Hepatic Tumors of Infancy and Childhood

Symposium on Hepatic Surgery

Hepatic Tumors of Infancy and Childhood Alfred A. de Lorimier, M.D.*

Primary tumors of the liver are rare, with an incidence of about 1. 9 per 1 million population. They account for 1.5 to 2.0 per cent of childhood cancers and approximately 15 per cent of abdominal tumors in children. 3 ,24 Metastatic masses to the liver occur primarily from neuroblastoma, Wilms' tumor, rhabdomyosarcoma, or Hodgkin's disease. With the exception of neuroblastoma in the first year of life, metastatic hepatic masses are almost never a primary clinical manifestation of tumor. Twothirds of the primary tumors of the liver are malignant.

Classification Liver tumors have been classified in many ways, and no agreement exists among the many proposed nomenclatures. A broad classification that provides some basis for discussion is modified from Edmondson 7 (Table 1). There are a number of reviews further defining the clinical course and histologic subtypes of hepatoblastoma. 17 , 18, 22 Clinical Manifestations Females more commonly develop focal nodular hyperplasia (female to male ratio = 3.4: 1) and hemangioma (female to male ratio = 2: 1).6, 19 However, males develop hepatoblastoma and hepatocarcinoma 1.3 times more frequently than females. 9 The age at onset of symptoms for focal nodular hyperplasia is in adolescence and early adulthood. 19 Hepatic hemangiomas are found predominantly in the first 6 months of life. 6 Hepatoblastoma is primarily noted in the first 3 years; most are infants less than 2 years 01d. 9 Hepatocarcinoma occurs in two age peaks, one less than 4 years old and the other between 12 and 15 years. 9 The predominant symptom is an abdominal mass or enlargement, which occurs in more than 90 per cent of cases. Other complaints include anorexia, weight loss, abdominal or lower chest pain, and vomiting. The "Associate Professor of Surgery, Pediatric Surgical Service, University of Califurnia, San Francisco, School of Medicine San Francisco, California

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Table 1. Classification of Liver Tumors BENIGN

Non-neoplastic tumors Focal nodular hyperplasia Epithelial tumors Hepatic adenoma Nonparasitic cyst Mesenchymal tumors Mesenchymal hamartoma Capillary hemangioendothelioma Cavernous hemangioma Lymphangioma Teratoma

MALIGNANT

Epithelial tumors Hepatoblastoma Hepatocellular carcinoma Mesenchymal tumors Mixed mesenchymoma Rhabdomyosarcoma Angiosarcoma Teratocarcinoma Sarcoma

rare occurrence of jaundice usually is related to extensive intrahepatic spread. Symptoms of fever, changes in bowel habit, and weakness are rare. Hepatomas occur in children with long-standing biliary atresia, type I glycogen storage disease, and galactosemia. 14 Physical findings include obvious abdominal distention due to hepatomegaly or a distinct mass within the liver. 8.9 Hepatomas have been associated with hemihypertrophy and virilization. 2 ,15 Subcutaneous metastases are a rare occurrence.t 3

Diagnostic Studies Laboratory studies might reveal either anemia or polycythemia. 16 Anemia is frequently caused by bleeding into the tumor. Serum calcium may be abnormally elevated and the serum phosphorus may be low, associated with a parathormone-like protein from the tumor producing osteoporosis. 28 ,31 Hyperlipemia and hypercholesterolemia, elevated serum transaminase, alkaline phosphatase, and bilirubin are frequent findings. 1, 4. 21 The serum albumin may be low and the globulin may be elevated. Serum alphafetoprotein levels are abnormally elevated in twothirds of malignant tumors, and these serum levels can be used to follow the progress oftreatment. 26 • 31 Blood studies should include gonadotropin analysis and hepatitis B antigen. Bleeding and clotting studies, such as prothrombin .time, plasma thromboplastin test, fibrinogen function, and platelet count must be obtained, because they are frequently abnormal.l. 30 Urine should be collected for a 24-hour period to quantitate excretion of vanilmandelic acid, homovanilic acid, and cystathionine in case the tumor might be a neuroblastoma. Renal function might be assessed by blood urea nitrogen and serum creatinine levels. Serial recording of height and weight on a growth chart might help indicate when the tumor began to interfere with growth. Radiologic studies must include a chest film and intravenous pyelogram. Calcification in the tumor may occur in hepatomas or hemangiomas. A skeletal survey might reveal osteoporosis. Hepatic arteriograms can be helpful to indentify the predominant position of the tumor, but extrahepatic retroperitoneal tumors can appear similar to intrahepatic

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lesions. 25 Benign tumors, such as focal nodular hyperplasia and hemangioma, may have vessels that mimic those seen in malignant tumors.23 The hepatic arteriogram is not reliable in determining the resectability of the tumor. The vascular pattern may appear to extend from one lobe to another, suggesting that transection of the liver between the lobes would result in cutting through the tumor or devascularizing the remaining liver. Very vascular tumors "steal" blood flow from the hepatic artery so that the uninvolved portion of the liver does not seem to have an intact blood supply. The patient must be thoroughly explored to determine resectability. The hepatic arteriogram can define an anomalous blood supply, such as aberrant hepatic arteries from the aorta or superior mesenteric artery. Liver scan is helpful in defining the intrahepatic origin of the tumor. Isotopes such as technicium or radioiodinated Rose Bengal will outline the normal liver, but the tumor mass does not visualize. Liver scan can help make the diagnosis of focal nodular hyperplasia, because the isotopes visualize in the area of the tumor mass. Ultrasonogram is helpful in discerning whether the tumor might be a large cyst or hematoma, rather than a solid mass. Computerized axial tomography is a very valuable study, with or without injection of radio contrast materials, to outline the size, relative position and the consistency of the tumor.

Preoperative Preparation The patient should be given vitamin K, 2 to 10 mg I.M. preoperatively. Whole blood or packed red cells should be cross-matched in volume equivalent to the patient's blood volume. Fresh frozen plasma and platelets might be needed if a coagulopathy is anticipated. The preoperative use of intravenous alimentation, using concentrated glucose solutions, amino acids and vitamins might be indicated to provide optimum nutrition if significant postresection hepatic failure is anticipated.

Operative Procedure Endotracheal anesthesia should be given with a heated ultrasonic nebulizer. A large bore catheter should be placed in the right atrium, and it may be desirable to have a percutaneously-placed radial artery catheter to record vessel pressures and to monitor blood gases and pH. A second venous catheter should be placed in a vein in the upper extremity to have available if a large volume of blood must be transfused in a short period of time. The transfused blood should be warmed to body temperature. Ringer's lactate solution should be infused at a rate of 10 to 15 ml per kg per hour during the operation. The patient should be placed on a water mattress that can be used for either cooling or warming. A Foley catheter should be placed in the bladder. A transverse upper abdominal incision is used to assess the location and extent of the tumor. The incision is lengthened as long as possible across the upper abdomen, and may be extended into the right or left chest at the seventh intercostal space. It may be necessary to completely mobilize and isolate the hepatic artery, portal vein and bile duct branches, and the inferior vena cava before the

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resectability of the tumor can be clarified. Resection of the tumor should be attempted if at all possible, because this is the only chance for cure with present techniques. Biopsy is indicated only when resection is not possible. The plans for hepatic resection, i.e., right or left hepatic lobectomy or extended hepatic resection, require a clear understanding of liver anatomy. The techniques for hepatectomy are well described. 5 • 20, 27, 29 It is imperative that the anesthesiologist paralyze the patient at the time of liver transection, and during isolation and division of hepatic venous tributaries to minimize the risk of air embolism. The use of hypothermic washout of hepatic blood prior to liver dissection is recommended when a safe margin between tumor and normal liver is in question.l1

Pathologic Findings The tumor is confined to the right lobe 2 to 3 times more commonly than the left.9 Involvement of both lobes or multicentric origin of the tumors may be found in a third of the patients. These tumors are usually greater than 10 cm in diameter, and there is no correlation between the size of the mass and the ultimate prognosis. 9 Not uncommonly, the tumor may have a very thin capsule cover, and rupture of the mass must be avoided.

Postoperative Care Following hepatic resection, transient liver failure occurs frequently.I Large volumes of 5 per cent dextrose in lactated Ringer's solution will be required to provide for third space losses. A safe initial calculated rate of infusion would be 1.5 to 2 times the usual maintenance fluid requirements during the first 24 hours. Skin perfusion, blood pressure, right atrial pressure, and urine output will help determine the need for readjustment of the fluid requirements. Although hypoglycemia has been described as a common concern following hepatic resection, it is my experience that hyperglycemia is a more frequent problem. 21 The blood and urine sugar will have to be monitored. It may be necessary to change to Ringer's lactate solution without glucose. Hypoalbuminemia is common, but infusion of albumin solutions are not often necessary and usually deferred until the third postoperative day. Vitamin K may have to be administered because of prolonged prothrombin time and other abnormally depressed clotting factors. Other indications of transient hepatic failure include: elevated direct and indirect bilirubin, rising transaminase and cholesterol, and an initial fall in alkaline phosphatase. The serum potassium and calcium must be carefully monitored intraoperatively and postoperatively because of the effect of massive transfusion and possible rapid uptake of calcium into bone following removal of the parathormone-like protein. "Regeneration" is actually hypertrophy and hyperplasia of the remaining liver. Regeneration occurs very rapidly, as assessed by liver scan and liver function tests. However, if irradiation and chemotherapy are indicated, a delay of 1 to 2 months has been recommended to allow for complete regeneration. IO

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Those patients with malignant tumors, in whom the tumor was unresect able orin whom there is concern about the margin of tumor resection, may benefit from x-irradiation. Chemotherapy should also be considered for patients with residual tumor, and for those who have apparent removal of all tumor. Regression of tumor has been reported with vincristine, actinomycin D, cyclophosphamide, methotrexate, and 5-fluorouracil. Combinations of these drugs are now on clinical trial, and these studies should be supported in the hope of gaining sufficient clinical volume that the poor prognosis might be improved.

Results Approximately one-half of the hepatic tumors in children are resectable. 9 When the tumor is found to be marginally unresectable, radiotherapy and intensive chemotherapy may be indicated, and if regression of tumor has been achieved, a second look should be considered. 12 The only cures for hepatoblastoma and hepatocarcinoma have occurred in those patients who have had complete removal of all tumor. In those resectable lesions, the cure for hepatoblastoma is 60 per cent, and for hepatocarcinoma it is 35 per cent. 9 The operative mortality during hepatic resection has been excessively high (15 to 33 per cent). 8.9 This is usually due to excessive hemorrhage and transfusion complications leading to cardiac arrest. Numerous lifethreatening postoperative complications include: hemorrhage, bile fistula, subphrenic abscess, and wound infection. The intraoperative and postoperative care demands a well established operative team and nursing care area.

REFERENCES 1. Aronsen, K. F., Ericsson, B., and Pihl, B.: Metabolic changes following major hepatic resection. Ann. Surg., 169:102-110, 1969. 2. Behrle, F. C., Mantz, F. A., Jr., Olson, R L., and Trombold, J. C.: Virilization accompanying hepatoblastoma. Pediatrics, 32:265-271, 1963. 3. Boles, E. T., Jr.: Tumors of the abdomen in children. PED. CLIN. N. AM., 9:467-484, 1962. 4. Chan, C. H.: Primary carcinoma of the liver. MED. CLIN. N. AM., 59:989-994, 1975. 5. Clatworthy, H. W., Jr., Boles, E. T., Jr., and Kottmeier, P. K.: Livertumors in infancy and childhood. Ann. Surg., 154:475-484, 1961. 6. de Lorimier, A. A., Simpson, E. B., Baum, R. S., and Carlsson, E.: Hepatic artery ligation for hepatic hemangiomatosis. N. Eng. J. Med., 277:333-337, 1967. 7. Edmondson, H. A.: Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. J. Dis. Child., 91 :168-186, 1956. 8. Exelby, P. R, EI-Domeri, A., Huvos, A. G., and Beattie, E. J., Jr.: Primary malignant tumors of the liver in children. J. Pediat. Surg., 6:272-276, 1961. 9. Exelby, P. R, Filler, R M., and Grosfeld, J. L.: Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics Surgical Section Survey. J. Pediat. Surg., 10:329-337, 1975. 10. Filler, R M., Tefft, M., Vawter, G. F., et al.: Hepatic lobectomy in childhood: Effects of x-ray and chemotherapy. J. Pediat. Surg., 4:31-41, 1969. 11. Fortner. J. G., Shiu, M. H., Kinne, D. W., et al.: Major hepatic resection using vascular isolation and hypothermic perfusion. Ann. Surg., 180:644-652, 1974. 12. Friesen, S. R, Hardin, C. A., and Kittle, C. F.: Prolonged survivals after partial hepatectomies and second-look procedures for primary and secondary carcinoma of the liver. Surgery, 61 :203-209, 1967.

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13. Helson, L., and Garcia, E. J.: Skin metastases and hepatic cancer in childhood. New York State J. Med., 75:1728-1730,1975. 14. Howell, R R, Stevenson, R E., Ben-Menachem, Y., and Phyliky, R L.: Hepatic adenomata with Type 1 glycogen storage disease. J.A.M.A., 236:1481-1484, 1976. 15. Hung, W., Blizzard, R. M., Migeon, G. J., et al.: Precocious puberty in a boy with hepatoma and circulating gonadotropin. J. Pediat., 63:895, 1963. 16. Ihde, D. C., Sherlock, P., Winawer, S. J., and Fortner, J. G.: Clinical manifestations of hepatoma. Am. J. Med., 56:83-91, 1974. 17. Ishak. K G., and Glunz, P. R: Hepatoblastoma and hepatocarcinoma in infancy and childhood. Cancer, 20:396-422, 1967. 18. Kasai, M., and Watanabe, I.: Histologic classification of liver-cell carcinoma in infancy and childhood and its clinical evaluation. A study of 70 cases collected in Japan. Cancer, 25:551-563, 1970. 19. Knowles, D. M., and Wolff, M.: Focal nodular hyperplasia of the liver. Hum. Pathol., 7:533-545, 1976. 20. Martin, L. W., and Woodman, K S.: Hepatic lobectomy for hepatoblastoma in infants and children. Arch. Surg., 98 :1-7, 1969. 21. McDermott, W. V., Jr., Greenberger, N. J., Isselbacher, K J., and Weber, A. L.: Major hepatic resection: diagnostic techniques and metabolic problems. Surgery, 54:56-66, 1963. 22. Misugi, K, Okajima, H., Misugi, N., and Newton, W. A., Jr.: Classification of primary malignant tumors of liver in infancy and childhood. Cancer, 20:1760-1771, 1967. 23. Moss, A. A., Clark, R E., Palubinskas, A. J., and de Lorimier,A. A.: Angiographic appearance of benign and malignant hepatic tumors in infants and children. Am. J. Roentgen., 13:61-69, 1971. 24. Myers, M. H., Young, J. L., Jr., Silverberg, E., and Heise, H. W.: Cancer incidence, survival and mortality for children under 15 years of age. American Cancer Society Professional Education Publication, 1976. 25. Shanser, J. D., Glickman, M. G., and Palubinskas, A. J.: Pitfalls in the arteriographic differentiation of intrahepatic and extrahepatic masses. Am. J. Roentgen., 121 :420-429, 1974. 26. Smith, J. B., and O'Neill, R T.: Alpha-fetoprotein. Occurrence in germinal cell and liver malignancies. Am. J. Med., 51 :767-771, 1971. 27. Starzl, T. E., Bell, R. H., Beart, R. W., and Putnam, C. W.: Hepatic trisegmentectomy and other liver resections. Surg. Gynec. Obstet., 141 :429-437, 1975. 28. Teng, C. T., Daeschner, C. W., Jr., Singleton, E. B., et al.: Liver diseases and osteoporosis in children. I. Clinical observations. J. Pediat., 59:684-708,1961. 29. Taylor, P. H., Filler, R. M., Nebesar, R. A., and Tefft, M.: Experience with hepatic resection in childhood. Am. J. Surg., 117:435-441, 1969. 30. Von Felton, A., Straub, P. W., and Frick, P. G.: Dysfibrinogenemia in a patient with primary hepatoma. First observation of an acquired abnormality of fibrin monomer aggregation. N. Eng. J. Med., 280:405-409, 1969. 31. Weintraub, B. D., and Rosen, S. W.: Competitive radioassays and "specific" tumor markers. Metabolism, 22:1119-1127,1973.

Pediatric Surgical Service School of Medicine University of California, San Francisco San Francisco, California 94143