An enormous pelvic tumor in a 46-year-old woman with an elevated serum CA 125 level, what lies beneath it? Investigation of uterine tumors in postmenopausal women

Abdominal and pelvic pain with an associated pelvic mass is a very common emergency situation. There is always a management dilemma for most emergency physicians regarding these patients. Physicians encoun- ter difficulties in differentiating a potential surgical prob- lem such as torsion of an enlarged ovary and a non-sur- gical pathology such as uterine leiomyoma in a physical examination. Different types of imaging examinations, e.g. ultrasonography (US), computed tomography (CT), and/or magnetic resonance imaging (MRI), are the gold standard imaging tools used to differentiate pelvic mass- es in women presenting with abdominal and pelvic pain to the emergency department (ED) [1]. Case report A 46-year-old postmenopausal woman was admit- ted to our ED with complaints of massive abdominal distention which started gradually 30 days ago. She also complained of difficulty in breathing and ambula- tion. There were no other gastrointestinal, gynecologi- An enormous pelvic tumor in a 46-year-old woman with an elevated serum CA 125 level, what lies beneath it? Investigation of uterine tumors in postmenopausal women Francesk Mulita, Elias Liolis, Dimitrios Kehagias, Levan Tchabashvili, Charalampos Kaplanis, Fotios Iliopoulos, Ioannis Perdikaris, Ioannis Kehagias Department of Surgery, General University Hospital of Patras, Rio, Greece

Abdominal and pelvic pain with an associated pelvic mass is a very common emergency situation. There is always a management dilemma for most emergency physicians regarding these patients. A 46-year-old post- menopausal woman was admitted to our emergency department (ED) with complaints of massive abdominal distention. Abdominal and pelvis magnetic resonance imaging (MRI) was performed, which revealed a huge pelvic abdominal mass. All tumor markers were within normal limits. However, the ovarian cancer antigen (CA 125) level was elevated. As there was a strong suspicion of malignancy, the patient underwent total ab- dominal hysterectomy with bilateral salpingo-oophorectomy. Her final histopathology report was suggestive of uterine leiomyoma. Uterine leiomyomas are the most common benign uterine tumors in women. Surgical treatment is the gold standard, especially for older women with severe symptoms and no desire for future fertil- ity. Although the combination of a pelvic tumor and a high-level of CA 125 arouses suspicion of gynecological ma- lignancy, other benign conditions should always be considered in the differential diagnosis. There is limited evi- dence to support an association between elevated CA 125 levels and uterine fibroids so far. However, conditions such as the coexistence of adenomyosis and tumor size can affect the level of this marker in uterine fibroids. Key words: menopause, uterine tumor, CA 125, leiomyoma. cal, or urinary symptoms. The woman had a significant past medical history of hypertension. Her family history is negative for ovarian and breast cancer in first-degree relatives. On physical examination, the patient’s abdo- men was distended. Blood analysis revealed hemoglobin of 13.9 g/dL, 8280 leukocytes, and 226 000 platelets. All tumor markers were within normal limits. However, the ovarian cancer antigen (CA 125) level was 260.9 U/mL (normal range: 0–35 U/mL). Abdominal and pelvis MRI was performed, which revealed a huge pelvic-abdom- inal mass measuring approximately 22 x 15 x 12 cm (Fig. 1 A, B, C). As there was a strong suspicion of ma- lignancy, the patient underwent total abdominal hys- terectomy with bilateral salpingo-oophorectomy. The enormous lobulated tumor weighing 6.7 kg had a thick wall with solid and cystic areas (Fig. 1 D). Her final his- topathology report was suggestive of uterine leiomyo- ma. The patient had no intra-operative or postoperative complications. On day 5 after the surgery, the patient was discharged home. Three months following the surgery, the CA 125 levels had regressed to the normal range. The patient has since been symptom-free, and the CA 125 levels have also remained normal. Corresponding author: Dr. Francesk Mulita, Department of Surgery, General University Hospital of Patras, Rio, Greece , e-mail: [email protected] Submitted: 14.04.2021 Accepted: 09.06.2021 Menopause Review/Przegląd Menopauzalny 20(3) 2021 155

Menopause is defined as the absence of menstrual cycles for at least twelve consecutive months, indicat- ing the end of the reproductive age for women as they are not able to get pregnant naturally [2, 3] Menopause is a natural biological event, but the mean age can dif- fer between women and it can be affected by several parameters, e.g. nationality, diet, other diseases. Meno- pause is also associated with hormonal changes. More specifically, the levels of estrogen, progesterone, folli- cle-stimulating hormone (FSH), and other hormones are affected. Early menopausal transition causes fluctua- tions in estrogen but eventually its production declines completely (last post-menopause stage). The same pat- tern is observed for FSH and progesterone [2]. These hormonal changes are associated with various symp- toms such as hot flushes, night sweats, etc. [4]. Studies also have demonstrated a potential role of menopause onset with hormone-related cancers such as ovarian, endometrial, and breast cancer as late menopause means higher hormone levels for women and longer exposure to estrogens. According to one hypothesis, estrogens play a  mitogenic role but mitotic activity increases the probability of DNA damage resulting in a mutation that can lead to the transformation of en- dometrial cells and tumor formation [2, 3, 5]. Therefore, a uterine tumor is a phenomenon usually observed in postmenopausal women. Abnormal uterine bleeding is the first sign that leads postmenopausal women to seek gynecological advice. Bleeding may be due to a tumor, but many oth- er diseases also can cause it [6, 7]. Therefore, it is very important to proceed with the right diagnosis. The first step is the physical examination that involves a pelvic examination to check for lumps that should be further checked. After that, the first tool that can be used is the transvaginal ultrasound (TVUS), an imaging tech- nique in which the doctor inserts an ultrasound probe into the vaginal canal to get images and to examine the organs of the female reproductive tract [6]. It has been observed that TVUS has 97% sensitivity and 74% spec- ificity for the detection of endometrial abnormalities [8]. If any abnormality is detected, the next step is to proceed with biopsy. During this procedure, a sample of cells is removed from the inside lining of the uterus and it is examined using a microscope. If the biopsy shows endometrial cancer, the appropriate treatment should be given. However, if the biopsy is normal or non-diag- nostic, other techniques can be used to investigate the cause of bleeding. More specifically, color Doppler can be used to differentiate between benign and malignant pathologies, and saline contrast hysterosonography is Fig. 1. A, B, C) magnetic resonance imaging images show 2 large subserosal fibroids arising from the anterior uterus, D) complete resection of the mass that weighed 6.7 kg and measured approximately 22 × 15 × 12 cm A C B D Menopause Review/Przegląd Menopauzalny 20(3) 2021 156 a technique used to evaluate the uterine cavity of post- menopausal women [6, 8]. Finally, hysteroscopy with biopsy is used when the biopsy results are unclear or enough tissue cannot be removed. During this proce- dure, the doctor examines the inside of the cervix and uterus using a  hysteroscope that resembles a  small microscope [9]. It is also considered a  safe technique and it has 100% sensitivity and 97% specificity for the detection of endometrial cancer [8]. As the most common symptom of a uterine tumor is abnormal uterine bleeding, it is very important to differentiate endometrial cancer at early stages from en- dometrial hyperplasia and endometrial polyps and also to differentiate advanced stages of cancer from uterine sarcoma or uterine lymphoma [10, 11]. Endometrial hyperplasia is an overgrowth of the endometrium which usually causes heavy or abnormal bleeding. Though it can increase the risk of endometrial cancer, it is very important to diagnose it accurately in order to proceed with the appropriate therapy. Therefore, an endometrial biopsy is the best tool to differentiate hyperplasia from cancer [12]. Endometrial polyps are localized hyperplastic overgrowths that occur in the endometrium, and their prevalence is higher among women with increasing age [13]. Most polyps are benign, in contrast with cancer tumors. Transvaginal US is usually the first tool for diag- nosis, but it seems that color Doppler is more effective in distinguishing benign and cancerous tumors. However, the gold standard is hysteroscopy with guided biopsy [8]. Another disease that should be differentiated is uterine sarcomas, rare gynecologic tumors which are usually diagnosed in postmenopausal women between 50 and 70 years old. However, their diagnosis is extremely chal- lenging. Imaging tools are not very helpful to distinguish sarcoma from endometrial hyperplasia or carcinoma, but it seems that endometrial biopsy is the best choice [14]. Finally, uterine lymphomas usually cause uterine bleed- ing and abdominal pain, but it is very important to distin- guish them from other diseases such as endometrial can- cer as they require different treatment options. Uterine lymphomas are rare malignancies (usually non-Hodgkin) of the female reproductive system and they are usually diagnosed using laparoscopy and biopsy [15]. Uterine leiomyomas (also known as fibroids) are the most common uterine tumors in women. Although the exact pathophysiology behind the development of these benign tumors remains unclear, they common- ly result in severe symptoms such as abnormal bleed- ing, pelvic pain, pelvic masses, infertility, anemia, bulk symptoms and obstetric complications [16, 17]. Treatment options mainly involve surgical inter - ventions, but the choice of treatment is individualized based on patient’s age, size and location of the lesions, severity of the symptoms, and desire for future fertility. Hysterectomy is the gold standard of leiomyoma treat- ment, especially for women who do not wish to con- ceive and/or women aged above 40–50 years, as it is immediately curative of the symptoms and can prevent their recurrence [18]. Our patient underwent surgery, as she was symptomatic and had completed having children. In addition, malignancy could not be excluded. Cancer antigen is mostly  used as a  relatively spe- cific marker for ovarian cancer. According to the litera- ture, the combination of a pelvic tumor and a high level of CA 125 arouses suspicion of a gynecological malig- nancy, but other benign conditions such as menstrua- tion, endometriosis, and pelvic inflammatory diseases should always be considered in the differential diag- nosis, particularly in pre-menopausal women [19–21]. Although there is limited evidence to support an as- sociation between elevated CA 125 levels and uterine fibroids, abnormally high levels have been reported in a  small number of patients. Furthermore, coexistence of adenomyosis and tumor size can affect the level of this marker in uterine fibroids. A large leiomyoma may be responsible for CA 125 elevations through an indirect mechanism such as peritoneal irritation [22].

Uterine leiomyomas are the most common benign uterine tumors in women. Surgical treatment is the gold standard, especially for older women with severe symp- toms and no desire for future fertility. Although the com- bination of a pelvic tumor and a high level of CA 125 arouses suspicion of a gynecological malignancy, oth- er benign conditions should always be considered in the differential diagnosis. There is limited evidence to support an association between elevated CA 125 lev- els and uterine fibroids so far. However, conditions such as coexistence of adenomyosis and tumor size can af- fect the level of this marker in uterine fibroids.

Informed consent was obtained from the patient for the publication of this article. Disclosure The authors report no conflict of interest.

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