Meigs Syndrome

Etiology

The etiologies of ascites and pleural effusions that define Meigs syndrome are poorly understood. Instances in which pleural effusion occurs without ascites, otherwise known as atypical or incomplete Meigs syndrome, suggest that the collection of fluid in both cavities can occur as independent pathological conditions and thus must warrant investigation for overlapping or mimicking pathologies.[4]

Epidemiology

Meigs syndrome is diagnosed in association with approximately 1% of ovarian tumors, most of which are found to be benign ovarian fibroma on final histologic analysis. Ovarian fibromas are, in turn, found in 2% to 5% of surgically removed ovarian tumors.[5] About 10% to 15% of women with ovarian fibromas have ascites, and 1% have hydrothorax.[6] Approximately 70% of pleural effusions are right-sided, 15% left-sided, and 15% are bilateral.[7] Meigs syndrome is rare before the third decade, but the incidence progressively increases thereafter and peaks in the seventh decade of life.[8]

Pathophysiology

Pleural effusions in Meigs syndrome have been hypothesized to be secondary to the passage of ascitic fluid to the pleural space through the diaphragm or diaphragmatic lymph nodes.[9] Several mechanisms have been proposed for the underlying pathophysiology of ascites in these patients, including fluid leakage from edematous fibromas, tumor pressure on pelvic and abdominal lymphatics, and lymphatic blockage.[10]

Vascular endothelial growth factor that raises capillary permeability has also been associated with the development and accumulation of pleural and peritoneal fluid. This association was directly investigated by Ishiko et al who reported a significant difference between the vascular endothelial growth factor levels in the pleural and peritoneal fluid before and after tumor removal in patients with Meigs syndrome.[11] Nevertheless, these mechanisms remain poorly understood, and studies are ongoing.

Histopathology

Benign tumors associated with Meigs syndrome include fibromas, thecomas, Brener tumors, or granulosa cell tumors.[12] The following histological findings help differentiate these tumors from one another:

• Fibroma: Characterized by spindled, ovoid to round cells within a variably collagenous stroma.[13]
• Thecoma: Features ovoid to round nuclei and pale gray cytoplasm.[14]
• Brenner tumor: Contains ovarian transition cells surrounded by dense fibrous tissue.[15]
• Granulosa cell tumor: Consists of Call-Exner bodies, such as eosinophilic, fluid-filled spaces surrounded by a disorganized arrangement of granulosa cells; FOXL2 has been identified in 97% of granulosa cell tumors.[16]

History and Physical

Meigs syndrome typically presents in postmenopausal women.[17] Symptoms related to pleural effusion include dyspnea and dry cough. The pleural effusions are typically right-sided, even though the left and bilateral effusions are possible.[4] Patients with ascites often present with painful abdominal distension. Given these nonspecific symptoms, clinical suspicion of an ovarian mass may remain low for a prolonged period. Therefore, consideration of Meigs syndrome, among other differential diagnoses, is essential to avoid diagnostic delays.[18] Physical examination findings may include a palpable adnexal mass; signs of pleural effusion, such as diminished breath sounds, egophony on pulmonary auscultation, dullness on chest percussion, and jugular venous distension; and signs of ascites, such as distended abdomen with fluid shift.

Meigs syndrome most commonly presents in postmenopausal women; however, it can rarely present with symptoms in younger children and adolescents.[19] In these younger patients, Gorlin syndrome should be excluded when an ovarian mass is found alongside ascites and hydrothorax. Gorlin syndrome is an autosomal dominant familial cancer syndrome characterized by multiple neoplasms arising in childhood, including ovarian and cardiac fibromas. Given the association with numerous basal cell carcinomas and skeletal, ophthalmologic, and neurologic abnormalities, suspicion of Gorlin syndrome should prompt genetic testing so that dermatologic surveillance and radiological screening can be promptly initiated. Girls diagnosed with Gorlin syndrome, before identification of any adnexal masses, should undergo a pelvic ultrasound at menarche or by the age of 18 to check for ovarian fibromas.[20]

Evaluation

Obtaining a detailed history and performing a thorough physical examination are crucial for the initial diagnosis of Meigs syndrome. Characteristic clinical features include insidious abdominal distension and dyspnea with speech or mild exertion. Therefore, in patients with this presentation, imaging is indicated to assess for pelvic mass and associated pulmonary nodules, hepatic lesions, carcinomatosis, or other pathology suggesting malignancy. A definitive diagnosis of Meigs syndrome is only confirmed after surgical removal of the tumor with frozen section analysis identifying benign pathology. The resolution of hydrothorax and ascites following the mass removal provides additional diagnostic confirmation of Meigs syndrome.[19]

Laboratory Studies

Patients presenting with clinical features of Meigs syndrome should be assessed for underlying conditions such as anemia, macrocytosis, hypoalbuminemia, proteinuria, liver failure, and congestive heart failure with laboratory studies including complete blood count, comprehensive metabolic panel, coagulation studies, brain natriuretic peptide, and urinalysis. Laboratory studies not only aid in excluding these conditions as the etiology for the patient’s symptoms but also guide the medical optimization for surgery in these patients if their eventual diagnosis is consistent with Meigs syndrome.

Ovarian tumors have no specific diagnostic markers. Although typically associated with ovarian malignancy, elevated serum CA-125 levels have been noted in some cases of Meigs syndrome. Therefore, patients with elevated CA-125 levels and adnexal mass are often misdiagnosed as having ovarian malignancy.[21] However, elevated serum CA125 levels are also associated with other biochemical processes, including elevated intraperitoneal pressure caused by mechanical stimulation of ascites to the peritoneum or peritoneal mesothelial cells, which might be misdiagnosed as endometriosis or ovarian malignancy.[22]

Diagnostic Imaging 

Pelvic and abdominal ultrasonography are the preferred imaging techniques to assess suspected adnexal masses and associated ascites. In addition, this modality can visualize irregularities, septations, and other malignant features.[23] A chest x-ray may be performed to check for pleural effusions and any pulmonary nodules suspicious of malignancy, which may exclude Meigs syndrome.[9] Computed tomography (CT) of the chest, abdomen, and pelvis can exclude differential diagnoses of ascites, such as metastases, masses originating from the gastrointestinal tract, pulmonary lesions, and liver cirrhosis.

Positron emission tomography (PET)/CT may confirm the benign nature of the ovarian mass and determine whether other malignant lesions are present. For instance, PET/CT using a fludeoxyglucose F18 (18F-FDG) radiotracer performed 1 hour after the intravenous administration of 407 MBq of 18F-FDG shows mild uptake in the event of a benign ovarian tumor, whereas a malignant mass demonstrates higher 18F-FDG metabolism.[24]

Endoscopy

In patients with risk factors for gastrointestinal malignancy, an esophagogastroduodenoscopy and colonoscopy should be considered to rule out esophageal, gastric, and colon cancers.

Fluid Analysis and Cytology

Thoracentesis and paracentesis are diagnostic modalities that can also provide temporary symptomatic relief for patients with ongoing symptoms. Pleural fluid analysis includes protein, lactate dehydrogenase, cytology, gram stain, and cultures. In most patients with Meigs syndrome, the pleural fluid is exudative with no malignant cells.[9] However, there have also been reports of transudative effusions in these patients.

Tuberculosis Screening

As ascites and pleural effusions may also be associated with pelvic tuberculosis, the exclusion of tuberculosis should be considered in patients with risk factors based on their symptoms before surgery. Tuberculosis evaluation can be achieved through skin tests, pleural and peritoneal fluid testing for acid-fast bacillus smears and cultures, and molecular testing.[25]

Treatment / Management

Once malignancy and other differential diagnoses have been excluded, treatment for Meigs syndrome primarily involves curative and symptomatic approaches.

Curative Treatment

Surgical removal of the ovarian mass through laparotomy or with minimally invasive techniques, such as laparoscopy, with an intraoperative tissue sample sent for frozen section histologic confirmation is curative.[26] For benign disease in young women of reproductive age who desire preservation of fertility, a unilateral salpingo-oophrectomy is the gold standard treatment. In postmenopausal women, a total abdominal hysterectomy with bilateral salpingo-oophrectomy is recommended.[27] Removal of the tumor results in the resolution of ascites and pleural effusion and normalization of CA-125 in Meigs and pseudo-Meigs syndrome.[9](B3)

Symptomatic Treatment

Surgery may not be a feasible or desirable option for all patients, particularly those with significant medical comorbidities or those for whom extensive abdominal surgery is inconsistent with their goals of care. Symptom management and palliative care are the primary therapeutic approaches in these individuals. Repeated large-volume paracentesis or thoracentesis are palliative choices for these patients. Abdominal indwelling peritoneal catheter placement, which allows patients or their caregivers to drain ascites as needed at home, is also an option.[28] Repeated thoracentesis, indwelling pleural catheter, and pleurodesis are the available therapeutic modalities for symptomatic management of pleural effusion. Multiple studies have reported that indwelling pleural catheter placement not only results in adequate symptomatic control but may also lead to spontaneous pleurodesis.[29] Therefore, clinicians should counsel Meigs syndrome patients who are not ideal candidates for surgery on the variety of options available to provide symptomatic control.(A1)

Differential Diagnosis

The definitive diagnosis of Meigs syndrome can only be made once a tissue sample has been obtained and the etiology of the ovarian mass has been identified. Therefore, the exclusion of differential diagnoses is essential before definitive surgical planning. The following differential diagnoses should be considered:

• Ovarian malignancy
• Hepatic cirrhosis
• Nongynecologic malignancies also associated with ascites and hydrothorax, such as pancreatic, gastrointestinal, and lung cancers
• Congestive heart failure
• Nephrotic syndrome
• Tuberculosis
• Thoracic endometriosis
• Pseudo-Meigs syndrome: Ascites and pleural effusion in a patient with a pelvic or abdominal tumor other than fibroma; other benign ovarian cysts, such as struma ovarii, mucinous cystadenoma, and teratomas; uterine leiomyoma; and secondary metastatic ovarian tumors.[30]
• Tjalma syndrome: Also known as Pseudo-pseudo Meigs syndrome, a clinical manifestation of systemic lupus erythematous characterized by ascites, pleural effusions, and elevated CA-125 levels in the absence of an ovarian tumor, whether benign or malignant.[8]

Prognosis

Meigs syndrome is a benign condition, and early detection and intervention result in an excellent prognosis. Pleural effusion and ascites resolve completely once the tumor is resected. The postoperative life expectancy of patients with Meigs syndrome is equivalent to that of the general population.[8]

Complications

Unrecognized and untreated patients could be subjected to multiple thoracenteses and paracenteses, which could lead to complications including infection, bleeding, dehydration, pneumothorax, iatrogenic injury to the bowel during paracentesis, and hypoalbuminemia. In addition, in cases in which malignancy is misdiagnosed as Meigs syndrome, patients may develop metastatic disease, cachexia, deep venous thrombosis, intestinal obstruction due to mass effect, and other complications of untreated malignancy.