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Table of Contents
Definition / general | Pathophysiology | Clinical features | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis | Additional referencesCite this page: Endometroid intraepithelial neoplasia (EIN) / Atypical endometrial hyperplasia. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/uterusein.html. Accessed July 16th, 2017.
Definition / general
- Prior to 2014, the World Health Organization classified endometrial hyperplasia as simple versus complex, and nonatypical versus atypical
- This system suffered from significant interobserver variation (Am J Surg Pathol 2008;32:691)
- Reproducibility improves with a two tier classification (Histopathology 2014;64:284, Int J Gynecol Pathol 2008;27:318)
- Accordingly, the classification system was simplified in 2014; it now divides hyperplasia into two categories, benign (nonatypical) hyperplasia and endometrioid intraepithelial neoplasia / atypical hyperplasia (both terms are considered synonyms / equivalents)
- The terms "simple" and "complex" have been removed from the classification; they, however, remain in parts of the following text when citing data prior to the 2014 WHO classification
- The 2014 WHO classification introduces "endometrioid intraepithelial neoplasia" instead of "endometrial intraepithelial neoplasia" to emphasize that this diagnosis is related to endometrial carcinomas of the endometrioid type, and is unrelated to endometrial serous carcinoma
- EIN has a 45x risk of progression to endometrial carcinoma compared to the general population (compared to 2 - 4x for benign endometrial hyperplasia) (Cancer 2005;103:2304)
- 18.6% prevalence of carcinoma diagnosis beyond 1 year after diagnosis of EIN (Mod Pathol 2005;18:324, Hum Pathol 2008;39:866), and 29% risk of carcinoma after diagnosis of atypical endometrial hyperplasia (Cancer 1985;56:403)
- Average interval to diagnosis of adenocarcinoma after an initial diagnosis of EIN is 4 years (Cancer 2005;103:2304)
Pathophysiology
- Endometrial intraepithelial neoplasia is a monoclonal outgrowth of premalignant glands with a risk for malignant transformation to endometrial endometrioid carcinoma
- Genes known to be altered in EIN are similarly affected in endometrioid endometrial adenocarcinoma, including:
- Inactivation (mutation or deletion) of the PTEN tumor suppressor gene (44 - 63%) (J Natl Cancer Inst 2000;92:924, Cancer Res 2001;61:4311)
- Inactivation of PAX2 gene (71%) (Cancer Res 2010;70:6225)
- KRAS mutations (16%) (Mol Pathol 1999;52:257)
- Microsatellite instability (20 - 25%) (Am J Clin Pathol 2000;113:576)
Criteria for EIN includes:
- A larger glandular area than stromal area (volume percent stroma < 55%)
- Cytology differs between the crowded glandular focus and the background glands
- The premalignant area is at least 1 mm
Clinical features
- Typically presents in peri-menopausal period; average age at presentation is 53 years
- Patients are frequently obese (66%), post-menopausal (48%), occasionally with polycystic ovarian syndrome (5%), tamoxifen use (5%) and infertility (5%) (Obstet Gynecol 2011;118:21)
- Unopposed estrogen stimulation is a known risk factor: 12% of patients receiving unopposed estrogens developed atypical hyperplasia (JAMA 1996;275:370)
- Postmenopausal bleeding or abnormal uterine bleeding are the most common presenting symptoms
Case reports
- 45 year old woman with menometrorhagia (Case of the Week #60)
Treatment
- In postmenopausal and pre-menopausal women with fulfilled pregnancy goals, hysterectomy is the treatment of choice (Eur J Obstet Gynecol Reprod Biol 2010;150:80)
- In pre-menopausal women who desire to preserve fertility, progestin therapy is a valid alternative (see Progestin therapy related changes)
Microscopic (histologic) description
- Gland to stroma ratio is greater than 1:1 (glands occupy more than 50% of the surface area)
- These areas of "gland crowding" still contain small amounts of stroma in between glands, and the individual glandular contours can be easily distinguished
- Cytologic atypia is defined as:
- Nuclear enlargement and rounding
- Open to coarse, irregularly distributed chromatin
- Inconspicuous nucleoli, visible at high power magnification
- Loss of polarity
- Conventional cytologic atypia, as defined above, suffers from significant interobserver variation (Am J Surg Pathol 2008;32:691) and is frequently absent or difficult to assess, for instance in cases with secretory of syncytial papillary differentiation (Mod Pathol 2013;26:868, Am J Surg Pathol 2013;37:167)
- Based on the above pitfalls, the use of diagnostic criteria for EIN is preferred; these criteria are:
- Architecture
- Area of glands exceeds that of the stroma (gland to stroma ratio > 1)
- Lesion composed of individual glands which may branch slightly and vary in shape
- Cytology
- Nuclear or cytoplasmic features of epithelial cells differ between architecturally crowded and normal background glands
- May include change in nuclear polarity, nuclear atypia (as defined above) or altered cytoplasmic differentiation
- If no normal glands present, highly abnormal cytology
- Size
- Maximum linear dimension exceeds 1 mm
- Exclude mimics
- Disordered proliferative, secretory or basalis endometria; polyp, benign (nonatypical) hyperplasia, carcinoma (maze-like glands, solid areas, significant cribriforming)
- Architecture
Microscopic (histologic) images
Images hosted on PathOut servers:
EIN, courtesy of Dr. Carlos Parra-Herran
Case of the Week #60
Images hosted on other servers:
Clear cell variant: H&E, p53 and Ki-67 (left); clear cell endometrial glandular dysplasia and clear cell EIC (right)
Serous EIC and possible precursor lesions
p53 staining
Differential diagnosis
- Benign (non atypical hyperplasia): no altered or abnormal cytology (cytology of crowded areas is similar to non crowded background areas)
- Benign endometrial metaplasia (tubal, secretory, mucinous): no crowding / expansile growth
- Endometrial polyp: polypoid shape, fibrotic stroma, thick blood vessels, no conventional atypia, no abnormal cytology; glands in a polyp are frequently crowded, a finding that does not warrant the diagnosis of hyperplasia
- Endometrial endometrioid carcinoma: increased glandular complexity with glandular confluence (cribriform, microacinar patterns) and loss of individual glandular contours and surrounding stroma
- Serous / clear cell carcinoma: high grade cytomorphology with high nuclear / cytoplasmic ratio and loss of polarity
Additional references
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