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Amylase elevation attributable to an ovarian neoplasm
0016~5085/78/7405-0907$02.00/O GASTROENTEROLOCY 74907-909, 1978 Copyright0 1978by the AmericanGastroenterological Association
Vol. 74, No. 5, Part1 Printedin Lr3.A.
AMYLASE ELEVATION ATTRIBUTABLE MARVIN B. CORLETTE, M.D.,
TO AN OVARIAN NEOPLASM
MORRIS DRATCH, M.D.,
Mount Auburn Hospital and the Department Massachusetts
of Pathology,
AND KARL SORGER, M.D.
Mount Auburn Hospital, Cambridge,
An ovarian carcinoma producing amylase-rich ascites and pleural effusions is reported; salivary type amylase was identified in tumor tissue. A variety of nonpancreatic diseases and tumors of lung, parotid, ovary, and other organs have been associated with elevated amylase in serum or body fluids. Amylase isoenzyme electrophoresis is of value in differentiating pancreatic from nonpancreatic sources of increased amylase. The finding of an elevated amylase in body fluids generally leads to consideration of pancreatic cause, yet many other sources of hyperamylasemia and amylaserich pleural effusion or ascites exist. This paper documents an unusual source for amylase in serum and pleural and ascitic fluid, and reviews the nonpancreatic causes for elevated body fluid amylase.
creatinine clearance ratio was 2.1%. Repeat upper gastrointestinal X-ray studies suggested the presence of a mass in the pelvis. While being evaluated she developed acute bacterial endocarditis with temperature of 40°C and blood cultures were positive for streptococcus, which proved fatal. At autopsy the pancreas, pancreatic duct, and biliary tree were normal. There were bilateral pleural effusions, and there was ascites. In the pelvis there was a partially necrotic, multiloculated tumor mass which arose from the left ovary and measured 20 cm in greatest dimension. Microscopically the tumor was a mutinous cystadenocarcinoma of low grade malignancy. There were no metastases. There was a congenital defect in the right diaphragmatic dome which allowed abdominal fluid access to the right pleural cavity. The patient expired as a result of subacute bacterial endocarditis of the aortic valve with perforation of the noncoronary cusp. Additional studies: mutinous contents of the ovarian carcinoma were aspirated and subjected to amylase determinations by the Dy Amy1 amyloclastic method (General Diagnostics). The amylase was strikingly elevated (32,960 U per 100 ml or 1,831 U per g of wet tumor tissue). There was no detectable lipase activity. An extract of tumor tissue was subjected to sheet polyacrylamide electrophoresis which revealed the tumor amylase to have the mobility of human salivary amylase (courtesy of Dr. Andrew Warshaw, Massachusetts General Hospital). Immunofluorescence studies using a rabbit antihuman conjugate against salivary type amylase showed ectopic amylase production in tumor cells but not in stromal cells.*
Case Report An 84-year-old female was hospitalized complaining of anorexia, upper abdominal discomfort, and dyspnea of 3-week duration. On examination she was afebrile, the respiratory rate was 40; the right chest was dull to percussion, the abdomen was full but no ascites was detected, and a pelvic examination was normal. A chest X-ray showed almost total opacification of the right lung field and 600 ml of clear fluid was obtained on aspiration of the right pleural space. The pleural fluid protein was 3.1 g per dl, the amylase was in excess of 45,000 Somogyi units per dl (normal, 40 to 2251, and the cell block was negative. The serum amylase was 750 Somogyi units per dl, and the serum lipase was 2.5 IU per dl (normal up to 1 III). Upper gastrointestinal series, oral cholecystogram, and abdominal ultrasound examinations were normal. An amylase-to-creatinine clearance ratio was 1.6% (normal, up to 2.3%). A hepatic scan was normal. She began to feel better and was discharged. During the following 6 months the patient lost 30 lb and required repeated thoracenteses. Serum amylase ranged from 500 to 700 Somogyi units per dl and pleural fluid amylase from 6,000 to 14,000 Somogyi units per dl. Ascites then appeared and yielded 6000 Somogyi units per dl of amylase. Repeated cytological examinations of both the pleural and abdominal fluids failed to yield malignant cells. The patient was then rehospitalized for massive recurrent right pleural effusion and congestive heart failure. The abdominal and pelvic examinations were unrevealing because of the ascites. The serum lipase was 1.7 IU, the amylase-to-
Discussion
Received September 6, 1977. Accepted November 16, 1977. Address requests for reprints to: Marvin B. Corlette, M.D., 821 Massachusetts Avenue, Arlington, Massachusetts 02174. Dr. Corlette is Clinical Instructor in Surgery, Harvard Medical School. Dr. Dratch is Clinical Instructor in Medicine, Harvard Medical School. Dr. Sorger is Associate Clinical Professor of Pathology, Tufts University School of Medicine (Divisions of Medicine and Surgery).
The prolonged but fruitless search for the presence of pancreatic disease in this patient illustrates the fact that consideration should have been given to the possibility of a nonpancreatic source for the elevated amylase levels. A large number of nonpancreatic causes for elevated amylase in serum, ascitic fluid, and pleural fluid exist and should be included in the differential diagnosis of elevated amylase. In a recent review, Salt and Schenker’ present many
907
* Localization of intracellular amylase was done by treating tissue sections with rabbit IgG produced against salivary amylase followed by peroxidase coupled antirabbit IgG (goat) and subsequent staining with benzidine, performed through the kindness of Dr. Robert C. Karn, Department of Medical Genetics, Indiana University School of Medicine.
908
CASE REPORTS
conditions associated with hyperamylasemia. Salivary gland diseases, appendicitis, cerebral trauma, and possibly prostatic disease may give rise to elevated serum amylase, in addition to the well known gastrointestinal causes. General conditions such as pregnancy, shock, diabetic ketoacidosis, burns, infectious mononucleosis,’ postrenal transplantation, and macroamylasemia have been associated with hyperamylasemia. Disorders of the Fallopian tube such as ectopic pregnancy,” gonococcal salpingitis4 ruptured Graafian folicle,’ hydrosalpinx,” also have demonstrated hyperamylasemia. Green” and McGeachin and colleagues7 have confirmed the presence of high amylase concentration in the Fallopian tube and paraovarian cystic structures which may be the source of hyperamylasemia in tubal disorders. Reports of hyperamylasemia in association with ovarian diseases, however, are conspicuous by their rarity. Tumor hyperamylasemia forms a special group among the nonpancreatic causes of elevated serum amylase. Several reports have appeared noting hyperamylasemia with carcinoma of the lung.‘+ g Pancreatic carcinoma may cause hyperamylasemia attributable either to pancreatitis distal to tumoral ductal obstruction,2 or to the tumor itself. ‘, ‘” Lehrner and associates” reported 2 patients with hyperamylasemia due to ovarian papillary cystoadenocarcinoma. Rare cases of elevated serum amylase with parotid tumors,” metastatic breast carcinoma,” prostatic cancer,’ and Hodgkin’s diseaseI have been noted In most of the tumors associated with hyperamylasemia the degree of the enzyme elevation in the serum has been minimal, usually lV2 to 2 times normal values. However, elevations to 30, 80, even 100 times the normal have been reported. ‘“3 ‘~3 Amylase-rich pleural effusions and ascites may also occur. Several diseases other than pancreatitis must be considered in the differential diagnosis of each, although pancreatitis, either acute or with pseudocyst or persistent ductal rupture, is still the most likely cause of elevated amylase in these fluids. Elevated amylase in pleural fluid has been recorded with tuberculosis, congestive heart failure, lupus, pulmonary embolism, pneumothorax,‘4 pneumonia, and esophageal perforation. ” Several lung cancers have been associated with high pleural fluid amylase,g as have one pancreatic carcinomaI and one ovarian carcinoma.g Most of the abdominal diseases producing hyperamylasemia can cause amylase-rich ascitic fluid. Tumors that have been associated with increased ascitic fluid amylase include pancreatic adenocarcinoma,i4 metastatic breast carcinoma, ovarian cystadenocarcinoma,” one renal carcinoma,g and one esophageal leiomyosarcoma.” Generally, in the malignancies with amylase-rich pleural or ascitic fluid, tumor cells have been present in the fluid on cytological examination. Thus the cause of such amylase-rich fluids most often will be suggested by pathological examination. Our case is the one exception to this we are aware of.
Vol. 74, No. 5, Part 1
Because serum amylase has components of varied origins, interest has been increasing in defining isoenzymes of human amylase as a possible diagnostic aid in the differential diagnosis of hyperamylasemia. Separated by electrophoretic methods and column chromatography, the two major isoenzyme types, pancreatic and salivary, are each comprised of multiple subunits. The reported tumor amylases have migrated with the salivary amylases. Ammann and co-workers* noted a salivary type amylase in their patient with carcinoma of the lung, and Lehrner and associates” reported 2 patients with ovarian carcinomas producing a salivary type amylase. Benjamin and Kenny’” emphasize that all nonpancreatic amylase elevations yield isoenzymes migrating with the salivary fraction. However, Sudo and Kanno’” have found differences in the mode of digestion and kinetic properties from true salivary type amylase in 1 patient with hyperamylasemia associated with carcinoma of the lung. In the case presented here a distinct salivary amylase isoenzyme pattern was found. These observations suggest the usefulness of electrophoresis to separate isoamylases when hyperamylasemia is found and pancreatitis is unlikely. Tumor tissue itself has shown high concentrations of amylase, again of salivary type, in neoplasms of lung, ovary, and parotid. g, “3 “; Unusual quantities of amylase were found in one colon cancer unassociated with hyperamylasemia.g High concentrations of amylase were found in the mutinous secretions of the tumor in our case, and immunological studies showed the tumor cells to be the source of amylase production. The present case illustrates the value of measuring amylase in pleural and ascitic fluid and emphasizes the possibility of nonpancreatic neoplastic causes of hyperamylasemia. Amylase electrophoresis to determine the isoenzyme present can be extremely helpful in directing a search for a nonpancreatic source of elevated amylase. REFERENCES 1. Salt WB, Schenker S: Amylase: its clinical significance: a review of the literature. Medicine (Baltimore) 55269-289, 1976 Lewison EF: The clinical value of the serum amylase test. Surg Gynecol Obstet 72:202-212, 1941 Kelley ML: Elevated serum amylase level associated with ruptured ectopic pregnancy. JAMA 164:406-407, 1957 Chow AW, Sol1 BA, Targan SR, et al: Hyperamylasemia associated with gonococcal salpingitis and peri hepatitis. Obstet Gynecol48 (1) (suppl):29-30, 1976 5. Hochberg CJ: Tubal amylase. Obstet Gynecol43:129-131, 1974 6. Green CL: Identification of alpha-amylase as a secretion of the human fallopian tube and “tubelike” epithelium of mullerian and mesonephric duct origin. Am J Obst Gynecol 73:402-407, 1957 7. McGeachin RL, Hargan LA, Potter BA, et al: Amylase in fallopian tubes. Proc Sot Exp Biol Med 99:130-131, 1958 8. Ammann RW, Berk JE Fridhandler L, et al: Hyperamylasemia with carcinoma of the lung. Ann Intern Med 78:521-525, 1973 9. Ende N: Studies of amylase in pleural effusions and ascites. Cancer 13:283-287, 1960 10. Shimamura J, Berk JE, Fridhandler L: Non-pancreatic hyperamylasemia in pancreatic cancer (abstr). Gastroenterology 68:985, 1975 11. Lehrner LM, Ward JC, Karn RC, et al: An evaluation of the
May 1978
CASE
usefulness of amylase isoenzyme differentiation in patients with hyperamylasemia. Am J Clin Path01 66:576-587, 1976 12. Light RW, Ball WC: Glucose and amylase in pleural effusions. JAMA 225:257-260, 1973 13. Hammarsten JF, Honska WL, Limes BJ: Pleural fluid amylase in pancreatitis and other diseases. Am Rev Tuberc 79606-611, 1959
REPORTS
909
14. Migueres J, Jorer A, Abou P: Valeur theorique et pratique de certains dosages enzymatiques au tours des epanchements pleuraux. J Fr Med Chir Thorac 23:443-458, 1969 15. Benjamin DR, Kenny MA: Clinical value of amylase isoenzyme determinations. Am J Clin Patho, 62:752-758, 1974 16. Sudo K, Kanno T: Properties of the amylase produced in carcinoma of the lung. Clin Chim Acta 73:1-12, 1976
Vol. 74, No. 5, Part1 Printedin Lr3.A.
AMYLASE ELEVATION ATTRIBUTABLE MARVIN B. CORLETTE, M.D.,
TO AN OVARIAN NEOPLASM
MORRIS DRATCH, M.D.,
Mount Auburn Hospital and the Department Massachusetts
of Pathology,
AND KARL SORGER, M.D.
Mount Auburn Hospital, Cambridge,
An ovarian carcinoma producing amylase-rich ascites and pleural effusions is reported; salivary type amylase was identified in tumor tissue. A variety of nonpancreatic diseases and tumors of lung, parotid, ovary, and other organs have been associated with elevated amylase in serum or body fluids. Amylase isoenzyme electrophoresis is of value in differentiating pancreatic from nonpancreatic sources of increased amylase. The finding of an elevated amylase in body fluids generally leads to consideration of pancreatic cause, yet many other sources of hyperamylasemia and amylaserich pleural effusion or ascites exist. This paper documents an unusual source for amylase in serum and pleural and ascitic fluid, and reviews the nonpancreatic causes for elevated body fluid amylase.
creatinine clearance ratio was 2.1%. Repeat upper gastrointestinal X-ray studies suggested the presence of a mass in the pelvis. While being evaluated she developed acute bacterial endocarditis with temperature of 40°C and blood cultures were positive for streptococcus, which proved fatal. At autopsy the pancreas, pancreatic duct, and biliary tree were normal. There were bilateral pleural effusions, and there was ascites. In the pelvis there was a partially necrotic, multiloculated tumor mass which arose from the left ovary and measured 20 cm in greatest dimension. Microscopically the tumor was a mutinous cystadenocarcinoma of low grade malignancy. There were no metastases. There was a congenital defect in the right diaphragmatic dome which allowed abdominal fluid access to the right pleural cavity. The patient expired as a result of subacute bacterial endocarditis of the aortic valve with perforation of the noncoronary cusp. Additional studies: mutinous contents of the ovarian carcinoma were aspirated and subjected to amylase determinations by the Dy Amy1 amyloclastic method (General Diagnostics). The amylase was strikingly elevated (32,960 U per 100 ml or 1,831 U per g of wet tumor tissue). There was no detectable lipase activity. An extract of tumor tissue was subjected to sheet polyacrylamide electrophoresis which revealed the tumor amylase to have the mobility of human salivary amylase (courtesy of Dr. Andrew Warshaw, Massachusetts General Hospital). Immunofluorescence studies using a rabbit antihuman conjugate against salivary type amylase showed ectopic amylase production in tumor cells but not in stromal cells.*
Case Report An 84-year-old female was hospitalized complaining of anorexia, upper abdominal discomfort, and dyspnea of 3-week duration. On examination she was afebrile, the respiratory rate was 40; the right chest was dull to percussion, the abdomen was full but no ascites was detected, and a pelvic examination was normal. A chest X-ray showed almost total opacification of the right lung field and 600 ml of clear fluid was obtained on aspiration of the right pleural space. The pleural fluid protein was 3.1 g per dl, the amylase was in excess of 45,000 Somogyi units per dl (normal, 40 to 2251, and the cell block was negative. The serum amylase was 750 Somogyi units per dl, and the serum lipase was 2.5 IU per dl (normal up to 1 III). Upper gastrointestinal series, oral cholecystogram, and abdominal ultrasound examinations were normal. An amylase-to-creatinine clearance ratio was 1.6% (normal, up to 2.3%). A hepatic scan was normal. She began to feel better and was discharged. During the following 6 months the patient lost 30 lb and required repeated thoracenteses. Serum amylase ranged from 500 to 700 Somogyi units per dl and pleural fluid amylase from 6,000 to 14,000 Somogyi units per dl. Ascites then appeared and yielded 6000 Somogyi units per dl of amylase. Repeated cytological examinations of both the pleural and abdominal fluids failed to yield malignant cells. The patient was then rehospitalized for massive recurrent right pleural effusion and congestive heart failure. The abdominal and pelvic examinations were unrevealing because of the ascites. The serum lipase was 1.7 IU, the amylase-to-
Discussion
Received September 6, 1977. Accepted November 16, 1977. Address requests for reprints to: Marvin B. Corlette, M.D., 821 Massachusetts Avenue, Arlington, Massachusetts 02174. Dr. Corlette is Clinical Instructor in Surgery, Harvard Medical School. Dr. Dratch is Clinical Instructor in Medicine, Harvard Medical School. Dr. Sorger is Associate Clinical Professor of Pathology, Tufts University School of Medicine (Divisions of Medicine and Surgery).
The prolonged but fruitless search for the presence of pancreatic disease in this patient illustrates the fact that consideration should have been given to the possibility of a nonpancreatic source for the elevated amylase levels. A large number of nonpancreatic causes for elevated amylase in serum, ascitic fluid, and pleural fluid exist and should be included in the differential diagnosis of elevated amylase. In a recent review, Salt and Schenker’ present many
907
* Localization of intracellular amylase was done by treating tissue sections with rabbit IgG produced against salivary amylase followed by peroxidase coupled antirabbit IgG (goat) and subsequent staining with benzidine, performed through the kindness of Dr. Robert C. Karn, Department of Medical Genetics, Indiana University School of Medicine.
908
CASE REPORTS
conditions associated with hyperamylasemia. Salivary gland diseases, appendicitis, cerebral trauma, and possibly prostatic disease may give rise to elevated serum amylase, in addition to the well known gastrointestinal causes. General conditions such as pregnancy, shock, diabetic ketoacidosis, burns, infectious mononucleosis,’ postrenal transplantation, and macroamylasemia have been associated with hyperamylasemia. Disorders of the Fallopian tube such as ectopic pregnancy,” gonococcal salpingitis4 ruptured Graafian folicle,’ hydrosalpinx,” also have demonstrated hyperamylasemia. Green” and McGeachin and colleagues7 have confirmed the presence of high amylase concentration in the Fallopian tube and paraovarian cystic structures which may be the source of hyperamylasemia in tubal disorders. Reports of hyperamylasemia in association with ovarian diseases, however, are conspicuous by their rarity. Tumor hyperamylasemia forms a special group among the nonpancreatic causes of elevated serum amylase. Several reports have appeared noting hyperamylasemia with carcinoma of the lung.‘+ g Pancreatic carcinoma may cause hyperamylasemia attributable either to pancreatitis distal to tumoral ductal obstruction,2 or to the tumor itself. ‘, ‘” Lehrner and associates” reported 2 patients with hyperamylasemia due to ovarian papillary cystoadenocarcinoma. Rare cases of elevated serum amylase with parotid tumors,” metastatic breast carcinoma,” prostatic cancer,’ and Hodgkin’s diseaseI have been noted In most of the tumors associated with hyperamylasemia the degree of the enzyme elevation in the serum has been minimal, usually lV2 to 2 times normal values. However, elevations to 30, 80, even 100 times the normal have been reported. ‘“3 ‘~3 Amylase-rich pleural effusions and ascites may also occur. Several diseases other than pancreatitis must be considered in the differential diagnosis of each, although pancreatitis, either acute or with pseudocyst or persistent ductal rupture, is still the most likely cause of elevated amylase in these fluids. Elevated amylase in pleural fluid has been recorded with tuberculosis, congestive heart failure, lupus, pulmonary embolism, pneumothorax,‘4 pneumonia, and esophageal perforation. ” Several lung cancers have been associated with high pleural fluid amylase,g as have one pancreatic carcinomaI and one ovarian carcinoma.g Most of the abdominal diseases producing hyperamylasemia can cause amylase-rich ascitic fluid. Tumors that have been associated with increased ascitic fluid amylase include pancreatic adenocarcinoma,i4 metastatic breast carcinoma, ovarian cystadenocarcinoma,” one renal carcinoma,g and one esophageal leiomyosarcoma.” Generally, in the malignancies with amylase-rich pleural or ascitic fluid, tumor cells have been present in the fluid on cytological examination. Thus the cause of such amylase-rich fluids most often will be suggested by pathological examination. Our case is the one exception to this we are aware of.
Vol. 74, No. 5, Part 1
Because serum amylase has components of varied origins, interest has been increasing in defining isoenzymes of human amylase as a possible diagnostic aid in the differential diagnosis of hyperamylasemia. Separated by electrophoretic methods and column chromatography, the two major isoenzyme types, pancreatic and salivary, are each comprised of multiple subunits. The reported tumor amylases have migrated with the salivary amylases. Ammann and co-workers* noted a salivary type amylase in their patient with carcinoma of the lung, and Lehrner and associates” reported 2 patients with ovarian carcinomas producing a salivary type amylase. Benjamin and Kenny’” emphasize that all nonpancreatic amylase elevations yield isoenzymes migrating with the salivary fraction. However, Sudo and Kanno’” have found differences in the mode of digestion and kinetic properties from true salivary type amylase in 1 patient with hyperamylasemia associated with carcinoma of the lung. In the case presented here a distinct salivary amylase isoenzyme pattern was found. These observations suggest the usefulness of electrophoresis to separate isoamylases when hyperamylasemia is found and pancreatitis is unlikely. Tumor tissue itself has shown high concentrations of amylase, again of salivary type, in neoplasms of lung, ovary, and parotid. g, “3 “; Unusual quantities of amylase were found in one colon cancer unassociated with hyperamylasemia.g High concentrations of amylase were found in the mutinous secretions of the tumor in our case, and immunological studies showed the tumor cells to be the source of amylase production. The present case illustrates the value of measuring amylase in pleural and ascitic fluid and emphasizes the possibility of nonpancreatic neoplastic causes of hyperamylasemia. Amylase electrophoresis to determine the isoenzyme present can be extremely helpful in directing a search for a nonpancreatic source of elevated amylase. REFERENCES 1. Salt WB, Schenker S: Amylase: its clinical significance: a review of the literature. Medicine (Baltimore) 55269-289, 1976 Lewison EF: The clinical value of the serum amylase test. Surg Gynecol Obstet 72:202-212, 1941 Kelley ML: Elevated serum amylase level associated with ruptured ectopic pregnancy. JAMA 164:406-407, 1957 Chow AW, Sol1 BA, Targan SR, et al: Hyperamylasemia associated with gonococcal salpingitis and peri hepatitis. Obstet Gynecol48 (1) (suppl):29-30, 1976 5. Hochberg CJ: Tubal amylase. Obstet Gynecol43:129-131, 1974 6. Green CL: Identification of alpha-amylase as a secretion of the human fallopian tube and “tubelike” epithelium of mullerian and mesonephric duct origin. Am J Obst Gynecol 73:402-407, 1957 7. McGeachin RL, Hargan LA, Potter BA, et al: Amylase in fallopian tubes. Proc Sot Exp Biol Med 99:130-131, 1958 8. Ammann RW, Berk JE Fridhandler L, et al: Hyperamylasemia with carcinoma of the lung. Ann Intern Med 78:521-525, 1973 9. Ende N: Studies of amylase in pleural effusions and ascites. Cancer 13:283-287, 1960 10. Shimamura J, Berk JE, Fridhandler L: Non-pancreatic hyperamylasemia in pancreatic cancer (abstr). Gastroenterology 68:985, 1975 11. Lehrner LM, Ward JC, Karn RC, et al: An evaluation of the
May 1978
CASE
usefulness of amylase isoenzyme differentiation in patients with hyperamylasemia. Am J Clin Path01 66:576-587, 1976 12. Light RW, Ball WC: Glucose and amylase in pleural effusions. JAMA 225:257-260, 1973 13. Hammarsten JF, Honska WL, Limes BJ: Pleural fluid amylase in pancreatitis and other diseases. Am Rev Tuberc 79606-611, 1959
REPORTS
909
14. Migueres J, Jorer A, Abou P: Valeur theorique et pratique de certains dosages enzymatiques au tours des epanchements pleuraux. J Fr Med Chir Thorac 23:443-458, 1969 15. Benjamin DR, Kenny MA: Clinical value of amylase isoenzyme determinations. Am J Clin Patho, 62:752-758, 1974 16. Sudo K, Kanno T: Properties of the amylase produced in carcinoma of the lung. Clin Chim Acta 73:1-12, 1976