Recurrent Ascites and Pleural Effusions After Surgery for Early-Stage Endometrial Adenocarcinoma.

ABSTRACT: A case of massive postoperative ascites in a woman treated for endometrial cancer is reported. A workup for typical causes of ascites yielded negative results, prompting a more detailed analysis of the patient's condition. Hypothyroidism was discovered. After correction of the hypothyroidism, the ascites slowly resolved. Since myxedema is an unconunon cause of ascites, this is usually a diagnosis of exclusion. However, hypothyroidism must be ruled out to prevent unnecessary and possibly inappropriate treatments for ascites.

ASCITES OCCASIONALLY OCCURS in patients with endometrial cancer and is usually associated with advanced-stage disease. The presence of cell washings positive for malignant ascites in the absence of other extrauterine spread upstages endometrial cancer to stage IIIA, according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. However, malignancy is not the only etiology of ascites in patients seen by a gynecologic oncology service. The causes of inn-a-abdominal fluid accumulation in a postoperative patient are multiple. These include malignancy, liver disease, infectious causes, endocrine problems, and other medical etiologies. As illustrated by our case report, a thorough workup is needed to determine the cause of the ascites and the appropriate treatment. Failure to correctly diagnose the source of ascites can lead to incorrect treatments that may further compromise the health of an oncology patient. Myxedema is an uncommon cause of ascites and is a diagnosis of exclusion. H owever, ascites that is not correctable by other methods may be amenable to treatment with correction of thyroid function, and this diagnosis must be considered during the workup for patients with ascites.

CASE REPORT

A 70-year-old white woman, gravida 2 para 2, was referred to our gynecologic oncology service after her general obstetrician/gynecologist diagnosed adenocarcinoma of the endometrium by endometrial biopsy after postmenopausal bleeding. Her medical history was significant for hypertension, type 2 diabetes, gastroesophageal reflux disease, dyspepsia, lacunar infarcts, appendectomy, and tonsillectomy with adenoidectomy. Medications at that time included atenolol, omeprazole, and cisapride. The patient denied any bistory of liver, pancreatic, or renal disease or other medical problems. The initial serum cancer antigen 125 (CA 125) level was [greater than]500 U/mL (normal, [less than]35 U/mL). A surgical staging procedure was planned within 2 weeks of diagnosis.

Preoperative laboratory values were white blood cell (WBC) count 3,300/[mm.sup.3] (normal, 4,500 to 11,000/[mm.sup.3]), hemoglobin 12.8 g/dL (normal, 11.7 to 16.1 g/dL), hematocrit 38.7% (normal, 35.0% to 47.0%), platelet count 205,000/[mm.sup.3] (normal, 150,000 to 450,000/[mm.sup.3]), mean corpuscular volume (MCV) 98.9 [micro][m.sup.3] (normal, 81.0 to 102.03 ), [micro][m.sup.3] prothrombin time 11.5 sec (normal, 10.0 to 13.2 sec), partial thromboplastin time 29.9 sec (normal, 22.4 to 32.8 sec), and albumin 4.1 g/dL (normal, 3.0 to 5.0 g/dL); electrolyte and liver enzyme values were normal.

The patient had an exploratory laparotomy with bilateral salpingo-oophorectomy, pelvic lymph node dissection, and high common iliac node sampling. A minimal amount (50 mL) of clear, yellowish abdominal fluid was found at the time of the procedure. Final pathology revealed pelvic washings to be negative for malignant cells. An intraoperative frozen section revealed probable superficial invasion. The grade 2 adenocarcinoma was confined to the endometrium, making the surgical stage IA. Despite the limited spread of the tumor, a full staging procedure was done to rule out pelvic node metastases, which can occur with grade 2 endometrial adenocarcinoma. All excised nodes were negative for metastases. The ovaries and tubes were normal.

Due to an acute intraoperative hypotensive episode, acute tubular necrosis developed postoperatively, and the patient was admitted to the intensive care unit for several days. Estimated blood loss was 300 mL. Although the intraoperative blood loss was fairly small, the hemoglobin level was found to have decreased by 3 g. To optimize oxygen-carrying capacity during this period, the patient received a transfusion of 2 units of packed red blood cells (PBCs). Hemodialysis was required for a transient period, but the patient was discharged home in stable condition after a hospital stay of 2 weeks. The patient was seen for a postoperative check 6 weeks after surgery, and examination results were normal.

Follow-up examinations remained unremarkable. Ten weeks after the procedure, the patient came to the emergency department with progressive abdominal swelling and right upper quadrant pain, which had been uncontrolled by narcotic analgesics. She denied having fevers, chills, nausea, vomiting, chest pain, dizziness, bowel complaints, or urinary difficulties. A physical examination revealed that she was afebrile, with a blood pressure of 159/99 mm Hg, pulse rate of 63/mm, respiratory rate of 24/mm, and oxygen saturation of 90%. Breath sounds were decreased over the lung bases bilaterally. The abdomen was distended with decreased bowel sounds, and the patient complained of mild right upper quadrant tenderness. The pelvic examination was normal for a postsurgical state. Pretibial edema (1+) was present in the extremities. Laboratory studies showed a hemoglobin level of 12.0 g/dL (normal, 11.7 to 16.1 g/dL) and MCV of 106.3 [micro][m.sup.3] (normal, 81.0 to 102.03 [micro][m.sup.3]), normal electrolyte values, normal liver function and amylase values, and a slightly low albumin level at 2.7 g/dL (normal, 3.0 to 5.0 g/dL).

Radiologic studies consisted of an abdominal series and chest film and showed bilateral pleural effusions that were slightly greater on the left than the right. There was no evidence of bowel obstruction, but intra-abdominal fluid was seen. The preliminary diagnosis on admission was abdominal ascites and pleural effusions of unknown etiology, and oxygen was administered by nasal canula. Macrocytosis, found on complete blood count, was believed to be due to inadequate nutritional intake, and folic acid supplements were begun. Abdominal ultrasonography with possible paracentesis was planned. The differential diagnosis included urinary leakage from intraoperative injury, occult liver disease, portal vein thrombosis, cardiogenic ascites, hypothyroidism, carcinomatosis, peritonitis, and infectious etiologies. Nephrology and gastroenterology consultations were obtained.

Abdominal ultrasonography revealed massive ascites, and paracentesis returned 6 L yellow, straw-colored fluid. Analysis of this fluid yielded 40 RBCs, 178 WBCs (91% mononuclear cells, 9% polymorphonuclear neutrophil leukocytes), sodium 137 mEq/L, glucose 113 mg/dL, creatinine 1.2 mg/dL (equal to the serum creatinine value), and potassium 3.7 mEq/L. Cytology later revealed that the fluid was negative for malignant cells. The patient had some symptomatic improvement after the paracentesis. A renal scan was also done that day and showed normal kidneys. Additionally, computed tomography (CT) of the chest and abdomen with intravenous contrast medium revealed no lymphadenopathy or lung nodules visible, and no masses were seen. Fluid was present (Figs 1 and 2). The ureters were intact. A purified protein derivative test was negative for tuberculous peritonitis. Despite all of the data available, the etiology of the ascites and pleural efiusions remained unclean.

On hospital day 3, other laboratory values were obtained. These included thyrotropin 177 [micro]U/mL (normal, [less than]5 [micro]IU/mL and serum free thyroxine 1.3 [micro]g/dL (normal, 5 to 12 [micro]g/dL), consistent with marked hypothyroidism. A total cholesterol level was measured at 220 mg/dL. Levothyroxine therapy was begun, but the question remained: was this just a coincidence or the cause of the hypothyroidism? The ascites slowly reaccumulated over several days, and the patient required two additional therapeutic paracenteses. In addition, a thoracentesis on hospital day 5 provided some symptomatic relief. Examination of the pleural fluid revealed no malignant cells or organisms, and protein content was measured at 3.1 g/L. Results of echocardiography and Doppler ultrasonography of the hepatic venous system were negative, ruling out hepatic vein thrombosis. A hepatitis screen yielded negative results.

Occult liver disease was thought to be unlikely due to the low albumin level, and a liver biopsy was not done at this time. The ascites was noted to gradually reaccumulate but at a much slower rate while the patient was taking levothyroxine. She was eventually discharged on hospital day 11 after a total of three paracenteses and two thoracenteses. Although some ascites remained, the patient was improving symptomatically. A diuretic was given. She was restored to the euthyroid state 5 months after discharge, and the ascites resolved after 8 months. Levels of GA 125 dropped to less than 15 U/mL after 12 months. In 35 months of follow-up after surgery, serial CT scans showed no evidence of recurrent ascites. Chest radiographs have been normal, and there has been no evidence of recurrent endometrial cancer.

DISCUSSION

Myxedema ascites is an uncommon manifestation of hypothyroidism. Ascites complicates hypothyroidism in approximately 4% of cases. The clinical picture as summed up in several case reports [1-3] indicates that the ascites is usually of long duration and resolves with thyroid replacement. There is a slight female predominance, as there is with typical hypothyroidism. Ascites is usually straw-colored and has a high serum-to-ascites albumin gradient. [2,4] Liver biopsies done on patients with this condition show a central fibrosis similar to that seen with cardiogenic ascites. [5] Ascitic fluid is sometimes exudative in type. [1,6] Also, a high proportion of lymphocytes is seen in the fluid. [7] Although our patient's case did not uniformly meet all these criteria, no other etiology of ascites could be found. Ascites of hypothyroidism is often a diagnosis of exclusion. It was likely the cause of ascites in our patient.

The pathologic basis of these conditions remains unknown, but several theories have been proposed, including increased capillary permeability, obstruction of lymphatics by hyaluronidase-albumin complexes, and impairment of free water secretion. [4] Myxedema patients have been shown to have increased capillary permeability in skin samples. It is hypothetically possible that the same could be seen in vessels in the abdomen. [4]

Despite the lack of understanding about the pathology of myxedema ascites, it should be considered as a possible diagnosis early to prevent inappropriate use of diuretics or even unnecessary laparotomy to determine the cause. The thorough workup and appropriate treatment in our patient circumvented another laparotomy. When ascites is encountered in a postoperative patient, even if the procedure was done for malignancy, hypothyroidism should be included in the differential diagnosis.

References

(1.) Sasaki H, Matsumoto S, Shijyo H, et al: Gross ascites as a first manifestation of primary hypothyroidism due to post-treatment of radioiodine therapy for Graves' disease. Intern Med 1992; 31:256-259

(2.) de Castro F, Bonacini M, Walden JM, et al: Myxedema ascites. report of two cases and review of the literature. J Clin Gastroenterrol 1991; 13:411-414

(3.) Chiprut RO, Knudsen KB, Liebermann TR, et al: Myxedema ascites. Am J Dig Dis 1976; 21:807-808

(4.) Wegdam JA, Kooistra HM, Kingma BJ, et al: Ascites due to hyperthyroidism. Ned Tijdschr Geneeskd 1997; 141:1741-1743

(5.) Baker A, Kaplan M, Wolfe H: Central congestive fibrosis of the liver in myxedema ascites. Ann Intern Med 1972; 77:927-929

(6.) Danilewitz M, Barbezat GO, Helman GA, et al: Myxoedema presenting with ascites: a case report. S Afr Med J 1977; 52:895-896

(7.) Desrame J, Mathurin P, Rozov R, et al: Isolated ascites revealing a hypothyroidism. study of 2 cases. Gastroenterol Clin Biol 1998; 22:732-735

KEY POINTS

* Myxedema ascites is an uncommon manifestation of hypothyroidism.

* Ascites usually has a long duration and resolves with thyroid replacement.

* There is a slight female predominance as with typical hypothyroidism.

* Ascites is usually straw-colored and has a high serum-to-ascites albumin gradient.

* Ascitic fluid is sometimes exudative, and there are a large amount of lymphocytes in the fluid.

* Several theories have been proposed for increased capillary permeability, obstruction of lymphatics by hyaluronidase-albumin complexes, and impairment of free water secretion.