CASE REPORTS                              809
                          HYALURONIC A C I D *

          By   SAMUEL DVOSKIN,        Captain, MC, United States Army, New York, N. Y.

              HYALURONIC acid has been isolated from the pleural or peritoneal fluid
          associated with mesothelioma by Meyer and Chaffee x and Blix.2 In our case
          this finding led to the suspicion of the diagnosis of mesothelioma, later confirmed
          by the autopsy findings.
                                                    CASE REPORT

               A 27 year old white female was admitted to the United States Army Hospital,
          Fort McClellan, Alabama, on May 1, 1952, for repair of a left inguinal hernia. Con-
          valescence was uneventful, and she was discharged on May 8. Several days after
          discharge from the hospital the patient noted that her abdomen was enlarging. On
          May 10 she developed left lower abdominal pain, accompanied by nausea and vomiting.
          She was re-admitted to the hospital on May 14. Complete system review was non-
          contributory. On examination no abnormality was found except for a markedly en-
          larged abdomen with evidence of fluid. No definite mass could be palpated. Rectal
          and pelvic examinations were within normal limits. No evidence of peripheral edema
          was found.
               On May 19 an exploratory laparotomy was performed. The entire peritoneum
          and omentum were found studded with multiple single and confluent nodules. The
          left ovary and a wedge of the greater omentum were removed for biopsy. The initial
          pathologic report was that of a chronic inflammation of these organs.
               Following surgery, the patient deteriorated rapidly. She required six abdominal
          paracenteses, which were performed in the interval between May 27 and June 11,
          each productive of approximately 6,000 c.c. of viscous mucoid brownish fluid. This
          fluid had a specific gravity of 1.018 and a protein content of 4.0 gm. per cent, and
          contained about 300 white blood cells per cubic centimeter. Repeated cultures for
          pathogens and search for tubercle bacilli were negative. Papanicolaou smears were
          reported as showing mesothelial cells. The fluid gave a positive test for "mucin,"
          using acetic acid. The addition of hyaluronidase to the fluid in vitro, followed by
          incubation at room temperature for 15 minutes, markedly reduced its viscosity as
          judged by gross examination. A specimen of the fluid was analyzed by Dr. Karl
          Meyer 3 at Columbia University. It contained 0.103 per cent sodium hyaluronate.
               The following laboratory data were obtained: Serum proteins ranged from 4.9
          to 4.3 grams per cent. The patient developed no evidence of anemia, and maintained
          her hemoglobin at approximately 16 gm. per cent. Her white blood cells increased
          from a level of 11,000 on admission to 25,000 the day before her death. Her admis-
          sion erythrocyte sedimentation rate was 26 mm. and fell to 4 mm., then to 2 mm.
          shortly before death.
               The patient had unusual difficulty in retaining food and was sustained by paren-
          teral fluids. She was afebrile during her entire illness. She developed terminal
          shock and anuria, and died on June 12, 1952.
               A complete autopsy, exclusive of the brain and spinal cord, revealed no evidence
          of significant abnormality except for the findings in the thoracic and abdominal
          cavities. The pleural cavities were free of fluid. The dome of the right diaphragm
          was high and was studded on the abdominal side with numerous white nodules, both
               * Received for publication August 31, 1953.

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         810                                  SAMUEL DVOSKIN

         single and confluent. A firm node measuring 2 cm. in diameter was found in the
         right side of the lower part of the anterior mediastinum which, on section, was com-
         posed of white homogeneous tissue. The lungs were grossly normal. There were
         approximately 100 c.c. of gelatinous viscous yellow fluid in the abdominal cavity.
         The parietal peritoneum was everywhere adherent to the greater omentum. The
         omentum was whitish red in appearance and markedly thickened, and its surface was
         everywhere studded with single and confluent nodules, varying in size from several
         millimeters to several centimeters in diameter. On section, the omentum was in-
         filtrated and virtually replaced by these nodules. The liver, spleen, stomach and
         intestines were not abnormal except for the presence of numerous nodules infiltrating
         the hila and mesenteric borders of these organs. The usual fatty structure of the
         appendices epiploicae was replaced by whitish nodular tissue. The serosal surfaces
         of the uterus, the right ovary and the tubes were covered and embedded in a confluent
         mass of nodular tissue.
              The principal finding on microscopic examination was the presence of peritoneal
         neoplastic lesions on the serosal surface of practically all of the abdominal and pelvic
         organs, and in the single lymph node in the anterior mediastinum. The neoplasm
         was composed of anaplastic cells that were closely related morphologically to meso-
         thelial cells. These cells had either oblong, oval or round nuclei that were vesicular,
         and cytoplasm that was swollen and finely granular. Partially necrotic areas were
         present. The sections were examined by Dr. Arthur Purdy Stout,4 who found that,
         at the time of the autopsy, the cells seemed entirely undifferentiated with no tendency
         to form tubes or papillary projections. In terms of his classification the tumor was a
         malignant diffuse tubular mesothelioma, undifferentiated.


             Earlier reports described the presence of hyaluronic acid in the amount of
         0.142 to 0.187 per cent as polysaccharide * and 0.7 per cent as hyaluronic acid 2
         in the peritoneal or pleural fluid associated with mesothelioma. In this case,
         0.103 per cent of sodium hyaluronate was recovered from the peritoneal fluid.
         The significance of this finding remains to be determined, since no survey has
         been reported of the content of hyaluronic acid in ascitic fluids due to other
         causes. Hyaluronic acid has been isolated from tissues of mesenchymal origin
         such as vitreous humor, umbilical cord and synovial fluid. Isolation of this
         substance from the ascitic fluid in cases of mesothelioma could be regarded as sug-
         gestive biochemical evidence of the mesenchymal origin of such tumors, a matter
         about which there has been some controversy.
             The short duration of this patient's illness—one month from onset of
         symptoms to death—again raises the speculation initially voiced by Meyer and
         Chaffee,1 that the invasiveness of neoplasms might be related to the presence of
         hyaluronic acid or similar constituents which might influence host resistance.
         This situation pertains in the case of infections where the virulence of bacteria
         is greatest in those which possess mucoid capsules containing hyaluronic acid.
         That other factors are involved is apparent from the case reported by Truedsson,5
         in which a period of over two years elapsed between onset of symptoms and death.


              A case of mesothelioma of the peritoneum is reported in which a viscous
          ascitic fluid was found to contain hyaluronic acid. This finding early in the

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                                                    CASE REPORTS                                   811
          patient's course led to the suspicion of the diagnosis of mesothelioma, later con-
          firmed by the autopsy findings.

          1. Meyer, K., and Chaffee, E.: Hyaluronic acid in the pleural fluid associated with a ma-
                 lignant tumor involving the pleura and peritoneum, J. Biol. Chem. 133: 83-91, 1940.
          2. Blix, G.: Hyaluronic acid in the pleural and peritoneal fluids from a case of mesothelioma,
                 Acta Soc. Med. Upsal. 56: 47-50, 1951.
          3. Meyer, K.: Personal communication, 1952.
          4. Stout, A. P.: Personal communication, 1952.
          5. Truedsson, E.: A case of mesothelioma of the pleura and peritoneum producing hyaluronic
                 acid, Acta Soc. Med. Upsal. 56: 39-45, 1951.

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