal uterine serous cancer (MUSC); Serous endometrial intraepithelial carcinoma (EIC); MUSC; Minimal uterine serous cancer
Overview
Endometrial intraepithelial neoplasia lesions was first described in the 1990s. Endometrial hyperplasia may be classified according to new World Health Organization (WHO2014) into two groups; hyperplasia without atypia (non-neoplastic) and atypical hyperplasia (endometrial intraepithelial neoplasm). Endometrial intraepithelial neoplasia arises from premalignant endometrial glands , which are risk of transmutatain to endometrial edometrioid carcinoma. Inactivation (mutation or deletion) of the PTEN tumor suppressor gene, inactivation of PAX2 gene, KRAS mutations, Microsatellite instability, Mutation in p53 gene are involved in the pathogenesis of endometrial intraepithelial neoplasia (EIN). Endometrial intraepithelial neoplasia may be caused by estrogenic stimulation of the endometrium that is unopposed by progestin. On microscopic histopathological analysis, individual glands are lined by a single layer of pseudostratified epithelium which is a characteristic finding of endometrial intraepithelial neoplasia. In 2002, the incidence of endometrial intraepithelial neoplasia (EIN) was estimated to be 144 cases per 100,000 individuals worldwide. The hallmark symptom of endometrial intraepithelial neoplasia is postmenopausal abnormal uterine bleeding. There are no specific laboratory findings associated with endometrial intraepithelial neoplasia. Transvaginal ultrasonography is the imaging modality of choice for endometrial intraepithelial neoplasia. Progestin therapy is recommended among patients with endometrial intraepithelial neoplasia. Hysterectomy is the mainstay of treatment for endometrial intraepithelial neoplasia to prevent endometrial carcinoma.
Historaical Perspective
- Endometrial intraepithelial neoplasia was first discovered through a combination of molecular, histologic, and clinical outcome studies beginning in the 1990s which provided a multifaceted characterization of this disease.
- EIN is a subset of a larger mixed group of lesions previously called "endometrial hyperplasia" The Endometrial intraepithelial neoplasia diagnostic scheme was intended to replace the previous "endometrial hyperplasia" classification as defined by the World Health Organization in 1994, which has been divided into benign (benign endometrial hyperplasia) and premalignant (EIN) classes in accordance to their behavior and clinical management.[1][2]
Classification
- Endometrial hyperplasia may be classified according to the new World Health Organization (WHO 2014) classification into two groups:[3]
- Hyperplasia without atypia (non-neoplastic)
- Atypical hyperplasia (endometrial intraepithelial neoplasm)
- Endometrial hyperplasia may be classified according to new World Health Organization (WHO1994) into 4 groups:[4]
- Simple hyperplasia without atypia
- Complex hyperplasia without atypia
- Simple atypical hyperplasia
- Complex atypical hyperplasia
Pathophysiology
- Endometrial intraepithelial neoplasia arises from premalignant glands , which risk of transmutatain to endometrial endometrioid carcinoma.[5]
- Genes involved in the pathogenesis of endometrial intraepithelial neoplasia (EIN) includ:[6][7][8][9][10]
- Inactivation (mutation or deletion) of the PTEN tumor suppressor gene
- Inactivation of PAX2 gene
- KRAS mutations
- Microsatellite instability
- Mutation in p53 gene
- On microscopic histopathological analysis, individual glands are lined by a single layer of pseudostratified epithelium which is a characteristic finding of endometrial intraepithelial neoplasia.[11][12]
Causes
- Endometrial intraepithelial neoplasia may be caused by estrogenic stimulation of the endometrium unopposed by progestins.[13]
Differentiating Endometrial intraepithelial neoplasia from other Diseases
- Endometrial intraepithelial neoplasia must be differentiated from other causes of postmenopausal differentiated from:[11][14]
- Benign (non atypical hyperplasia)
- Benign endometrial metaplasia (tubal, secretory, mucinous)
- Endometrial glandular dysplasia
- Hyperplastic polyps
- Metastatic carcinoma
- Serous clear cell carcinoma
Epidemiology and Demographics
Prevalence and Incidence
- In 2002, the incidence of endometrial intraepithelial neoplasia (EIN) was estimated to be 144 cases per 100,000 individuals worldwide.[15]
Age
- The incidence of endometrial intraepithelial neoplasia (EIN) increases with age; the median age at diagnosis is 52 years.[16]
Race
- Endometrial intraepithelial neoplasia (EIN) usually affects individuals of the African American race. Asian individuals are less likely to develop endometrial intraepithelial neoplasia.[17]
Risk Factors
- The most potent risk factor in the development of endometrial intraepithelial neoplasia (EIN) is exposure to endogenous (exogenous estrogen without opposing by a progestin).[18]
- Other risk factors include:[19][20][21][22][23][24]
- Aging
- Early menarche
- Late menopause (after age 55)
- Obesity
- Diabetes
- Tamoxifen therapy
- Polycystic ovary syndrome (chronic anovulation)
- Nulliparity
- Infertile women
- Hypertension
- Cowden syndrome
- Lynch syndrome (hereditary conditions such as hereditary nonpolyposis colorectal cancer)
- Family history (endometrial, ovarian, breast, colon cancer)
- White race
- Cigarette smoking
Natural History, Complications and Prognosis
- If left untreated, 38% of the patients with endometrial intraepithelial neoplasia may progress to develop endometrial cancer.[25]
- Common complications of endometrial intraepithelial neoplasia include:[26]
- Carcinoma
- Metastases
- Death
- The Prognosis of endometrial intraepithelial neoplasia is generally good with treatment.
Diagnosis
Diagnostic Criteria
- The diagnosis histologic criteria of endometrial intraepithelial neoplasia are:[27]
- Area of glands is larger than stroma area
- Cytology differs between architecturally crowded focus and background
- size ≥ 1mm
- Forbiddance of adenocarcinoma
- Forbiddance of mimics
Symptoms
- The hallmark symptom of endometrial intraepithelial neoplasia is postmenopausal abnormal uterine bleeding; spotting or staining.[28][29]
- Premonpausal women with endometrial intraepithelial neoplasia may have a positive history of abnormal uterine bleeding:[30][31]
- Intermenstrual beeding
- Frequent bleeding (episodes of bleeding that are less than 21 days long)
- Heavy bleeding (volume e more than 80 ml)
- Prolonged bleeding (more than 7 days)
- Prolonged amenorrhea (more than 6 months)
- Chronic anovulation
Physical Examination
- Rectovaginal examination may be reveal:[32]
- Palpable pelvic masses
- Supraclavicular nodes (in cases of advanced disease)
Laboratory Findings
- There are no specific laboratory findings associated with endometrial intraepithelial neoplasia.
Imaging Findings
- Transvaginal ultrasonography is the imaging modality of choice for endometrial intraepithelial neoplasia.[33]
- On transvaginal ultrasonography, endometrial intraepithelial neoplasia is characterized by endometrial thickness > 4 mm.
- Biopsy should be performed for patients who have:
- Endometrial thickness > 4 mm
- Bleeding (even if the endometrial thickness is less than 4 mm)
- Biopsy should be performed for patients who have:
Other Diagnostic Studies
- Endometrial intraepithelial neoplasia is mainly diagnosed using endometrial suction curette, hematoxylin and eosin staining and hysteroscopy.[34]
Treatment
Medical Therapy
- Progestin therapy is recommended for patients with endometrial intraepithelial neoplasia.
- patient should be followed up by biopsy every 6 months until obtaining 3 consecutive negative biopsies .[35][36]
Surgery
- Hysterectomy is the mainstay of treatment for endometrial intraepithelial neoplasia to prevent endometrial carcinoma.[12]
Prevention
- Effective measures for the primary prevention of endometrial intraepithelial neoplasia include:[37]
- Effective measures for the secondary prevention of endometrial intraepithelial neoplasia include hysterectomy to prevent endometrial carcinoma.[38]
References
- ↑ 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.
- ↑ Emons G, Beckmann MW, Schmidt D, Mallmann P (February 2015). "New WHO Classification of Endometrial Hyperplasias". Geburtshilfe Frauenheilkd. 75 (2): 135–136. doi:10.1055/s-0034-1396256. PMC 4361167. PMID 25797956.
- ↑ Wang, Steven; Wang, Zhenglong; Mittal, Khushbakhat (2015). "Concurrent endometrial intraepithelial carcinoma (EIC) and endometrial hyperplasia". Human Pathology: Case Reports. 2 (1): 1–4. doi:10.1016/j.ehpc.2014.07.003. ISSN 2214-3300.
- ↑ Jarboe EA, Mutter GL (November 2010). "Endometrial intraepithelial neoplasia". Semin Diagn Pathol. 27 (4): 215–25. PMID 21309257.
- ↑ Mutter GL, Ince TA, Baak JP, Kust GA, Zhou XP, Eng C (June 2001). "Molecular identification of latent precancers in histologically normal endometrium". Cancer Res. 61 (11): 4311–4. PMID 11389050.
- ↑ Faquin WC, Fitzgerald JT, Lin MC, Boynton KA, Muto MG, Mutter GL (April 2000). "Sporadic microsatellite instability is specific to neoplastic and preneoplastic endometrial tissues". Am. J. Clin. Pathol. 113 (4): 576–82. doi:10.1309/F4TU-6AFE-R7NU-39Y3. PMID 10787358.
- ↑ Monte NM, Webster KA, Neuberg D, Dressler GR, Mutter GL (August 2010). "Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer". Cancer Res. 70 (15): 6225–32. doi:10.1158/0008-5472.CAN-10-0149. PMC 2912978. PMID 20631067.
- ↑ Mutter GL, Ince TA, Baak JP, Kust GA, Zhou XP, Eng C (June 2001). "Molecular identification of latent precancers in histologically normal endometrium". Cancer Res. 61 (11): 4311–4. PMID 11389050.
- ↑ O'Hara AJ, Bell DW (March 2012). "The genomics and genetics of endometrial cancer". Adv Genomics Genet. 2012 (2): 33–47. doi:10.2147/AGG.S28953. PMC 3415201. PMID 22888282.
- ↑ 11.0 11.1 McCluggage WG (August 2006). "My approach to the interpretation of endometrial biopsies and curettings". J. Clin. Pathol. 59 (8): 801–12. doi:10.1136/jcp.2005.029702. PMC 1860448. PMID 16873562.
- ↑ 12.0 12.1 Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL (November 2012). "Management of endometrial precancers". Obstet Gynecol. 120 (5): 1160–75. doi:http://10.1097/AOG.0b013e31826bb121 Check
|doi=value (help). PMC 3800154. PMID 23090535. - ↑ Owings, Richard A.; Quick, Charles M. (2014). "Endometrial Intraepithelial Neoplasia". Archives of Pathology & Laboratory Medicine. 138 (4): 484–491. doi:10.5858/arpa.2012-0709-RA. ISSN 0003-9985.
- ↑ McCluggage, W. Glenn (2011). "Benign Diseases of the Endometrium": 305–358. doi:10.1007/978-1-4419-0489-8_7.
- ↑ Lacey JV, Chia VM, Rush BB, Carreon DJ, Richesson DA, Ioffe OB, Ronnett BM, Chatterjee N, Langholz B, Sherman ME, Glass AG (October 2012). "Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan". Int. J. Cancer. 131 (8): 1921–9. doi:10.1002/ijc.27457. PMID 22290745.
- ↑ Carlson JW, Mutter GL (September 2008). "Endometrial intraepithelial neoplasia is associated with polyps and frequently has metaplastic change". Histopathology. 53 (3): 325–32. doi:10.1111/j.1365-2559.2008.03104.x. PMC 2574678. PMID 18637968.
- ↑ Hou, June Y.; McAndrew, Thomas C.; Goldberg, Gary L.; Whitney, Kathleen; Shahabi, Shohreh (2013). "A Clinical and Pathologic Comparison Between Stage-Matched Endometrial Intraepithelial Carcinoma and Uterine Serous Carcinoma". Reproductive Sciences. 21 (4): 532–537. doi:10.1177/1933719113503414. ISSN 1933-7191.
- ↑ Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R (January 2016). "Therapeutic options for management of endometrial hyperplasia". J Gynecol Oncol. 27 (1): e8. doi:10.3802/jgo.2016.27.e8. PMC 4695458. PMID 26463434.
- ↑ Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, Wolk A, Wentzensen N, Weiss NS, Webb PM, van den Brandt PA, van de Vijver K, Thompson PJ, Strom BL, Spurdle AB, Soslow RA, Shu XO, Schairer C, Sacerdote C, Rohan TE, Robien K, Risch HA, Ricceri F, Rebbeck TR, Rastogi R, Prescott J, Polidoro S, Park Y, Olson SH, Moysich KB, Miller AB, McCullough ML, Matsuno RK, Magliocco AM, Lurie G, Lu L, Lissowska J, Liang X, Lacey JV, Kolonel LN, Henderson BE, Hankinson SE, Håkansson N, Goodman MT, Gaudet MM, Garcia-Closas M, Friedenreich CM, Freudenheim JL, Doherty J, De Vivo I, Courneya KS, Cook LS, Chen C, Cerhan JR, Cai H, Brinton LA, Bernstein L, Anderson KE, Anton-Culver H, Schouten LJ, Horn-Ross PL (July 2013). "Type I and II endometrial cancers: have they different risk factors?". J. Clin. Oncol. 31 (20): 2607–18. doi:10.1200/JCO.2012.48.2596. PMC 3699726. PMID 23733771.
- ↑ Smith RA, von Eschenbach AC, Wender R, Levin B, Byers T, Rothenberger D, Brooks D, Creasman W, Cohen C, Runowicz C, Saslow D, Cokkinides V, Eyre H (2001). "American Cancer Society guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: update 2001--testing for early lung cancer detection". CA Cancer J Clin. 51 (1): 38–75, quiz 77–80. PMID 11577479.
- ↑ Elwood, J. Mark; Cole, Philip; Rothman, Kenneth J.; Kaplan, Samuel D. (1977). "Epidemiology of Endometrial Cancer
2". JNCI: Journal of the National Cancer Institute. 59 (4): 1055–1060. doi:10.1093/jnci/59.4.1055. ISSN 1460-2105. line feed character in
|title=at position 35 (help) - ↑ La Vecchia C, Franceschi S, Decarli A, Gallus G, Tognoni G (September 1984). "Risk factors for endometrial cancer at different ages". J. Natl. Cancer Inst. 73 (3): 667–71. PMID 6590913.
- ↑ Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P (February 2013). "Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer". Obstet Gynecol. 121 (2 Pt 2 Suppl 1): 461–4. doi:http://10 1097/AOG.0b013e318270444f Check
|doi=value (help). PMC 3799979. PMID 23344409. - ↑ Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R (January 2016). "Therapeutic options for management of endometrial hyperplasia". J Gynecol Oncol. 27 (1): e8. doi:10.3802/jgo.2016.27.e8. PMC 4695458. PMID 26463434.
- ↑ Kalin A, Merideth MA, Regier DS, Blumenthal GM, Dennis PA, Stratton P (February 2013). "Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer". Obstet Gynecol. 121 (2 Pt 2 Suppl 1): 461–4. doi:http://10 1097/AOG.0b013e318270444f Check
|doi=value (help). PMC 3799979. PMID 23344409. - ↑ Soslow RA (January 2016). "Practical issues related to uterine pathology: staging, frozen section, artifacts, and Lynch syndrome". Mod. Pathol. 29 Suppl 1: S59–77. doi:10.1038/modpathol.2015.127. PMC 4821462. PMID 26715174.
- ↑ Owings, Richard A.; Quick, Charles M. (2014). "Endometrial Intraepithelial Neoplasia". Archives of Pathology & Laboratory Medicine. 138 (4): 484–491. doi:10.5858/arpa.2012-0709-RA. ISSN 0003-9985.
- ↑ Mutter GL, Zaino RJ, Baak JP, Bentley RC, Robboy SJ (April 2007). "Benign endometrial hyperplasia sequence and endometrial intraepithelial neoplasia". Int. J. Gynecol. Pathol. 26 (2): 103–14. doi:10.1097/PGP.0b013e31802e4696. PMID 17413975.
- ↑ "ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer". Obstet Gynecol. 106 (2): 413–25. August 2005. PMID 16055605.
- ↑ Nicula R, Costin N (2015). "Management of endometrial modifications in perimenopausal women". Clujul Med. 88 (2): 101–10. doi:10.15386/cjmed-421. PMC 4576794. PMID 26528056.
- ↑ Marnach, Mary L.; Laughlin-Tommaso, Shannon K. (2019). "Evaluation and Management of Abnormal Uterine Bleeding". Mayo Clinic Proceedings. 94 (2): 326–335. doi:10.1016/j.mayocp.2018.12.012. ISSN 0025-6196.
- ↑ López F, Rodrigo JP, Silver CE, Haigentz M, Bishop JA, Strojan P, Hartl DM, Bradley PJ, Mendenhall WM, Suárez C, Takes RP, Hamoir M, Robbins KT, Shaha AR, Werner JA, Rinaldo A, Ferlito A (April 2016). "Cervical lymph node metastases from remote primary tumor sites". Head Neck. 38 Suppl 1: E2374–85. doi:10.1002/hed.24344. PMID 26713674.
- ↑ Kotdawala P, Kotdawala S, Nagar N (January 2013). "Evaluation of endometrium in peri-menopausal abnormal uterine bleeding". J Midlife Health. 4 (1): 16–21. doi:10.4103/0976-7800.109628. PMC 3702059. PMID 23833528.
- ↑ Li XC, Song WJ (2013). "Endometrial Intraepithelial Neoplasia (EIN) in endometrial biopsy specimens categorized by the 1994 World Health Organization classification for endometrial hyperplasia". Asian Pac. J. Cancer Prev. 14 (10): 5935–9. PMID 24289604.
- ↑ Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL (November 2012). "Management of endometrial precancers". Obstet Gynecol. 120 (5): 1160–75. doi:http://10.1097/AOG.0b013e31826bb121 Check
|doi=value (help). PMC 3800154. PMID 23090535. - ↑ Owings, Richard A.; Quick, Charles M. (2014). "Endometrial Intraepithelial Neoplasia". Archives of Pathology & Laboratory Medicine. 138 (4): 484–491. doi:10.5858/arpa.2012-0709-RA. ISSN 0003-9985.
- ↑ Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL (November 2012). "Management of endometrial precancers". Obstet Gynecol. 120 (5): 1160–75. doi:http://10.1097/AOG.0b013e31826bb121 Check
|doi=value (help). PMC 3800154. PMID 23090535. - ↑ Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, Higgins R, Zaino R, Mutter GL (November 2012). "Management of endometrial precancers". Obstet Gynecol. 120 (5): 1160–75. doi:http://10.1097/AOG.0b013e31826bb121 Check
|doi=value (help). PMC 3800154. PMID 23090535.