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Primary hepatic malignancy in pregnant women
Primary hepatic malignancy in pregnant women DAVID J.
T.
V.
PURTILO,
CLARK,
M.B.,
M.S., B.S.,
M.D. M.R.C.PATH.*
ROGER
WILLIAMS,
M.D.,
Washington,
D. C., and London,
England
Three women
dying from hepatic carcinoma during a hepatoceilular carcinoma had alpha
women with
to hepatitis
F.R.C.P.
pregnancy fetoprotein
are presented. in the serum
One of these and antibod)
B antigen.
A fourth patient died 2 months post partum with a cholangiocarcipregnancy test suggested that she had metastatic choriocarcinoma in and a panhysterectomy was performed. The clinical diagnosis with the use of alpha and chorionic gonadotropin for detection of hepatoma and the etiopathogenesis hepatic malignancy in pregnancy are discussed.
noma. A false positive the liver, fetoprotein of
primary
from Guatemala to the United States for evaluation and treatment. A palpable mass extended 6 cm. beneath the right costal margin. The uterus was 2 cm. above the umbilicus, and fetal heart sounds were heard. Tests of liver function were normal on admission to the hospital but later reflected deteriorating function. Radiographic studies were noncontributory. At 17 years of age, a hepatocellular carcinoma had been resected by left hemihepatectomy. She had remained asymptomatic for 11 years until an abdominal mass was detected 4 days prior to admission to the hospital. She was considered to have recurrent hepatocellular carcinoma and was treated symptomatically. Cesarean section was contemplated, but hepatic deterioration ensued, and she died. At necropsy, ecchymoses were noted on the extremities. The liver weighed 3,950 grams and contained tumor nodules, the largest measuring 13 by 7 by 7 cm. A welldifferentiated hepatocellular carcinoma contained numerous cytoplasmic acidophilic globules which were intensely periodic acid-Schiff (PAS) positive. The adjacent liver was noncirrhotic and free of PAS-positive inclusions. Multiple pulmonary emboli and foci of acute bronchopneumonia were present. The placenta was firmly attached at its margin but was separated centrally by unclotted blood. The fetus was in utero, and necropsy revealed a 2,100 gram female fetus which had died of anoxia and was free from metastases. Patient 2. A 25-year-old black woman was in the seventh month of gestation when she cdmplained of generalized aching and pain in the eyes. The blood pressure was 128/80 mm. Hg, and the temperature was 98.6O F. Fetal heart sounds were heard. Nausea then developed which was followed by vomiting and a rise of
PRIMARY HEPATIC tumors occur mostly in elderly men. They are rare in pregnant women. The only case that has been reported was that of a 43year-old woman with cirrhosis who died from a hemorrhagic hepatoma that was diagnosed by bi0psy.l No autopsy was performed to confirm the diagnosis. Comprehensive reviews of malignant tumors and hepatic disease in pregnant women do not mention the occurrence of other cases.2-6 This report describes two cholangiocarcinomas and two hepatocellular carcinomas occurring in women, three of whom died while pregnant and another who died postpartum. Case
reports
Patient 1. A 28-year-old white woman, gravida 3, para 2, from Guatemala complained of a pain in the abdomen during the eighth month of pregnancy. She was flown
From
the Infectious
Diseases Branch, Armed of Pathology, the Department Pathology, University of Edinburgh, and the Liver Unit, Department of Medicine, King’s College Hospital Medical School.
Forces Institute
Received
for
Accepted
May
publication 21,
March
4, 1974.
1974.
Reprint requests: Dr. David T. Purtilo, Department of Pathology, University of Massachusetts Medical School, 55 N. Lake Worcester, Massachusetts 01604. *Supported Endowments
General
of
Ave.,
by a grant from the Scottish Hospital Research Trust. Present address: Hospital, Northampton NNl 5BD,
England.
41
42
Purtilo,
Clark,
and
Williams
temperature to 102.4O F. The fetal membranes ruptured, and she was delivered of a stillborn baby by a breech presentation. Following parturition, the chest became purpuric, and the blood pressure dropped to 74/30 mm. Hg. A diagnosis of meningiococcemia was confirmed, and Neisseria meningitides was isolated from cerebrospinal fluid. She died despite therapy with penicillin, sulfisoxazole, and hydrocortisone. Necropsy revealed purpura over the sternum. The brain weighed 1,300 grams, the meninges were gray and semitranslucent, and the cerebrospinal fluid was cloudy. A noncirrhotic liver weighed 2,000 grams. The capsule contained multiple hemorrhagic foci, and numerous tanyellow nodules measuring up to 2 cm. in diameter were present in the right lobe. Microscopically, these showed moderately well-differentiated cholangiocarcinoma that contained traces of mucin. Patient 3. A 34-year-old American Indian woman, gravida 9, para 9, was admitted to the hospital 5 months post partum complaining of anorexia and epigastric pain. Slight enlargement of the epigastrium was first noted one month post partum. Two months post partum, the tests of liver function and pregnancy tests were normal. The blood pressure was lOO/SO mm. Hg; pulse, 110 beats per minute; and the temperature bras 101.4O F. The white blood cell count was 25,000 cells per milliliter, with 77 per cent neutrophils. The hemoglobin was 7.8 Gm. per cent, and the hematocrit was 26 per cent. Tests of liver function included a total serum bilirubin of 5.7 mg. per cent (direct 3.0 mg. per cent), thymol turbidity of 4 U., a total serum protein of 7.4 Gm. per cent (albumin 2.4 Gm. per cent), and an alkaline phosphatase of 8.5 Shinowara-Johnson units. Coin lesions were identified on the chest radiogram. Pregnancy tests were repeated and were positive. A percutaneous liver biopsy revealed a poorly differentiated adenocarcinoma. Because of the positive pregnancy test and the possibility of a choriocarcinoma with metastases to the liver, the patient underwent an abdominal hysterectomy and bilateral salpingo-oophorectomy. At laparotomy, the liver was three times the normal size and was studded with tumor masses. Histologic examination of the hysterectomy specimen showed no evidence of cholangiocarcinoma or choriocarcinoma. Postoperatively, loss of weight occurred, and the temperature ranged from 100° to 102O F. She deteriorated to a semicomatose state and died on the twentyfirst day of hospitalization. At necropsy, the liver weighed 2,000 grams and contained soft yellow tumor masses measuring up to 5 cm. in diameter. The gallbladder and extrahepatic biliary tree were normal, but the pancreas was .slightly fibrotic. The tumor was anaplastic, and a few acini contained mucin. Hence, a diagnosis of intrahepatic cholangiocarcinoma was made, and extensive pulmonary metastases were present. The adjacent liver was not cirrhotic. Patient 4. ,4 37-year-old Jamaican woman with cir-
rhosis and a duodenal ulcer underwent a gastrectomy and gastrojejunostomy 2 years prior to the final hospitalization. She was admitted to King’s College Hospital with a 3 day history of rectal bleeding. She had complained of upper abdominal pain and was in the twentyfifth week of pregnancy. Physical examination revealed a blood pressure of 110/80 mm. Hg and a heart rate of 100 beats per minute. She was extremely pale, there was finger clubbing, and the liver was palpable in the epigastrium. The uterus was enlarged to just above the umbilicus. A hepatic scan revealed right lobular atrophy and enlargement with irregular colloid uptake in the left lobe. Other tests of liver function included a total serum protein of 4.5 Cm. per 100 ml. and albumin of 1.8 Gm. per 100 ml., serum glutamic oxaloacetic transaminase of 60 U. per milliliter, total serum bilirubin 2.1 mg. per 100 ml., and a prothrombin time that was prolonged 3 seconds. Alpha fetoprotein (AFP) was detected by a bi-dimensional immunodiffusion technique described elsewhere.r The patient’s serum was weakly positive for AFP in a 1: 4 dilution. A control sample of AFP, assayed through the kindness of Professor Abelev and found to contain 150 to 200 pg per milliliter, was similarly weakly positive in a 1: 32 dilution. This semiquantitative technique revealed that the patient had about 20 to 25 pg per milliliter of AFP in the serum. The patient’s hospital course was marked by recurrent, massive hemorrhage from esophageal varices. The hemorrhage was arrested by a portal systemic shunt, but 3 weeks later massive hemorrhage recurred from an esophageal varix, and the patient died. The pregnancy was intact until just before death. i\t necropsy, the upper gastrointestinal tract was distended by hlood. The liver was small and cirrhotic, and the left lobe contained a poorly differentiated hepatocellular carcinoma. Comment In Western countries, primary hepatic tumors are most commonly hepatocellular carcinomas and occur chiefly in elderly men with cirrhosis.s-to This may explain their rarity in pregnant women. The clinical signs and symptoms of the 4 patients reported here were similar to the manifestations of other diseases of the liver occurring in pregnant women.“. fi Yet, antemortem diagnoses were achieved in 3 of the patients. Patient 3 was postpartum. Radiographic evidence of metastases to the lungs, a positive pregnancy test: and carcinoma in a hepatic biopsy specimen led to an erroneous clinical and pathologic diagnosis of metastatic cholangiocarcinoma. Braunstein and associates”. I? have reported ectopic production of human chorionic gonadotropin in hepatocellular
Volume Number
121 1
Hepatic
carcinomas and other neoplasms. The pregnancy test employed in Case 3 was the Ascheim-Zondek frog test. Braunstein and associates,12 using a radioimmunoassay, detected human chorionic gonadotropin in the sera of approximately 17 per cent of patients with hepatocellular carcinoma. The physician should be aware that other malignant neoplasms besides trophoblastic neoplasia may produce chorionic gonadotropin. Another protein that is produced by fetal hepatocytes and hepatocellular carcinomas is AFP.?, I3 The sera of normal adults contain approximately 1 to 20 ng. per milliliter of AFP. In normal pregnancy, maternal serum contains 53 to 550 ng. per milliliter of AFP, and with fetal death in utero the level may rise to 9 pg per milliliter.14-17 AFP is increased approximately twofold in the serum of women bearing twins. I8 Many patients with hepatocellular carcinomas have AFP levels in excess of 10 pg per mil1iliter.l” The finding of about 20 to 25 pg per milliliter of AFP in the serum of Patient 4 in the absence of an intrauterine death indicated a diagnosis of hepatocellular carcinoma rather than fetomaternal passage of AFP. The etiopathogenesis of primary hepatic neoplasms is unclear, and many etiologic agents have been incriminated. An androgenic steroid milieu may account for the approximately 5: 1 male-tofemale ratio. At least 9 patients have developed hepatocellular carcinoma during or following treatment with androgenic-anabolic steroids.*0-23 A report of 7 patients developing hepatocellular adenomas after receiving oral contraceptives for periods ranging from 6 months to 5 years incriminates estrogens as etiologic agents for adenoma.24 The occurrence of primary hepatic malignancies in the 4 pregnant women presented here does not negate the potential role of androgenic steroids in hepatocarcinogenesis. But the occurrence of hepatic malignancy in pregnant women is contrary to the observation that liver-cell carcinoma appears to favor an androgenic environment.‘” Cirrhosis occurs concurrently with approximately two thirds of hepatocellular carcinomas, and only one of our patients had cirrhosis.8-10 Mycotoxins, especially aflatoxins, may be important etiologic
malignancy
in
pregnant
women
43
agents in hepatocellular carcinoma in Africa where the incidence of this neoplasm is high.25 Hepatitis B antigen (HB-Ag) has been reported in the sera of 80 per cent of individuals with hepatocellular carcinoma residing in Taiwan, in 55 per cent in Uganda, and by radioimmunoassay in 23 per cent of patients studied in London.2G-28 Most of the patients with hepatocellular carcinoma and HB-Ag in the sera have underlying cirrhosis although exact figures for the high-frequency areas of Africa and the Far East are not known. It seems significant to us that none of the 4 patients was American or British white. The distribution of HB-Ag is not entirely known, but a recent survey revealed differences in antigenic determinants of HB-Ag in different geographic areas.2g Tests for HB-Ag and antibody were performed in only one of our cases, and the serum was positive for the HB antibody. However, the patient had previously received blood transfusions 2 years prior to the appearance of hepatocellular carcinoma, which may, therefore, be the explanation. The liver is often so destroyed by the carcinoma that it is not possible to determine whether or not cirrhosis was present previously. However, hepatocellular carcinoma is a known sequel to other types of cirrhosis, i.e., alcoholic, and also occurs in hemochromatosis in which HB-Ag is rarely found.lO Therefore, the evidence that HB-Ag is oncogenic is, at present, inconclusive. The significance of depression of cellular immunity in pregnant women on the behavior of malignant neoplasms such as carcinoma of the breast remains obscure.30-32 We are unable to assess the impact of pregnancy on the growth and dissemination of the hepatomas in our 4 patients because hematomas are notoriously aggressive, although pregnancy, possibly combined with other factors that suppress immunologic surveillance, may have tipped the tumor-host balance to permit the hepatocellular carcinoma, which has been dormant for 11 years in Patient 1, to progress. But it seems more likely a new tumor developed. The authors thank the Director of the Armed Forces Institute, Washington, D. C., for permission to use the cases from the Armed Forces Institute of Pathology files.
REFERENCES
1. 2. 3.
Roddie, T. W.: Br. Med. J. 1: 31, 1957. Nieminen, U., and Remes, N.: Acta Obstet. Stand. 49: 315, 1970. McGowan, L.: Obstet. Gynecol. Survey 1964.
4. Gynecol. 19:
285,
5. 6. 7.
Haemmerli, U. P.: Acta Med. Stand. (Suppl. 444) 179: 1, 1966. Sherlock, S.: Br. Med. Bull. 24: 39, 1968. Iber, F. L.: AM. J. OBSTET. GYNECOL. 91: 721, 1965. Clark, J. V.: In Peeters, H., editor: Protides of the
44
8.
9.
10. 11.
12. 13. 14. 15. 16. 17. 18. 19. 20.
Purtilo,
Clark,
and
Williams
Biological Fluids, Oxford, 197 1, Pergamon Press, Inc., pp. 235-238. Edmondson, H. A.: Tumors of the liver and intrahepatic bile ducts, in Atlas of Tumour Pathology, Washington, D. C., 1958, Armed Forces Institute of Pathology. Section VII, Fascicle 25. Leon-Sotomayor, L., and Moore, V. A.: Unusual Clinical Features of Cirrhosis and Primary Liver Cell Carcinoma, Springfield, Illinois, 1967, Charles C Thomas, Publisher. Purtilo, D. T., and Gottlieb, L. S.: Cancer 32: 458, 1973. Braunstein, G. D., Vogel, C. L., Vaitukaitis, J. L., Carbone, P. P., and Ross, G. T.: Ann. Intern. Med. 78: 39, 1973. Braunstein, G. D., Vogel, C. L., Vaitukaitis, J. L., and Ross, G. T.: Cancer 32: 223, 1973. Purtilo, D. T., and Yunis, E. J.: Lab. Invest. 25: 291, 1971. Foy, H., Kondi, A., Parker, A. M., Stanley, R., and Venning, C. D.: Lancet 1: 1336, 1970. Ruoslahti, E., and Seppala, M.: Int. J. Cancer 8: 374, 1971. Purves, L. R., and Purves, M.: S. Afr. Med. J. 46: 1290, 1972. and Ruoslahti, E.: AM. J. OBSTET. Seppala, M., GYNECOL. 115: 48, 1973. Ishiguro, T.: Lancet 2: 1214, 1973. SeppIlP, M., and Ruoslahti, E:. Lancet 2: 278, 1972. Johnson, F. L., Lerner, K. G., Siegel, M., Feagler,
21. 22. 23. 24. 25. 26.
27. 28.
29. 30. 31.
32.
J. R., Majerus, P. W., Hartmann, J. R., and Thomas, E. D.: Lancet 2: 1273. 1972. Ziegenfuss, J., and Carabasi, R.: Lancet 1: 262, 1973. Henderson, J. T., Richmond, J., and Sumerling, M. D.: Lancet 1: 934, 1973. Meadows, A. T., Naiman, J. L., and Valdes-Dapena, M.: J. Pediatr. 84: 109, 1974. Baum, J. K., Holtz, F., Bookstein, J. J., and Klein, E. W.: Lancet 2: 926, 1973. Keen, P., and Martin, P.: Trop. Geogr. Med. 23: 44, 1971. Tong, M. J., Sun, S. C., Schaeffer, B. T., Chang, N. J., Lo, K. J., and Peters, R. L.: Ann, Intern. Med. 75: 687, 1971. Primack, A., Vogel, C. L., and Barker, L. F.: Br. Med. J. 1: 16, 1973. Reed, W. D., Stern, R. B., Eddleston, A. L. W. F., Williams, R., Zuckerman, A. J., Bowes, A., and Earl, P. M.: Lancet 2: 690, 1973. Mazzur, S., Burget, S., and Blumberg, B. S.: Nature 247: 38, 1974. Purtilo, D. T., Hallgren, H. M., and Yunis, E. J,: Lancet 1: 769, 1972. Finn, R., St. Hill, C. A., Govan, A. J., Ralfs, I. G., Curney, F. J., and Denye, V.: Br. Med. J. 3: 150, 1972. Nelson, J. H., Lu, T., Hall, J. E., Krown, S., Nelson, J. M., and Fox, C. W.: AM. J. OBSTET. GYNECOI.. 117: 689. 1973.
T.
V.
PURTILO,
CLARK,
M.B.,
M.S., B.S.,
M.D. M.R.C.PATH.*
ROGER
WILLIAMS,
M.D.,
Washington,
D. C., and London,
England
Three women
dying from hepatic carcinoma during a hepatoceilular carcinoma had alpha
women with
to hepatitis
F.R.C.P.
pregnancy fetoprotein
are presented. in the serum
One of these and antibod)
B antigen.
A fourth patient died 2 months post partum with a cholangiocarcipregnancy test suggested that she had metastatic choriocarcinoma in and a panhysterectomy was performed. The clinical diagnosis with the use of alpha and chorionic gonadotropin for detection of hepatoma and the etiopathogenesis hepatic malignancy in pregnancy are discussed.
noma. A false positive the liver, fetoprotein of
primary
from Guatemala to the United States for evaluation and treatment. A palpable mass extended 6 cm. beneath the right costal margin. The uterus was 2 cm. above the umbilicus, and fetal heart sounds were heard. Tests of liver function were normal on admission to the hospital but later reflected deteriorating function. Radiographic studies were noncontributory. At 17 years of age, a hepatocellular carcinoma had been resected by left hemihepatectomy. She had remained asymptomatic for 11 years until an abdominal mass was detected 4 days prior to admission to the hospital. She was considered to have recurrent hepatocellular carcinoma and was treated symptomatically. Cesarean section was contemplated, but hepatic deterioration ensued, and she died. At necropsy, ecchymoses were noted on the extremities. The liver weighed 3,950 grams and contained tumor nodules, the largest measuring 13 by 7 by 7 cm. A welldifferentiated hepatocellular carcinoma contained numerous cytoplasmic acidophilic globules which were intensely periodic acid-Schiff (PAS) positive. The adjacent liver was noncirrhotic and free of PAS-positive inclusions. Multiple pulmonary emboli and foci of acute bronchopneumonia were present. The placenta was firmly attached at its margin but was separated centrally by unclotted blood. The fetus was in utero, and necropsy revealed a 2,100 gram female fetus which had died of anoxia and was free from metastases. Patient 2. A 25-year-old black woman was in the seventh month of gestation when she cdmplained of generalized aching and pain in the eyes. The blood pressure was 128/80 mm. Hg, and the temperature was 98.6O F. Fetal heart sounds were heard. Nausea then developed which was followed by vomiting and a rise of
PRIMARY HEPATIC tumors occur mostly in elderly men. They are rare in pregnant women. The only case that has been reported was that of a 43year-old woman with cirrhosis who died from a hemorrhagic hepatoma that was diagnosed by bi0psy.l No autopsy was performed to confirm the diagnosis. Comprehensive reviews of malignant tumors and hepatic disease in pregnant women do not mention the occurrence of other cases.2-6 This report describes two cholangiocarcinomas and two hepatocellular carcinomas occurring in women, three of whom died while pregnant and another who died postpartum. Case
reports
Patient 1. A 28-year-old white woman, gravida 3, para 2, from Guatemala complained of a pain in the abdomen during the eighth month of pregnancy. She was flown
From
the Infectious
Diseases Branch, Armed of Pathology, the Department Pathology, University of Edinburgh, and the Liver Unit, Department of Medicine, King’s College Hospital Medical School.
Forces Institute
Received
for
Accepted
May
publication 21,
March
4, 1974.
1974.
Reprint requests: Dr. David T. Purtilo, Department of Pathology, University of Massachusetts Medical School, 55 N. Lake Worcester, Massachusetts 01604. *Supported Endowments
General
of
Ave.,
by a grant from the Scottish Hospital Research Trust. Present address: Hospital, Northampton NNl 5BD,
England.
41
42
Purtilo,
Clark,
and
Williams
temperature to 102.4O F. The fetal membranes ruptured, and she was delivered of a stillborn baby by a breech presentation. Following parturition, the chest became purpuric, and the blood pressure dropped to 74/30 mm. Hg. A diagnosis of meningiococcemia was confirmed, and Neisseria meningitides was isolated from cerebrospinal fluid. She died despite therapy with penicillin, sulfisoxazole, and hydrocortisone. Necropsy revealed purpura over the sternum. The brain weighed 1,300 grams, the meninges were gray and semitranslucent, and the cerebrospinal fluid was cloudy. A noncirrhotic liver weighed 2,000 grams. The capsule contained multiple hemorrhagic foci, and numerous tanyellow nodules measuring up to 2 cm. in diameter were present in the right lobe. Microscopically, these showed moderately well-differentiated cholangiocarcinoma that contained traces of mucin. Patient 3. A 34-year-old American Indian woman, gravida 9, para 9, was admitted to the hospital 5 months post partum complaining of anorexia and epigastric pain. Slight enlargement of the epigastrium was first noted one month post partum. Two months post partum, the tests of liver function and pregnancy tests were normal. The blood pressure was lOO/SO mm. Hg; pulse, 110 beats per minute; and the temperature bras 101.4O F. The white blood cell count was 25,000 cells per milliliter, with 77 per cent neutrophils. The hemoglobin was 7.8 Gm. per cent, and the hematocrit was 26 per cent. Tests of liver function included a total serum bilirubin of 5.7 mg. per cent (direct 3.0 mg. per cent), thymol turbidity of 4 U., a total serum protein of 7.4 Gm. per cent (albumin 2.4 Gm. per cent), and an alkaline phosphatase of 8.5 Shinowara-Johnson units. Coin lesions were identified on the chest radiogram. Pregnancy tests were repeated and were positive. A percutaneous liver biopsy revealed a poorly differentiated adenocarcinoma. Because of the positive pregnancy test and the possibility of a choriocarcinoma with metastases to the liver, the patient underwent an abdominal hysterectomy and bilateral salpingo-oophorectomy. At laparotomy, the liver was three times the normal size and was studded with tumor masses. Histologic examination of the hysterectomy specimen showed no evidence of cholangiocarcinoma or choriocarcinoma. Postoperatively, loss of weight occurred, and the temperature ranged from 100° to 102O F. She deteriorated to a semicomatose state and died on the twentyfirst day of hospitalization. At necropsy, the liver weighed 2,000 grams and contained soft yellow tumor masses measuring up to 5 cm. in diameter. The gallbladder and extrahepatic biliary tree were normal, but the pancreas was .slightly fibrotic. The tumor was anaplastic, and a few acini contained mucin. Hence, a diagnosis of intrahepatic cholangiocarcinoma was made, and extensive pulmonary metastases were present. The adjacent liver was not cirrhotic. Patient 4. ,4 37-year-old Jamaican woman with cir-
rhosis and a duodenal ulcer underwent a gastrectomy and gastrojejunostomy 2 years prior to the final hospitalization. She was admitted to King’s College Hospital with a 3 day history of rectal bleeding. She had complained of upper abdominal pain and was in the twentyfifth week of pregnancy. Physical examination revealed a blood pressure of 110/80 mm. Hg and a heart rate of 100 beats per minute. She was extremely pale, there was finger clubbing, and the liver was palpable in the epigastrium. The uterus was enlarged to just above the umbilicus. A hepatic scan revealed right lobular atrophy and enlargement with irregular colloid uptake in the left lobe. Other tests of liver function included a total serum protein of 4.5 Cm. per 100 ml. and albumin of 1.8 Gm. per 100 ml., serum glutamic oxaloacetic transaminase of 60 U. per milliliter, total serum bilirubin 2.1 mg. per 100 ml., and a prothrombin time that was prolonged 3 seconds. Alpha fetoprotein (AFP) was detected by a bi-dimensional immunodiffusion technique described elsewhere.r The patient’s serum was weakly positive for AFP in a 1: 4 dilution. A control sample of AFP, assayed through the kindness of Professor Abelev and found to contain 150 to 200 pg per milliliter, was similarly weakly positive in a 1: 32 dilution. This semiquantitative technique revealed that the patient had about 20 to 25 pg per milliliter of AFP in the serum. The patient’s hospital course was marked by recurrent, massive hemorrhage from esophageal varices. The hemorrhage was arrested by a portal systemic shunt, but 3 weeks later massive hemorrhage recurred from an esophageal varix, and the patient died. The pregnancy was intact until just before death. i\t necropsy, the upper gastrointestinal tract was distended by hlood. The liver was small and cirrhotic, and the left lobe contained a poorly differentiated hepatocellular carcinoma. Comment In Western countries, primary hepatic tumors are most commonly hepatocellular carcinomas and occur chiefly in elderly men with cirrhosis.s-to This may explain their rarity in pregnant women. The clinical signs and symptoms of the 4 patients reported here were similar to the manifestations of other diseases of the liver occurring in pregnant women.“. fi Yet, antemortem diagnoses were achieved in 3 of the patients. Patient 3 was postpartum. Radiographic evidence of metastases to the lungs, a positive pregnancy test: and carcinoma in a hepatic biopsy specimen led to an erroneous clinical and pathologic diagnosis of metastatic cholangiocarcinoma. Braunstein and associates”. I? have reported ectopic production of human chorionic gonadotropin in hepatocellular
Volume Number
121 1
Hepatic
carcinomas and other neoplasms. The pregnancy test employed in Case 3 was the Ascheim-Zondek frog test. Braunstein and associates,12 using a radioimmunoassay, detected human chorionic gonadotropin in the sera of approximately 17 per cent of patients with hepatocellular carcinoma. The physician should be aware that other malignant neoplasms besides trophoblastic neoplasia may produce chorionic gonadotropin. Another protein that is produced by fetal hepatocytes and hepatocellular carcinomas is AFP.?, I3 The sera of normal adults contain approximately 1 to 20 ng. per milliliter of AFP. In normal pregnancy, maternal serum contains 53 to 550 ng. per milliliter of AFP, and with fetal death in utero the level may rise to 9 pg per milliliter.14-17 AFP is increased approximately twofold in the serum of women bearing twins. I8 Many patients with hepatocellular carcinomas have AFP levels in excess of 10 pg per mil1iliter.l” The finding of about 20 to 25 pg per milliliter of AFP in the serum of Patient 4 in the absence of an intrauterine death indicated a diagnosis of hepatocellular carcinoma rather than fetomaternal passage of AFP. The etiopathogenesis of primary hepatic neoplasms is unclear, and many etiologic agents have been incriminated. An androgenic steroid milieu may account for the approximately 5: 1 male-tofemale ratio. At least 9 patients have developed hepatocellular carcinoma during or following treatment with androgenic-anabolic steroids.*0-23 A report of 7 patients developing hepatocellular adenomas after receiving oral contraceptives for periods ranging from 6 months to 5 years incriminates estrogens as etiologic agents for adenoma.24 The occurrence of primary hepatic malignancies in the 4 pregnant women presented here does not negate the potential role of androgenic steroids in hepatocarcinogenesis. But the occurrence of hepatic malignancy in pregnant women is contrary to the observation that liver-cell carcinoma appears to favor an androgenic environment.‘” Cirrhosis occurs concurrently with approximately two thirds of hepatocellular carcinomas, and only one of our patients had cirrhosis.8-10 Mycotoxins, especially aflatoxins, may be important etiologic
malignancy
in
pregnant
women
43
agents in hepatocellular carcinoma in Africa where the incidence of this neoplasm is high.25 Hepatitis B antigen (HB-Ag) has been reported in the sera of 80 per cent of individuals with hepatocellular carcinoma residing in Taiwan, in 55 per cent in Uganda, and by radioimmunoassay in 23 per cent of patients studied in London.2G-28 Most of the patients with hepatocellular carcinoma and HB-Ag in the sera have underlying cirrhosis although exact figures for the high-frequency areas of Africa and the Far East are not known. It seems significant to us that none of the 4 patients was American or British white. The distribution of HB-Ag is not entirely known, but a recent survey revealed differences in antigenic determinants of HB-Ag in different geographic areas.2g Tests for HB-Ag and antibody were performed in only one of our cases, and the serum was positive for the HB antibody. However, the patient had previously received blood transfusions 2 years prior to the appearance of hepatocellular carcinoma, which may, therefore, be the explanation. The liver is often so destroyed by the carcinoma that it is not possible to determine whether or not cirrhosis was present previously. However, hepatocellular carcinoma is a known sequel to other types of cirrhosis, i.e., alcoholic, and also occurs in hemochromatosis in which HB-Ag is rarely found.lO Therefore, the evidence that HB-Ag is oncogenic is, at present, inconclusive. The significance of depression of cellular immunity in pregnant women on the behavior of malignant neoplasms such as carcinoma of the breast remains obscure.30-32 We are unable to assess the impact of pregnancy on the growth and dissemination of the hepatomas in our 4 patients because hematomas are notoriously aggressive, although pregnancy, possibly combined with other factors that suppress immunologic surveillance, may have tipped the tumor-host balance to permit the hepatocellular carcinoma, which has been dormant for 11 years in Patient 1, to progress. But it seems more likely a new tumor developed. The authors thank the Director of the Armed Forces Institute, Washington, D. C., for permission to use the cases from the Armed Forces Institute of Pathology files.
REFERENCES
1. 2. 3.
Roddie, T. W.: Br. Med. J. 1: 31, 1957. Nieminen, U., and Remes, N.: Acta Obstet. Stand. 49: 315, 1970. McGowan, L.: Obstet. Gynecol. Survey 1964.
4. Gynecol. 19:
285,
5. 6. 7.
Haemmerli, U. P.: Acta Med. Stand. (Suppl. 444) 179: 1, 1966. Sherlock, S.: Br. Med. Bull. 24: 39, 1968. Iber, F. L.: AM. J. OBSTET. GYNECOL. 91: 721, 1965. Clark, J. V.: In Peeters, H., editor: Protides of the
44
8.
9.
10. 11.
12. 13. 14. 15. 16. 17. 18. 19. 20.
Purtilo,
Clark,
and
Williams
Biological Fluids, Oxford, 197 1, Pergamon Press, Inc., pp. 235-238. Edmondson, H. A.: Tumors of the liver and intrahepatic bile ducts, in Atlas of Tumour Pathology, Washington, D. C., 1958, Armed Forces Institute of Pathology. Section VII, Fascicle 25. Leon-Sotomayor, L., and Moore, V. A.: Unusual Clinical Features of Cirrhosis and Primary Liver Cell Carcinoma, Springfield, Illinois, 1967, Charles C Thomas, Publisher. Purtilo, D. T., and Gottlieb, L. S.: Cancer 32: 458, 1973. Braunstein, G. D., Vogel, C. L., Vaitukaitis, J. L., Carbone, P. P., and Ross, G. T.: Ann. Intern. Med. 78: 39, 1973. Braunstein, G. D., Vogel, C. L., Vaitukaitis, J. L., and Ross, G. T.: Cancer 32: 223, 1973. Purtilo, D. T., and Yunis, E. J.: Lab. Invest. 25: 291, 1971. Foy, H., Kondi, A., Parker, A. M., Stanley, R., and Venning, C. D.: Lancet 1: 1336, 1970. Ruoslahti, E., and Seppala, M.: Int. J. Cancer 8: 374, 1971. Purves, L. R., and Purves, M.: S. Afr. Med. J. 46: 1290, 1972. and Ruoslahti, E.: AM. J. OBSTET. Seppala, M., GYNECOL. 115: 48, 1973. Ishiguro, T.: Lancet 2: 1214, 1973. SeppIlP, M., and Ruoslahti, E:. Lancet 2: 278, 1972. Johnson, F. L., Lerner, K. G., Siegel, M., Feagler,
21. 22. 23. 24. 25. 26.
27. 28.
29. 30. 31.
32.
J. R., Majerus, P. W., Hartmann, J. R., and Thomas, E. D.: Lancet 2: 1273. 1972. Ziegenfuss, J., and Carabasi, R.: Lancet 1: 262, 1973. Henderson, J. T., Richmond, J., and Sumerling, M. D.: Lancet 1: 934, 1973. Meadows, A. T., Naiman, J. L., and Valdes-Dapena, M.: J. Pediatr. 84: 109, 1974. Baum, J. K., Holtz, F., Bookstein, J. J., and Klein, E. W.: Lancet 2: 926, 1973. Keen, P., and Martin, P.: Trop. Geogr. Med. 23: 44, 1971. Tong, M. J., Sun, S. C., Schaeffer, B. T., Chang, N. J., Lo, K. J., and Peters, R. L.: Ann, Intern. Med. 75: 687, 1971. Primack, A., Vogel, C. L., and Barker, L. F.: Br. Med. J. 1: 16, 1973. Reed, W. D., Stern, R. B., Eddleston, A. L. W. F., Williams, R., Zuckerman, A. J., Bowes, A., and Earl, P. M.: Lancet 2: 690, 1973. Mazzur, S., Burget, S., and Blumberg, B. S.: Nature 247: 38, 1974. Purtilo, D. T., Hallgren, H. M., and Yunis, E. J,: Lancet 1: 769, 1972. Finn, R., St. Hill, C. A., Govan, A. J., Ralfs, I. G., Curney, F. J., and Denye, V.: Br. Med. J. 3: 150, 1972. Nelson, J. H., Lu, T., Hall, J. E., Krown, S., Nelson, J. M., and Fox, C. W.: AM. J. OBSTET. GYNECOI.. 117: 689. 1973.