A Rare Case Presentation of Endometrial Clear-Cell Carcinoma

Introduction

Endometrial cancer is the most common genital-tract malignancy in women throughout the United States, with >54,870 new cases estimated for 2015 by the American Cancer Society. ¹ This cancer is primarily categorized as: endometrioid type (50% of cases); papillary serous type (17%–22% of cases); and clear-cell carcinoma (1%–6% of cases). ² While rare, endometrial clear-cell carcinoma (ECCC) is the most aggressive type, with an estimated 40% of newly diagnosed patients already presenting with metastases ³ as well as a 5-year overall survival of 62% relative to 83% for the endometrioid type. ⁴ ECCC is almost exclusively found in menopausal women (mean age of 65), and more commonly in African American women. ³ Unlike the endometrioid type, ECCC has not been associated with use of estrogen. ³ However, ECCC is more likely to be found in women previously treated with tamoxifen for breast cancer or women who have undergone prior pelvic radiation therapy. ² A distinction must be made between ECCC and cervical clear-cell carcinoma. Cervical clear-cell carcinoma is associated with diethylstilbestrol exposure in utero, whereas ECCC has no association with this compound. ³

Case

A 31-year-old Caucasian woman, gravida 3, para 2012, with a past medical history of hypertension, obesity, and depression presented to a clinic with a complaint of sudden onset of heavy bleeding and passing fleshy-appearing masses between her periods. A recent Papanicolaou smear was noted to be remarkable for atypical glandular cells (AGC) with negative human papilloma virus (HPV) 16 and 18 cotesting. Her history included menarche starting at age 9, with a regular 28-day menstrual cycle and menses of 6 days duration. She had no history of sexually transmitted diseases or other abnormal Papanicolaou smears. Her obstetrical history included one dilatation and curettage secondary to a miscarriage, a spontaneous vaginal delivery, and a cesarean delivery with bilateral tubal ligation. She did not have a history of smoking, alcohol abuse, or drug abuse. Significant family history included cervical cancer and breast cancer in a paternal aunt and unspecified gynecologic cancer in her paternal grandmother.

Secondary to heavy menstrual bleeding, a transvaginal ultrasound was performed and revealed normal bilateral ovaries, a normal-size uterus, and irregular endometrium. A follow-up sonohysterogram a few weeks later was remarkable for multiple large polyps seen within the endometrium. Secondary to heavy uterine bleeding on the day of the examination, a colposcopy was not feasible. Despite this barrier, she was able to have an in-office endometrial pipelle biopsy. Endometrial pathology was found to be remarkable for clear-cell carcinoma of the endometrium (Fig. 1 and Fig. 2). She was referred to the gynecologic oncology department for definitive management. She underwent exploratory laparotomy, total abdominal hysterectomy and bilateral salpingo-oophorectomy, and pelvic and para-aortic lymph-node dissection.

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FIG. 1.

Endometrial clear-cell carcinoma at 20×.

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FIG. 2.

Endometrial clear cell-carcinoma at 40×.

Results

Final staging was reported as Stage 1A grade 3 endometrial clear-cell carcinoma. She received 6 cycles of carboplatin/taxol. A follow up computed tomography scan 6 months later of her chest, abdomen, and pelvis showed no evidence of residual or recurrent disease.

Discussion

A literature search was conducted on PubMed.gov with search terms including endometrium, cancer, endometrial cancer, and endometrial clear cell carcinoma, used separately and together to capture the most comprehensive literature available. Inclusion criteria was limited to publications in the last 10 years, reviews, systematic reviews, clinical trials, full-text availability, and articles written in the English language.

As a 31-year-old Caucasian woman, the current patient falls outside the typical epidemiologic presentation for her disease, as ECCC has a higher incidence in African American, nonobese menopausal women without previous unopposed estrogen exposure. ³ The most important physical findings suggestive of a neoplastic endometrial process found in this patient were new onset of heavy menstrual bleeding and passage of fleshy masses between menses. Findings of AGC on her Papanicolaou smear indicated a need for endometrial biopsy and colposcopy per current guidelines. ⁵ Endometrial biopsy is a reliable method of diagnosis of endometrial cancer, and has a sensitivity of ∼99%. ² Although colposcopy was not feasible because of her heavy menstrual bleeding, vigilance to follow current guidelines allowed for early detection of ECCC via endometrial biopsy. Transvaginal ultrasound showed an irregular endometrial stripe; however, there are no established parameters for this finding when evaluating for endometrial cancer in a reproductive-age patient. The endometrial stripe could have been interpreted as likely normal endometrial tissue development in a reproductive-age female and therefore has little value.

Women with Papanicolaou smears showing AGC comprise <1% of the general population. ⁶ Current American Society for Colposcopy and Cervical Pathology (ASCCP) management guidelines state that patients with AGC on Papanicolaou smears should undergo colposcopy with endocervical sampling in all women. ⁴ The guidelines go even further to recommend endometrial sampling in women who are >35 years old or who are at high risk for endometrial hyperplasia. ⁵ High-risk features include unexplained vaginal bleeding or conditions suggesting chronic anovulation. ⁴ Despite these guidelines, adherence is low, with one study finding that as few as 36% of women have comprehensive evaluations following Papanicolaou smears showing AGC. ⁷

Conclusions

The current case was a diagnosis of ECCC in an atypical patient whose diagnosis could have easily been delayed or missed. Her history of new onset of heavy menstrual bleeding might have easily been managed inappropriately with common therapies, such as observation, nonsteroidal anti-inflammatory drugs, hormonal contraception, tranexamic acid, or placement of a levonorgestrel intrauterine device.

The current authors commonly recommend endometrial biopsy for women with new onset of heavy menstrual bleeding who are 35 years of age or older, which the current patient was not. The fact that this patient had AGC on her Papanicolaou smear was an alert that something more ominous might be the cause of her bleeding. The current authors recommend that endometrial biopsy should be performed on all women reported to have AGC as part of cervical cytology with risk factors. This recommendation is in agreement with the recommendations established by the ASCCP. Currently, there are insufficient data to recommend HPV DNA testing alone in the management of women with AGC. By performing endometrial biopsy in atypical patients with AGC on their Papanicolaou smears, delayed or missed diagnosis of ECCC might be avoidable.