Meigs syndrome: a case report and literature review

Introduction

Meigs syndrome is a rare condition, with 1% of benign ovarian tumors (1). The diagnostic criteria are the presence of a benign mass of the ovary, ascites, and pleural effusion with the restoration of normal conditions after the removal of adnexal formation (2–5); 2–5% of the surgically removed ovarian mass was revealed to be a fibroma, which was associated with ascites in 10–15% and with pleural effusion in 1% of cases (6). The entity of ascites is variable (7), and its origin seems to be correlated to irritation of the peritoneal surfaces, or to pressure on lymphatics or vessels, or to hormonal stimulation, or to release of factors increasing vessel permeability, even if the effective patho-genesis remains unclear (6). The pleural effusion is usually unilateral and is on the right side. A hypothesis regarding its origin, reported in the literature, suspected the passage of ascitic fluid to the pleural space, even if its quantity is independent of the amount of ascites (8). Meigs syndrome is typical of the post-menopausal period, with a peak of incidence at 70 years old; however, there are also cases reported in fertile women (3, 9)). Usually, these patients remain asymptomatic for a long period of time, but, sometimes, virilization, abnormal vaginal bleeding, menstrual irregularity, and precocious puberty could be reported in case of tumors secreting sexual hormones. Furthermore, in the case of a large mass, symptoms associated with the compression of neighboring organs could be detected. The clinic could be influenced also by the entity of ascites and pleural effusion, demonstrating compressive symptoms, dyspnea, cough, asthenia, and tachycardia (7). There isn’t a specific blood test that could guide the diagnosis. An elevation of CA 125 is frequently described. It is expressed not only by the epithelium of the genital tract but also by the pleural and peritoneal mesothelium (6, 10). Although an increase of CA 125 has been reported in association with Meigs syndrome, a level above 1000 IU/mL is exceptional, and nowadays, there is no information about the possible factors influencing this elevation (6). Some studies hypothesized that this increase could be correlated with different mechanisms concerning its mesothelial production, such as the peritoneum irritation due to the compression by the ovarian mass or the pressure exerted by ascites (11–17). A retrospective study, comparing 580 patients with benign ovary mass, found a possible association between an increase of CA 125 > 35 IU/mL, ascites, hydrothorax, and tumor size > 10 cm. In addition, they underlined the likely production of CA 125 by the peritoneal mesothelium (18). In 2009, Benjapabal et al. conducted a literature review that analyzed all cases of Meigs syndrome associated with CA 125 elevation between 1989 and 2007. They reported 18 studies describing 28 cases in which only 6 patients presented CA 125 levels over 1000 IU/mL; however, the authors did not report any hypothetical cause of this increment (6). To the best of our knowledge, there isn’t a clear association reported between patients or tumor characteristics and CA 125 over 1000 IU/mL in the literature. Therefore, we decide to share our case, considering the rarity of Meigs syndrome, with the presence of a big adnexal mass, ascites, and a high elevation of CA 125 elevation, suspected to be an ovarian malignancy. Moreover, we conducted a literature review of cases of Meigs syndrome in which an elevation of CA 125 was found, and subsequently, we performed a comparison between the cases (reported in the literature and our study) to evaluate any influencing factor that elevates the increase of CA 125.

Methods

First, we described our case report of an ovary fibroma determining a Meigs syndrome associated with an increment of CA 125. Subsequently, we conducted research in literature in PubMed, EMBASE, Cochrane Library, and Medline, starting with individual case reports, retrospective case series, and reviews concerning Meigs syndrome associated with CA 125 levels over the normal range in peer-reviewed journals. The publication range was from January 1989 to March 2022. Pseudo-Meigs syndrome without ovarian mass or associated with malignancies is not included. Then, we divided all cases found in the literature and our study, considering the increase of CA 125 = 1000 IU/mL or <1000 IU/mL, and we compared the two groups to find the possible factors influencing a high increment of CA 125. Comparisons between the two study groups were performed using Pearson’s chi-square test for categorical variables and the one-way ANOVA test for continuous ones. Subsequently, a multivariate analysis was performed, considering the most clinically relevant parameters or the ones significantly different between the two study groups. We used SPSS version 22.0 and the R software version 3.2.20, and a p-value < 0.05 was considered significant.

Results

Case presentation

A 55-year-old Caucasian woman was admitted to the emergency room for fever and dyspnea. There were no anamnestic features except for obesity (BMI: 36.5 kg/m²). She reported two pregnancies with regular course, namely, one delivered vaginally and the other delivered through cesarean. Menopause started 2 years before. The last gynecological evaluation, 8 years earlier, was regular. Her blood test demonstrated an increment of white cell count (12.6 × 10^∧9/L), C-reactive protein (25.6 mg/dL), and platelets (437 × 10^∧9/L). Blood culture results were negative. The molecular SARS-CoV19 swab was negative. The electrocardiogram was normal. A thromboprophylaxis therapy and an antibiotic therapy were started. A chest radiography showed a right hydrothorax (Figure 1A). A CT scan excluded pulmonary infection and embolism, confirmed the right pleural effusion with atelectasis (Figure 1B), and detected an adnexal mass of 26 × 14 × 19 cm (Figure 1C). A gynecological visit combined with ultrasound was performed and reported a normal uterus and right ovary, while in the left, dishomogeneous adnexal mass, multilocular, solid, with vascularization at Doppler evaluation was confirmed. Accordingly, she was admitted to the Gynecological Department. CA 125 was 1713 IU/mL. During the hospitalization, she performed a thoracentesis, which removed 1400 mL of pleural effusion, showing a negative result for malignancies. She underwent a colonoscopy, which showed negative findings. After the administration of antibiotics, the fever disappeared, and the blood test improved. She underwent a laparotomy surgery: 700 mL of ascites was detected and sent for cytology, which showed a negative result. The surgeons performed a hysterectomy with bilateral ovariectomy and the intraoperative diagnosis of the removed left adnexal mass was consistent with a cystadenofbroma of 3304 g (Figure 1D). Blood loss was 50 mL. The postoperative course was regular. The follow-up was negative, with a normalization of CA 125.

Figure 1. (A) Chest radiography demonstrated a right hydrotho-rax. (B) A CT scan confirmed the right pleural effusion, with atelectasis. (C) CT scan detected an adnexal mass of 26 × 14 × 19 cm. (D) Surgical images of left mass resulted in a fibroma of 3304 g.

Histopathological finding

Grossly, the huge mass was characterized by a predominantly solid component, with a few small superficial cysts filled with citrine limpid fluid, with occasional small vegetations. The cut surface was fasciculated and whitish, with only small cystic spaces inside. A minor part of the mass was slightly darker, with seemingly bland ischemic features, possibly consequent of compression due to the large size. On frozen sections, depicted in Figure 2A, the findings were consistent with a cystadenofbroma. The histological finding showed a spindle cell tumor with bland cytological features, often with edematous stromal areas. Sections of the cysts showed a benign-looking lining epithelium with regular papillae (Figure 2A). On permanent sections, depicted in Figures 2B–F, the histological findings confirmed the intraoperative diagnosis of papillary cystadenofbroma. As said, part of the fibroma had a dense stroma, and other areas were frankly edematous (Figures 2B, C). The small cysts, both superficial and internal, were lined by a bland-looking epithelium consistent with that of a cystadenoma, often with some papillae (Figure 2D). The grossly suspected ischemic features were confirmed (Figure 2F), with a small part of the fibromatous cells showing necrosis, ischemic changes, and a moderate chronic active inflammatory infiltrate [Figure 2F, CD45 (LCA) immunostaining]. In this approach, combine all your researched information in the form of a journal or research paper. In this, the researcher can take the reference of already accomplished work as a starting building block of the paper.

Figure 2. Histopathological evaluation of the ovarian mass. (A) Frozen section with a key field to render a diagnosis of cys-tadenofbroma. (B) The fibromatous component was composed of densely stromal areas, and (C) more edematous ones. (D) Cys-tadenofbroma had some wide papillae, with bland stroma and regular epithelial lining. (E) An area with ischemic and hemor-rhagic changes, possibly due to compression of this part of the mass. (F) An active chronic inflammatory infiltrate is evident close to such areas, shown by CD45 (LCA) immunostain.

Literature review

Our literature review found 43 articles (41 full texts and 2 abstracts), collecting 55 cases of Meigs syndrome with an increment of CA 125, resumed in Table 1. In addition to our patient, we reported 56 cases. The mean of the CA 125 level was 1112.35 ± 944.20 IU/mL, with 14 (25%) cases presenting an increment over 1000 IU/mL. The mean age of patients was 53.48 ± 16.97 years. In 27 (48.2%) cases, a unilateral adnexal mass was reported, with a mean of bigger tumor diameter of 15.73 ± 5.94 [other 10 cm in 44 (78.6%) cases]. Different histological types of mass such as fibroma and fibrothecoma (39 cases, 69.6%) were found. The ascites was found in 51 (91.1%) cases, while pleural effusion was found in 31 (55.4%) cases; moreover, in 23 (41.1%) cases, it was observed on the right side.

Table 1. Literature review.

Retrospective analysis

We compared two groups, divided considering the CA 125 values: 42 patients with CA 125 < 1000 IU/mL were grouped under the first group, and 14 patients with CA 125 = 1000 IU/mL were grouped under the second group. Table 2 shows the characteristics of the two study groups; they reported similar age, mass diameters, presence of ascites and hydrothorax, hydrothorax localization and its quantity. The groups did not differ significantly in the histological classification of ovarian masses. The group with elevated CA 125 = reported a higher incidence of the bilateral lesion (21.4 vs 2.4%, p = 0.04) and a bigger amount of ascites (4911.1 ± 2897.6 mL vs 1814 ± 2073 mL, p = 0.003). The results of the multivariate analysis are described in Table 3. In particular, the presence of bilateral masses and the ascites over 2 L represented independent risk factors for the elevation of CA 125 over 1000 IU/mL, while no influence seems to be reported by the tumor dimension, the presence of ascites or hydrothorax, and the histological origin of the mass. Specifically, bilateral masses increase the possibility to find an important increment of CA 125 over 1000 IU/mL of 13 times and the ascites quantity over 2 L of 6 times.

Table 2. Population characteristics.

Table 3. Multivariate regression analysis—influencing factors for CA 125 elevation over 1000.

Discussion

Ovarian fibroma is the most common tumor found in the case of Meigs syndrome, associated with ascites in 10–15% and with pleural effusion in 1% of cases (1, 6). Our review of literature collecting 43 articles (55 cases) of Meigs syndrome with CA 125 over the normal range confirmed that this condition the post-menopausal period (3, 9) and that it is correlated most frequently with fibroma or fibrothecoma more than other histotypes. Only 14 out of 56 patients (55 cases reported in the literature and 1 case in our study) presented a CA 125 over 1000 IU/mL, which is a rare condition (6, 11–17). In our comparison, we associated the increment of CA 125 of over 1000 IU/mL with a higher incidence of the bilateral lesion and a bigger amount of ascites (over 2 L), even if the presence of ascites itself is not a risk factor for the increment of CA 125. At multivariate analysis, we confirmed the univariate results: we found that bilateral masses increment by 13 times and the ascites quantity over 2 L increment by 6 times the possibility, to detect an important increment of CA 125 over 1000 IU/mL. To the best of our knowledge, this is the first review that tried to define an association between patient/mass characteristics and high increment of CA 125.

We are aware that using data from the literature could be a bias, but the strength of our paper is to try to define a connection between the pelvic mass elevation of CA 125 and patients’ characteristics in order to better understand the disease. Only a previous retrospective study that compared 580 patients with benign ovary masses showed an association between an increase of CA 125 > 35 IU/mL, ascites, hydrothorax, and tumor size > 10 cm, but it did not report possible factors determining a high increment of CA 125 (18). Our study is a comparison between masses collected by 33 years of literature review, with a lack of some patients’ data and possible confounding factors in the older paper, which are certain study biases However, the power of the review and our analysis concerning the rarity of Meigs syndromes, moreover in case of high elevation of CA 125, with difficulties in the possibility to collect an adequate number of cases. Therefore, we think that our contribution could be helpful in pre-surgery hypothesis; even in case of bilateral mass and high amount of ascites, a possibility of benignity could be maintained considering our results. Certainly, the differential diagnosis must be performed after surgery, with histological evaluation of the mass, to exclude malignancies; however, in case of ascites, pleural effusion, ovarian mass, or high increment of CA 125, the physician should shift malignant and benign mass hypothesis, especially in the absence of malignancy characteristics of tumor at the ultrasound and the absence of pelvic and peritoneal metastasis, omental cake, and lymph nodes involvement.

Conclusion

Meigs syndrome is a rare condition, which frequently mimics ovarian cancer. However, a possible hypothesis of a benign tumor, even if ovarian cancer must be suspected, could be maintained, moreover if there are no other malignancies characteristics. Indeed, we found that the presence of a bilateral mass and an elevated amount of ascites, typically found in ovarian cancer, determine a high increase of CA 125 in a benign condition like Meigs syndrome. This article guides a stepwise walkthrough by experts for writing a successful journal or a research paper starting from the inception of ideas till their publication. Research papers are highly recognized in the scholar fraternity and form a core part of PhD curriculum. Research scholars publish their research work in leading journals to complete their grades. In addition, the published research work also provides a big weightage to get admissions in reputed varsity. Now, in this study, we enlist the proven steps to publish the research paper in a journal.

Author contributions

AP wrote the manuscript and collected the data. SM collected the data and revised the manuscript. MM gave pathological information and revised the manuscript. CF performed the surgical and clinical management of the patient. AM revised the manuscript and managed the patient. CM performed the surgical and clinical management of the patient.

References