Premalignant Lesions of the Endometrium - Causes, Diagnosis, and Treatment

What Are Premalignant Lesions of the Endometrium?

Premalignant endometrial lesions are a distinctive series of intraepithelial neoplasia or atypical endometrial hyperplasia that may result in either of the two primary forms of endometrial carcinomas,

• Type 1- It resembles proliferative endometrium and develops when there is an excess of estrogen or insufficient progesterone. The majority of endometrial cancers, between 80% and 85%, are type 1 endometrial cancers.

• Type 2- When P53 is mutated, intraepithelial carcinoma develops and progresses, making type 2 endometrial cancer a serious type that is typically associated with post-menopausal endometrial atrophy.

Hysterectomy is one treatment option for premalignant lesions. In addition, medical care with high-dose gestagen therapy with appropriate close histological monitoring may be used in certain younger people who desire to become parents. However, almost all endometrial premalignant lesions would develop over a few years into invasive cancer if left untreated.

What Are the Causes of Premalignant Lesions of Endometrium?

The incidence of endometrial cancer is rising globally as a direct result of the aging population and the rise in obesity. Premalignant lesions typically appear several years before invasive endometrial cancer does.

The following risk factors increase the chances of developing atypical endometrial hyperplasia or EH (precursor of type 1 endometrial carcinoma)

• Age of women is more than 35.

• Caucasian race.

• Early menarche, protracted perimenopause, late menopause, post-menopausal status, and family history of endometrial hyperplasia or cancer.

• Comorbidities like diabetes mellitus type 2, obesity, and granulosa cell tumor of the ovary or HNPCC (hereditary non-polyposis colorectal cancer).

• Exposure to Tamoxifen medication, estrogen-only hormone replacement therapy, and any other exogenous hormonal exposure.

• Environmental factors like smoking and genetic mutations.

The following risk factors increase the chances of developing endometrial intraepithelial carcinoma or EIC (precursor of type 2 endometrial carcinoma)-

• The precursor lesion of type 2 ECs, endometrial intraepithelial carcinoma (EIC), has the propensity to be estrogen-independent and develops into the clinically aggressive "serous" and "clear cell" histological subtypes.

• Compared to type 1 ECs, which are more frequently linked with endometrial hyperplasia (EH), type 2 ECs are more frequently associated with endometrial atrophy in post-menopausal women.

What Are Signs and Symptoms Of Premalignant Lesions of the Endometrium?

The most common signs and symptoms of patients with endometrial hyperplasia are as follows-

• Abnormal uterine bleeding present in the form of menorrhagia (extremely heavy or prolonged bleeding during menstruation), metrorrhagia (unpredictable uterine bleeding, especially between periods that are expected to occur), or post-menopausal bleeding.

• Bleeding caused by uterine bleeding necessitates urgent medical or surgical treatments, causes infertility, and requires blood transfusion therapy.

• Abnormal vaginal discharge.

• Pap smear results show glandular abnormalities.

How Are Premalignant Endometrial Lesions Diagnosed?

• Physical Examination - A thorough history and physical examination are required when abnormal bleeding is present. The lower genital tract should be carefully examined for lesions of the vulva, vagina, and cervix, and the uterus and ovaries should be palpated. It is important to take note of the cause of any vaginal discharge or to bleed, the size of the uterus and endometrial cavity, and any pelvic tumors.

• Pelvic Ultrasonography - If the patient is obese and a pelvic examination is inadequate, pelvic ultrasonography may be helpful to assess for ovarian masses.

• Endometrial Biopsy - The patient requires a diagnostic procedure to rule out hyperplasia or cancer if they exhibit symptoms or have cytological abnormalities. Endometrial biopsies performed in the office are typically used to sample the endometrial cavity and diagnose endometrial hyperplasia. Women with risk factors who exhibit signs of abnormal vaginal bleeding or discharge should have tissue samples taken. Women over 35 with abnormal bleeding, those under 35 with bleeding and risk factors, those with recurrent bleeding, those undergoing unopposed estrogen replacement, those receiving Tamoxifen therapy, and those with HNPCC cancer syndrome are all included in this category.

What Is the Treatment of Premalignant Endometrial Lesions?

The following factors are included in the management plan for patients with premalignant endometrial lesions, according to the American College of Obstetricians and Gynecologists (ACOG)-

• Excluding the possibility of endometrial cancer concurrently.

• A strategic management plan to accommodate an occult carcinoma's late diagnosis.

• Preventing the development of endometrial cancer.

Surgical and non-surgical treatments are both available for treating premalignant endometrial lesions. For premalignant endometrial lesions, the preferred therapy is a total hysterectomy (not a supracervical hysterectomy). In addition, high-dose progestin medication with proper careful histopathological monitoring is favored in younger patients who desire to become parents.

1. Surgical Management:

• The current gold standard of treatment for premalignant endometrial lesions is total hysterectomy. According to ACOG, a total hysterectomy offers conclusive therapy and evaluation for a potential concomitant cancer in clinically suitable circumstances.

• Supracervical hysterectomy, morcellation, and endometrial ablation are not indicated due to the risk of missing underlying cancer.

• A total hysterectomy involves removing the cervix and performing bilateral salpingo-oophorectomy (BSO), if necessary, can stage any endometrial neoplasia that is unintentionally found and reduces the chance of any undiscovered or persistent disease.

• Depending on the degree of the intended surgery, one may choose from a variety of surgical alternatives, including abdominal, vaginal, and minimally invasive techniques (such as laparoscopic or robotic approach).

• For the vast majority of patients with premalignant endometrial lesions, lymphadenectomy is not advised because it is seen to be overtreatment and has an elevated surgical risk.

2. Non-surgical Management: Younger individuals who want to retain their fertility or patients with medical comorbidities are offered non-surgical treatment since they are poor surgical candidates due to an increased risk of complications. The three therapeutic aims are-

• To restore normal endometrium.

• Completely eradicate the illness.

• Avoid invasive cancer.

• Hormonal therapy is a reliable non-surgical treatment. Progestins, or the suppression of estrogenic effects, make up the majority of hormonal therapy. Other options like Selective estrogen receptor modulators (SERMS) may also be used in the treatment. Aromatase inhibitors, gonadotropin-releasing hormone (GnRH) antagonists, and sulfatase inhibitors are other medications used to lessen the effects of estrogen. Progesterone derivatives are frequently used in hormonal therapy for any patient who wants to preserve fertility.

• Endometrial ablation is not recommended because it cannot be determined whether the ablation is complete. Furthermore, it could result in fibrosis with endometrial cavity adhesions, making subsequent follow-up surveillance difficult or impossible.

What Other Conditions Mimic Premalignant Lesions of Endometrium?

When biopsies are analyzed, other benign tumors that could imitate premalignant and malignant lesions include mucinous metaplasia, papillary mucinous metaplasia, and endometrial polyps. The Arias-Stella reaction could be mistaken for a premalignant lesion if a pregnancy history is not given. Sometimes it can be challenging to tell endometrial hyperplasia with secretory alterations from a late secretory endometrium with its vast and proliferative "cork-screw"-shaped glands.

What Are the Complications Associated With Premalignant Lesions of Endometrium?

Atypical hyperplasia complications can include severe uterine bleeding that needs immediate medical or surgical attention. In addition, a blood transfusion may be necessary in cases of severe acute bleeding.

Conclusion:

Premalignant endometrial lesions are a typical progression of endometrial hyperplasia and endometrial cancer. Endometrial carcinomas can develop from two different types of precursor lesions. The premalignant stage of endometrioid adenocarcinoma or type 1 endometrial cancer is known as atypical hyperplasia or endometrioid intraepithelial neoplasia. Endometrioid carcinomas are believed to develop from preexisting lesions in over 90% of cases. Pre- and peri-menopausal women are most frequently affected by type 1 endometrial cancer. The predominance of estrogen in combination with insufficient progesterone is one of the causative causes.

Atypical hyperplasia is infrequently linked to mucinous or secretory cell types. It is believed that some endometrial clear cell carcinomas and type 2 or serous carcinomas have their origins in endometrial intraepithelial carcinoma. It is common for post-menopausal women to develop premalignant endometrial lesions, a series of Type 2 serous carcinoma linked to endometrial atrophy.