Meigs Syndrome

Background

Meigs syndrome is defined as the triad of benign ovarian tumor with ascites and pleural effusion that resolves after resection of the tumor. Ovarian fibromas constitute the majority of the benign tumors seen in Meigs syndrome. Meigs syndrome, however, is a diagnosis of exclusion, only after ovarian carcinoma is ruled out.^[1]

In 1934, Salmon described the association of pleural effusion with benign pelvic tumors. In 1937, Meigs and Cass described 7 cases of ovarian fibromas associated with ascites and pleural effusion.^[2] The syndrome was named as Meig’s syndrome by Rhoads and Terrel in 1937.^[3] In 1954, Meigs proposed limiting true Meigs syndrome to benign and solid ovarian tumors accompanied by ascites and pleural effusion, with the condition that removal of the tumor cures the patient without recurrence. Histologically, the benign ovarian tumor may be a fibroma, thecoma, cystadenoma, or granulosa cell tumor.

Pseudo-Meigs syndrome consists of pleural effusion (an example of which can be seen in the image below), ascites, and benign tumors of the ovary other than fibromas. These benign tumors include those of the fallopian tube or uterus and mature teratomas, struma ovarii, and ovarian leiomyomas.^[4] This terminology sometimes also includes ovarian or metastatic gastrointestinal malignancies.

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Chest radiograph showing left-sided pleural effusion.

Atypical Meigs characterized by a benign pelvic mass with right-sided pleural effusion but without ascites has been reported at least twice. As in Meigs syndrome, pleural effusion resolves after removal of the pelvic mass.

Pseudo-pseudo Meigs syndrome includes patients with systemic lupus erythematosus and enlarged ovaries.^[5]

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Pathophysiology

Ascites is present in 10-15% of cases, and hydrothorax is found in only 1% of cases.^{[6, 7]}

Etiology of ascitic fluid

The pathophysiology of ascites in Meigs syndrome is speculative. Meigs suggested that irritation of the peritoneal surfaces by a hard, solid ovarian tumor could stimulate the production of peritoneal fluid. Samanth and Black studied ovarian tumors accompanied by ascites and found that only tumors larger than 10 cm in diameter with a myxoid component to the stroma are associated with ascites.^[8] These authors believe that their observations favor secretion of fluid from the tumor as the source of the ascites.

Other proposed mechanisms are direct pressure on surrounding lymphatics or vessels, hormonal stimulation, and tumor torsion. Development of ascites may be due to release of mediators (eg, activated complements, histamines, fibrin degradation products) from the tumor, leading to increased capillary permeability.

Origin of pleural effusion

The etiology of pleural effusion is unclear. Efskind and Terada et al theorize that ascitic fluid is transferred via transdiaphragmatic lymphatic channels. The size of the pleural effusion is largely independent of the amount of ascites. The pleural fluid may be located on the left side or may be bilateral.^{[1, 9, 10]}

Efskind's study

Efskind injected ink into the lower abdomen of a woman with Meigs syndrome and found that the ink particles accumulated in the lymphatics of the pleural surface within half an hour. Blockage of these lymphatics prevented accumulation of pleural fluid and caused an increase in ascitic fluid.

Terada and colleagues' study

In 1992, Terada and colleagues injected labeled albumin into the peritoneum and found that the maximum concentration was detected in the right pleura within 3 hours.

Nature of the ascitic and pleural fluid

Ascitic fluid and pleural fluid in Meigs syndrome can be either transudative or exudative. ^[9]  Meigs performed electrophoresis on several cases and determined that pleural and ascitic fluids were similar in nature. Tumor size, rather than the specific histologic type, is thought to be the important factor in the formation of ascites and accompanying pleural effusion.

In 2015, the findings of Krenke et al. in their systematic literature review of 541 cases reported with Meig’s syndrome revealed that an exudative origin in pleural effusions was significantly more prevalent than the ones from transudative origin.^[11]

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Epidemiology

Frequency

United States

Ovarian tumors are more prevalent in women in upper socioeconomic groups. Ovarian fibromas represent approximately 2-5% of surgically removed ovarian tumors, and Meigs syndrome occurs in only 1-2% of these cases; thus, it is a rare condition. Ascites is present in 10-15% of women with ovarian fibroma, and hydrothorax is present in 1%, especially those with larger lesions.

Age-related demographics

The incidence of ovarian tumor begins to increase in the third decade and increases progressively in postmenopausal women, with an average of about 50 years.^{[1, 9]} Meigs syndrome in prepubertal girls with benign teratomas and cystadenomas has been reported.

International statistics

The international prevalence is unknown.

Mortality/Morbidity

Life expectancy of patients with Meigs syndrome mirrors that of the general population after surgery, and less than 1% of fibromas progress to fibrosarcoma.

Although Meigs syndrome mimics a malignant condition, it is a benign disease and has a very good prognosis if properly managed. Life expectancy after surgical removal of the tumor is the same as the general population.^[10]

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History

Patients with Meigs syndrome may have a family history of ovarian cancer. The chief complaints are vague and generally manifest over time; they include the following:

• Fatigue
• Shortness of breath
• Increased abdominal girth
• Weight gain/weight loss
• Nonproductive cough
• Bloating
• Amenorrhea for premenopausal women
• Menstrual irregularity

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Physical

Positive signs include the following:

• Vital signs - Tachypnea, tachycardia
• Lungs - Dullness to percussion; decreased tactile fremitus; decreased vocal resonance; decreased breath sounds, suggesting pleural effusion, which is mostly observed on the right side but can also be left sided
• Abdomen - Most patients present with an asymptomatic, solid, and unilateral pelvic mass, most often left sided; the mass may be large,^[6] but sometimes, no mass is felt; ascites is present, with shifting dullness and/or fluid thrill
• Pelvis - Examination reveals a pelvic mass

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Causes

When an ovarian mass is associated with Meigs syndrome and an elevated CA-125 serum level, a malignant process may be suspected until proven otherwise histologically. A negative cytologic examination result of ascitic effusion, the absence of peritoneal implantation, and benign histology should limit surgical procedures. This decision should be made by an experienced gynecologic surgeon or a gynecologic oncologist.

Note the following:

• Case reports exist of pseudo-Meigs syndrome associated with malignant struma ovarii and elevated CA-125 levels.^{[12, 13]} The choice of not performing adjuvant therapy is feasible after optimal surgery and adequate staging procedure given to the usually clinical benign course and the low incidence of metastases in malignant struma ovarii. Careful patient counseling is required.
• Struma ovarii is a rare cause of ascites, hydrothorax, elevated CA-125 levels, and hyperthyroidism.^[13] This rare condition should be considered in the differential diagnosis in patients with ascites and pleural effusions but with negative cytologic test results.
•  Liao and colleagues reported a case of right benign struma ovarii in a patient presenting with ascites and CA-125 of 3515 U/Ml, who presented complete remission of symptoms and return to normal CA-125 after surgical resection of the mass.^[3]
• The combination of ascites, pleural effusion, CA-125 level elevation, and no tumor in a patient with systemic lupus erythematosus is either a Tjalma syndrome or due to the migrated Filshie clips a pseudo-Meigs syndrome.^[14]

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Laboratory Studies

CBC count

This study provides information about hemoglobin, hematocrit, and platelet levels. A low hemoglobin count requires further workup, including reticulocyte count, total iron-binding capacity, and iron and ferritin levels. Anemia in patients with Meigs syndrome is most likely due to iron deficiency. Anemia can be corrected emergently by blood transfusion in patients undergoing surgery for Meigs syndrome. Anemia can be treated with iron supplementation postoperatively.

Basic metabolic profile

Studies of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, and glucose levels are included. These electrolytes are checked before the patient undergoes surgery. If necessary, corrections of these electrolytes are made.

Prothrombin time

Prothrombin time is checked before surgery. If elevated, it is a marker of coagulopathy. Elevated prothrombin time is corrected before surgery, either by administering vitamin K to the patient or by transfusing fresh frozen plasma.

Serum cancer antigen 125 test

Other than serum electrolytes and CBC count, the study of interest is the serum cancer antigen 125 (CA-125) test. Tumor marker serum levels of CA-125 can be elevated in Meigs syndrome, but the degree of elevation does not correlate with malignancy. In fact, a normal CA-125 level does not exclude the possibility of malignancy.^[15] The CA-125 level is not used as a screening test. Immunohistochemical studies suggest that serum CA-125 elevation in patients with Meigs syndrome is caused by mesothelial expression of the antigen rather than by fibroma.^[1] The highest reported level of CA-125 after laparotomy is 1808 U/mL. This would be a false-positive result.

Physiologic sources of CA-125 are fetal coelomic epithelium and its derivatives, including the following:

• Müllerian epithelium
• Pleura
• Pericardium
• Peritoneum

Pathologic conditions related to an elevated CA-125 level include the following:

• Pelvic inflammatory disease (PID)
• Peritoneal damage or regeneration (eg, abdominal surgery)
• Ovarian malignancy
• Endometriosis

In 1992, Lin et al conducted a study to determine whether the ovarian fibroma was the source of serum CA-125 elevation. Using an immunohistochemical technique specific for the tumor marker, they localized CA-125 expression in the omentum and peritoneal surfaces rather than in the fibroma.^[16]

Papanicolaou test

Papanicolaou test findings are normal.

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Imaging Studies

Chest radiography confirms pleural effusion.

Abdominal and pelvic ultrasound confirms the ovarian mass and ascites.

CT scan of the abdomen and pelvis

CT scanning confirms ascites and ovarian, uterine, fallopian tube, or broad ligament mass.

No signs of distant metastasis are observed.

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Procedures

Paracentesis

Ascitic fluid is mostly transudative. Findings are negative for malignant cells but can be positive for reactive mesothelial cells.

Thoracentesis

Pleural fluid is usually transudative. Findings can be exudative and negative for malignant cells.

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Histologic Findings

Ovarian tumors are divided into the following histologic subgroups, and Meigs syndrome can be observed with any of the benign tumors.

Coelomic epithelial tumors

These tumors, which originate from the coelomic epithelium, constitute 80-85% of all ovarian tumors.

• Serous cystadenoma and mucinous cystadenoma: 15-20% are malignant.
• Endometrioid type and clear cell: 95-98% are malignant.
• Brenner tumor: 2% are malignant.

Germ cell tumors

These tumors originate from the germ cell and constitute 10-15% of all ovarian tumors. All are malignant except mature teratomas and gonadoblastomas, which are always benign.

• Mature teratoma
• Immature teratoma
• Dysgerminoma
• Gonadoblastoma
• Endodermal sinus
• Embryonal carcinoma
• Nongestational choriocarcinoma

Gonadal-stromal cell tumors

Gonadal-stromal cell tumors constitute 3-5% of all tumors.

• Granulosa cell
• Fibroma: Fewer than 5% are malignant.
• Thecoma: Fewer than 5% are malignant.
• Sertoli-Leydig cell: Fewer than 5% are malignant.
• Lipid cell type: 30% are malignant.
• Gynandroblastoma: 100% are malignant.

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Medical Care

Medical care of patients with Meigs syndrome is intended to provide symptomatic relief of ascites and pleural effusion by means of therapeutic paracentesis and thoracentesis.

Consultations

Consult with a gynecologic surgeon for surgical management of the patient.

Consult with a pulmonologist for management of pleural effusion. Medical pleuroscopy is typically not indicated but may be useful in complicated patients.

Activity

Patients can maintain activities as tolerated.

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Surgical Care

Note the following:

• Resolution after tumor resection has been widely documented.  ^{[3, 17, 9]}
• Exploratory laparotomy with surgical staging is the treatment of choice. Perform a frozen section of the ovarian mass during exploratory laparotomy. If the frozen section is consistent with benign tumor, conservative surgery (salpingo-oophorectomy or oophorectomy) is appropriate. Findings of lymph node biopsies and omentum and pelvic washings are negative for malignancy if these procedures are performed during surgery.
• In women of reproductive age, perform unilateral salpingo-oophorectomy.
• In postmenopausal women, options include bilateral salpingo-oophorectomy with total hysterectomy and unilateral or occasionally bilateral salpingo-oophorectomy.
• In prepubertal girls, options include wedge resection of ovary and unilateral salpingo-oophorectomy.
• The cure rate after either type of surgery is high and recurrence is rare.

Observe standard postsurgical management protocols.

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Further Outpatient Care

As described by Meigs, ascites and pleural effusion resolve dramatically within a few weeks to months after removal of the pelvic mass, without any recurrence. Use of chest ultrasound to follow pleural effusion progression is superior to chest radiography in identifying residual pleural effusion and can detect amounts as small as 3-5 mL.^[1]

The serum CA-125 level also returns to normal after surgery.

For patient education resources, see Women's Health Center and Cancer Center, as well as Ovarian Cancer.

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Prognosis

Meig's syndrome is a benign disease, if properly treated. No recurrence after sugical removal of the mass has been reported.

Clinicans should be aware of this rare and treatable condition.

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