PRIMARY TUMORS OF THE LIVEI

Bernard B. Anderson, MD, FACS, Ferdinand Ukah, MD, Amadea Tette, MD, Sioc-Go Villaflor, MD, Dae Koh, MD, and Phillip Seton, MD Washington, DC

Primary tumors of the liver that are of clinical significance are rare. Ninety-five percent of such lesions when encountered will be malignant and only 5% will be benign. Malignant primary hepatic lesions represent 2% to 3% of primary cancers encountered in the United States. Hepatocellular carcinoma constitutes 90% of malignant liver primaries in the adult. Seventy-five percent of cases are associated with cirrhosis of the liver and patients with hepatitis B infection have a 33- to 200-fold excess risk for this malignancy. Cholangiocarcinoma represents 5% to 10% of hepatic primary malignancies while hepatoblastoma is distinctly uncommon in adults. Treatment is primarily surgical, and resectability is limited by the presence of cirrhosis and spread of the tumor within and outside of the liver. Of the benign liver tumors, the liver cell adenoma seem to be associated with oral contraception and have a proclivity for intraperitoneal hemorrhage, especially during pregnancy. Focal nodular hyperplasia is a tumor-like condition that also may be associated with oral contraception. This article describes five cases, two of which had quite unique presentations. (J Nati Med Assoc. 1992;84:129-135.)
Key words * tumor * liver* malignancy Primary tumors of the liver represent an infrequent occurrence in the practice of most general surgeons. This article describes five cases and reviews the literature.
From the District of Columbia General Hospital, Howard University, Washington, DC. Requests for reprints should be addressed to Dr Bernard B Anderson, Dept of Surgery, District of Columbia General Hospital, 19th & Massachusetts Ave, SE, Washington, DC 20003.
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CASE REPORTS Case 1

A 21-year-old black female was admitted for elective cholecystectomy for symptomatic gallstones diagnosed by gallbladder ultrasound. She was operated on and discovered to have a 3X3>x3 cm mass of the liver adjacent to the fundus of the gallbladder. A cholecystectomy was performed, and the tumor was removed by wedge resection. The bisected specimen was yellowbrown with a prominent fibrous center. Histologic analysis suggested focal nodular hyperplasia (Figure 1). This patient had been taking birth control pills for more than 1 year.

Case 2
A 76-year-old insulin-dependent diabetic male with labile hypertension controlled by nadolol, bumetanide, and hydralazine underwent a work-up for a suspected pheochromocytoma. The patient underwent cholecystectomy several years prior and had no symptoms referable to the abdomen and its viscera. Computerized tomography (CT) of the abdomen discovered an unsuspected tumor of the right lobe of the liver (Figure 2). The patient had a full work-up of the lung and gastrointestinal (GI) tract that failed to discover a primary tumor of any other site. Needle biopsy of the mass confirmed hepatocellular carcinoma. The patient denied alcohol and tobacco use in the past. He admitted to prior hepatitis and jaundice. Preoperatively, his blood pressure was 160/100 mm/Hg, and his liver function tests, complete blood cell count, and Sequential Multiple Analyzer 7 were all normal. Preoperative selective hepatic artery angiography identified the tumor in the right lobe of the liver without any other associated tumor (Figure 3). The patient underwent right hepatic lobectomy with adequate surgical margins (Figure 4). Histologic analysis confirmed hepatocellular carcinoma (Figure 5), and microscopic features in the resected specimen were consistent with cirrhosis of
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Figure 1. Low-power photomicrograph showing central stellate fibrosis septating the liver parenchyma into various sized nodules.
Figure 3. Selective arteriogram showing tumor effect in the location of the tumor seen on CT.

most of his life but was never diagnosed as having hepatitis or cirrhosis.

Case 4
A 39-year-old black male was admitted for massive upper GI bleeding. He admitted to a 10-pound weight loss over a 4-month period, progressive epigastric pain, and abdominal distention. The patient had a prior hospitalization for GI bleeding 1 year before. He also had hospitalizations in the past for pneumonia and pancreatitis. The patient admitted to smoking one pack of cigarettes per day for 20 years. On physical examination, he seemed chronically ill. He was asthenic; his abdomen was distended and a 10 X 10 cm firm and tender epigastric mass was palpated. Hematocritlhemoglobin was 26/9.1 g/dL. Total protein/albumin ratio was 5.0/2.5 mg %. Serum amylase and other liver function tests were normal. The patient was thought to have a leiomyomatous tumor of the stomach and underwent upper GI endoscopy that revealed an extramucosal tumor of the stomach. The patient continued to bleed and underwent emergency laparotomy and was found to have a massive tumor involving the diaphragm pericardium, left lobe of the liver, the stomach, and the gastrocolic ligament (Figure 7). The patient underwent resection en bloc of one third of the left diaphragm, part of the pericardium, the left lobe of the liver, the distal esophagus, the proximal two thirds of the stomach, the spleen, and the greater omentum. The specimen measured 25 X 17 X 13 cm and weighed 1650 g (Figure 8).
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Figure 2. CT of abdomen showing a wellcircumscribed solitary tumor of the posterior portion of the right lobe of the liver.
the liver (Figure 6). The patient had a relatively uneventful postoperative course for the first week, but subsequently developed progressive liver failure and died from multi-organ failure and sepsis after 31 days.

Case 3
A 75-year-old black male underwent emergency laparotomy subsequent to an iatrogenic sigmoid colon perforation during colonoscopy for colonic polyps. A large tumor of the right lobe of the liver that extended into the left lobe was identified during surgery. The perforation of the colon was repaired primarily, and the liver tumor was biopsied. The histologic features were consistent with hepatocellular cancer. This patient had a "stormy" hospital course ending in death from multi-organ failure and sepsis on his 25th hospital day. The patient was a "heavy" user of alcohol throughout
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Figure 4. Section through the resected right hepatic lobectomy specimen showing grossly free margins and a well-circumscribed tumor.

Figure 6. Photomicrograph showing histologic features consistent with postnecrotic cirrhosis in the uninvolved liver.

Figure 5. Photomicrograph showing a welldifferentiated hepatocellular carcinoma with a prominent trabecular and acinar pattern.
Gross and histologic analysis identified a mixed type hepatoblastoma arising from the left lobe of the liver with penetration into the diaphragm, esophagus and stomach, and spread to four of 17 lymph nodes. There were multiple sites of vascular invasion within the tumor (Figures 9 and 10). The patient had reconstruction of the GI tract by esophagogastrostomy and pyloroplasty. The stretched-out diaphragm was redundant enough to be apposed. The patient made an uneventful recovery and was placed on chemotherapy postoperatively. Eighteen months postoperatively he was reoperated for small bowel obstruction and found to be grossly free of cancer in the liver and abdominal

Figure 7. lntraoperative view of massive epigastric tumefaction involving the diaphragm, pericardium, left lobe of the liver, proximal two thirds of the stomach, and the gastrocolic
omentum.

old female presented to the hospital with a tender epigastric mass. She was evaluated with plain abdominal radiographs that identified a mass in the epigastrium and a downward displacement of the transverse colon. The sonogram showed the epigastric mass to be solid (Figure 11). At exploratory laparotomy, she was found
to have a 16-cm diameter liver tumor that arose from the inferior edge of the left lobe of the liver at the insertion

cavity.

Case 5
A severely mentally and physically retarded 22-yearJOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 2

of the falciform ligament from a 4-cm diameter pedicle. The tumor had undergone spontaneous torsion and was infarcted. This was easily resected. Further exploration revealed a second 10-cm diameter tumor in the right lobe of the liver. This was removed by wedge resection using finger fracture technique. Histologic analysis revealed both tumors to be benign liver cell adenomas.
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Figure 10. High-power photomicrograph of

Figure 8. En bloc resected specimen that included the proximal two thirds of the stomach, the left lobe of the liver, the gastrocolic omentum, spleen, and part of the diaphragm and pericardium.

hepatoblastoma.

...

......

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Figure 9. Low-power photomicrograph of mixed type hepatoblastoma showing typical nests of malignant epithelial and mesenchymal cells.
The patient was discharged on hospital day 9 but had to be readmitted subsequently for treatment of a perihepatic abscess. On late follow-up, CT of the abdomen suggested recurrence of the right hepatic

Figure 11. Upper abdominal ultrasound of patient in Case 5 showing a large epigastric mass, which at surgery represented a pedun culated hepatic adenoma that had undergone spontaneous torsion.

adenoma.

DISCUSSION
The liver is a common site for the spread of cancers originating from primary malignancies of abdominal viscera and from cancers of extra-abdominal viscera such as the lung and the breast. By contrast, however, primary malignancies of the liver are rare in the United States and Europe and account for only 2% to 3% of all
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malignancies of the GI tract. In Asia, Africa, and certain parts of the developing world, primary cancers of the liver are more frequent. Primary liver cancer is said to account for more than 50% of malignant lesions in men and more than 20% in women in certain regions of Africa.I According to McSween,2 benign neoplasms of the liver are distinctly infrequent, accounting for only 5% of all primary hepatic neoplasms. The remaining 95% of primary neoplasms of the liver are malignant. It is convenient to classify primary liver tumors according to whether they are neoplasms or tumor-like conditions, and the neoplasms into benign and malignant subtypes and their cell type of origin (Tables 1 and 2). Benign primary neoplasms developing from the liver
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TABLE 1. PRIMARY TUMORS OF THE LIVER: BENIGN (5% OF ALL PRIMARY LIVER TUMORS) Cell Type of Origin Pertinent Clinicopathological Features Type of Tumor Liver cell Liver cell adenoma Female predominance; five times more common in women on oral contraception; tend to be vascular and have proclivity to bleed during pregnancy Bile duct epithelium Bile duct adenoma Usually less than 1 cm in size Most common benign tumor of liver; usually single Mesenchymal cells Hemangioma Focal nodular Tumor-like lesion; most often seen in women; hyperplasia possibly associated with oral contraception Hamartoma Tumor-like lesion; usually found in children; 1 to 22 cm in size TABLE 2. PRIMARY TUMORS OF THE LIVER: MALIGNANT (95% OF ALL PRIMARY LIVER TUMORS) Pertinent Clinicopathological Features Cell Type of Origin Type of Tumor Liver cell

Hepatocarcinoma

Bile duct epithelium

Cholangiocarcinoma

Mixed (epithelial and mesenchymal cell lines)

Hepatoblastoma

90% of all malignant primary liver tumors; cirrhosis is present in 43% to 75% of hepatocarcinoma cases, usually the macronodular variety; hepatitis B virus, aflatoxins, and liver cell dysplasia are also associated factors; male:female ratio 3:1; alphafetoprotein positivity in 90% of patients 5% to 10% of all malignant primary tumors; in the Far East, liver flukes (Clonorchris sinensis and Opisthorchis viverrin,) have been found in 58% of cholangiocarcinoma; thoratrast has also been etiologically implicated; there is no sex predilection, and oL-fetoprotein is not typically increased Rare; 26 cases reported in adults; most common primary liver tumor in children-found almost exclusively in the first 3 years of life; male:female ratio 2:1; oa-fetoprotein is elevated in 100% of cases; cirrhosis of the liver is seldom present

Mesenchymal (Kupffer's cells)

Hemangiosarcoma

Rare; most common malignant mesenchymal tumor

of the liver; found almost exclusively in adults; associated etiologically with thoratrast, vinyl chloride, and arsenicals

cell line are referred to as liver cell adenomas. They may be causally related to the use of oral contraceptive agents and sex hormones. They tend to be vascular lesions and have a propensity to cause intraperitoneal bleeding, especially during pregnancy.3'4 Benign tumors arising from the bile duct epithelium are referred to as bile duct adenomas. They are usually less than 1 cm in size and are rare. Benign tumors arising from the mesenchymal cells of the liver also occur; the most common of these is the hemangioma. The hemangioma is said to be the most common benign tumor of the liver. It occurs in all ages with a 7%
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 2

incidence in autopsy series.5 The hemangioma is usually single and less than 5 cm in size. Focal nodular hyperplasia is a tumor-like lesion. It occurs more commonly in women and has been linked to long-term use of oral contraceptive steroids.4 Mesenchymal hamartoma of the liver is a rare cyst-like congenital abnormality usually found in children younger than 2 years of age. Treatment is by simple enucleation or partial hepatectomy.6 Of the malignant primary neoplasms of the liver, the hepatocarcinoma is the most frequent and accounts for almost 91% of all primary malignancies of the liver.7
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Forty-three percent to 75% of hepatocarcinoma patients in North America have cirrhosis, primarily of the macronodular variety.8 The association between hepatocarcinoma and cirrhosis is further validated by the finding that 20% to 40% of patients dying of cirrhosis have hepatocarcinoma on autopsy.9 However, the overwhelming evidence is that the hepatitis B virus is responsible for cases of hepatocarcinoma worldwide. A 200-fold excess risk of developing hepatocarcinoma has been described in chronic hepatitis B virus carriers in one prospective study.10 Aflatoxin B, produced by the fungus Aspergillus flavus, has been implicated in the pathogenesis of hepatocarcinoma."l Sex also seems to be a factor in that males develop hepatocarcinoma three times more frequently than females. Cholangiocarcinoma arises from the epithelial cells of the bile ducts and represents 5% to 10% of primary malignant neoplasms of the liver. There is no sex predilection with males and females being equally affected. In the Far East, infection is caused by liver flukes-Clonorchis sinensis and Opisthorchis viverrini are the most common causes of cholangiocarcinoma. Clonorchis was found to be present in 58% of autopsied cases of cholangiocarcinoma.'2 In the United States, thoratrast is probably the best documented cause of cholangiocarcinoma. Hepatoblastoma represents a third type of primary liver cancer. It arises from embryonic tissues. Two histologic types have been described. In one type, the tumor consists of epithelial cells only. In the second type, referred to as the mixed type, the tumor consists of both epithelial and mesenchymal cells.'3 While hepatoblastoma is the most common liver tumor in children,14 with most cases occurring before the third year of life, it is distinctly rare in adults. By 1985, Kawarada et al'5 reported two personal cases and reviewed only 22 other reported cases. Male to female ratio is 2.5:1 according to Isak and Glunz.16 The lesion characteristically develops in noncirrhotic livers, and tends to be solitary and localized to one lobe. These are all characteristics that favor resection. Hemangiosarcoma, also known as Kupffer's cells sarcoma, is a rare primary malignant neoplasm of the liver. Nevertheless, it is considered to be the most common of the malignant mesenchymal tumors of the liver.17 It occurs almost exclusively in adults and has been associated with protracted exposure to vinyl chloride, arsenicals, and thoratrast.18 The presenting symptoms of patients with primary liver tumors are nonspecific. There may be no symptoms at all. In symptomatic patients, the presenting
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complaints have no distinguishing features from patients with other neoplasms affecting the liver. Certain historical and physical findings may be relevant, however, and these may include the use of sex hormones; exposure to vinyl chloride, arsenicals, and thoratrast; a history of cirrhosis; hepatitis B infection; and the age, sex, and country of origin of the patient. Any of the above may be relevant in a patient being evaluated for a liver mass. Useful diagnostic modalities in suspected cases include the following: 1. Alpha-fetoprotein determination. Reportedly afetoprotein is positive in 100% of patients with hepatoblastoma, 70% of patients with hepatocellular carcinoma,19 and not significantly elevated in cholangiocarcinoma or angiosarcoma. Okuda, however, noted elevations in 20% of patients with cholangiocarcinoma.19 Higher concentrations of bilirubin and alkaline phosphatase have been reported in patients with cholangiocarcinoma. 2. Sonogram, CT and magnetic resonance imaging (MRI). The sonogram, CT, and MRI scan effectively localize the lesions, differentiate between cystic and solid tumors, and facilitate biopsy. 3. Angiography. Selective angiography is useful in further defining the lesion and its extensions prior to embarking on laparotomy. Treatment for clinically significant benign liver tumors and malignant primary tumors is primarily surgical. There are certain basic facts that may be useful when resection is being considered: anatomically, 85% of the normal liver may be resected with the expectation that regeneration of the liver will occur from the remaining 15% of the original liver mass.20 The presence of cirrhosis adversely affects the regenerative propensity of the liver. Major resection in such cases should be reluctantly considered. Experience with orthotopic liver transplantation for primary liver cancer has been described. It appears that the recurrence of cancer after transplantation is high unless the primary liver cancer was an incidental finding in the recipient's resected liver in the course of transplantation for another indication.21 Radiation therapy and chemotherapy have a limited, but still not fully defined, curative benefit.
Literature Cited 1. Lee YNM. Primary cancer of the liver: diagnosis, prognosis, and management. J Surg Oncol. 1983;22:17-25. 2. McSween RNM. Liver, biliary tract and exocrine pancreas. In: Anderson JR, ed. Muir's Textbook of Pathology. 1 0th ed. Chicago, III: Yearbook Medical Publishers Inc; 1976:601 659.
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3. Mays E, Christopherson WM, Mahr MM, Williams HC. Hepatic changes in young women ingesting contraceptive steroids: hepatic hemorrhage and primary hepatic tumors. JAMA. 1976;235:730-732. 4. Mays E, Christopherson WM. Hepatic tumors induced by sex steroids. Semin Liver Dis. 1984;4:147-157. 5. Clouse ME. Current diagnostic imaging modalities of the liver. Surg Clin North Am. 1989;69:193-234. 6. Grases PJ, Matos-Villalobos M, Arcia-Romero F, Lecuna-Torres V. Mesenchymal hamartoma of the liver. Gastroenterology. 1979;76:1466-1469. 7. Tobe T, Liver Cancer Study Group of Japan. Primary liver cancers in Japan. Ann Surg. 1990;211:277-287. 8. Nagorney DM, Van Heerden JA, llstrup DM, Adson MA. Primary hepatic malignancy: surgical management and determinants of survival. Surgery. 1989;106:740-749. 9. Hoofnagle JH. The natural history of hepatocellular carcinoma. Ann Intern Med. 1988;108:390-401. 10. Beasley RP, Hwang L. Hepatocellular carcinoma and hepatitis B virus. Semin Liver Dis. 1984;4:113-121. 11. Peers FG, Linsell CA. Dietary aflatoxins and liver cancer-a population based study in Kenya. Br J Cancer 1 973;27:473-483. 12. Schwartz DA. Cholangiocarcinoma associated with liver fluke infection: a preventable source of morbidity in Asian immigrants. Am J Gastroenterol. 1 986;81 :76-79. 13. Sugino K, Dohi K, Matsuyama T, Asahara T, Yamamoto

M. A case of hepatoblastoma occurring in an adult. Jpn J Surg. 1989; 1 9:489-493. 14. Guzzetta PC, Randolph JG. Pediatric hepatic surgery. Surg Clin North Am. 1986;69:251-257. 15. Kawarada Y, Uehara S, Noda M, Yatani R, Mizumoto R. Nonhepatocytic malignant mixed tumor primary in the liver. Cancer 1985;55:1790-1798. 16. Isak KG, Glunz PR. Hepatoblastoma and hepatocarcinoma in infancy and childhood: report of 47 cases. Cancer 1967;20:396-422. 17. Ginsberg F, Slavin JD, Spencer RP. Hepatic angiosarcoma: mimicking of angioma on three-phase technetium-99m red blood cell scintigraphy. J Nucl Med. 1986;27:1861-1863. 18. Locker GY, Doroshow JH, Zwelling LA, Chabner BA. The clinical features of hepatic angiosarcoma: a report of four cases and a review of the English literature. Medicine (Baltimore). 1979;58:48-64. 19. Okuda K, Liver Cancer Study Group of Japan. Primary liver cancers in Japan. Cancer 1980;45:2663-2669. 20. Pizzo PA, Misver JS, Cassady JR, Filler RM. Solid tumors of childhood. In: Devita VT Jr, Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology. 2nd ed. Philadelphia, Pa: JB Lippincott Co; 1985:1511-1590. 21. lwatsuki S, Gordon RD, Shaw BW, Starzl TE. Role of liver transplantation in cancer therapy. Ann Surg. 1 985;202:401 -407.

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