Endometrial intraepithelial neoplasia
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.

# Classification
- Endometrial hyperplasia may be classified according to the new World Health Organization (WHO 2014) classification into two groups:
- 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:
- 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.
- Genes involved in the pathogenesis of endometrial intraepithelial neoplasia (EIN) includ:
Inactivation (mutation or deletion) of the PTEN tumor suppressor gene
Inactivation of PAX2 gene
KRAS mutations
Microsatellite instability
Mutation in p53 gene
- 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.

# Causes
- Endometrial intraepithelial neoplasia may be caused by estrogenic stimulation of the endometrium unopposed by progestins.

# Differentiating Endometrial intraepithelial neoplasia from other Diseases
- Endometrial intraepithelial neoplasia must be differentiated from other causes of postmenopausal differentiated from:
- 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.

## Age
- The incidence of endometrial intraepithelial neoplasia (EIN) increases with age; the median age at diagnosis is 52 years.

## Race
- Endometrial intraepithelial neoplasia (EIN) usually affects individuals of the African American race. Asian individuals are less likely to develop endometrial intraepithelial neoplasia.

# 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).
- Other risk factors include:
- 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.
- Common complications of endometrial intraepithelial neoplasia include:
Carcinoma
Metastases
Death
- 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:
- 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.
- Premonpausal women with endometrial intraepithelial neoplasia may have a positive history of abnormal uterine bleeding:
- 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:
Palpable pelvic masses
Supraclavicular nodes (in cases of advanced disease)
- 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.
- 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:
Endometrial thickness > 4 mm
Bleeding (even if the endometrial thickness is  less than 4 mm)
- Endometrial thickness > 4 mm
- Bleeding (even if the endometrial thickness is  less than 4 mm)

## Other Diagnostic Studies
- Endometrial intraepithelial neoplasia is mainly diagnosed using endometrial suction curette, hematoxylin and eosin staining and hysteroscopy.

# 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 .

## Surgery
- Hysterectomy is the mainstay of treatment for endometrial intraepithelial neoplasia to prevent endometrial carcinoma.

## Prevention
- Effective measures for the primary prevention of endometrial intraepithelial neoplasia include:
Combination of estrogen and progestin for hormone therapy
Physical exercise
Keep healthy weight ( BMI: 18.5 - 24.9)
- Combination of estrogen and progestin for hormone therapy
- Physical exercise
- Keep healthy weight ( BMI: 18.5 - 24.9)
- Effective measures for the secondary prevention of endometrial intraepithelial neoplasia include hysterectomy to prevent endometrial carcinoma.