Medical and Pediatric Oncology 19:139-144 (1991)

Hepatocellular Carcinoma With Central Nervous System Metastasis: A Case Report and Literature Review Henry Dan Friedman, In the United States and western Europe, hepatocellular carcinoma is not generally regarded as a distantly metastasizing tumor. The ability of hepatocellular carcinoma to metastasize to the brain i s illustrated by the example of a 65-year-old white American

MD

man with no identifiable risk factors for primary liver cancer. Though hepatocellular carcinoma rarely metastasizes to the central nervous sytem, such metastases are reported to have led to tumor diagnosis or signaled tumor relapse.

Key words: brain metastasis, tumor diagnosis, tumor relapse

INTRODUCTION

Although hepatocellular carcinoma (HCC) is the 22nd most common form of cancer in the United States, it is far more prevalent in parts of sub-Sahara Africa and Asia and is possibly the most common malignancy in the world [I]. HCC accounts for 22% of autopsied patients with malignancy in Taiwan [2J and 1620% in Singapore [3]. These demographic differences may be related to the prevalence of hepatitis B and dietary exposure to mycotoxins, such as aflatoxin B 1 [ 11. At diagnosis, approximately one-half of all cases have clinically detectable metastases [4]. Recent experience with liver transplantation for HCC has shown that 44% of patients without clinically detectable metastases will recur, which emphasizes the prevalence of micrometastases [5]. The frequency of metastases appears to depend on the degree of tumor anaplasia and on the presence of liver cirrhosis [4]. In the noncirrhotic liver, local metastases are more common, while distant metastases do not depend on the presence of cirrhosis [4]. This apparent dependence on cirrhosis may in part be caused by the survival disadvantage of liver-damaged individuals (i.e., patients with cirrhosis have less opportunity to metastasize). The most common sites for local metastasis include the regional lymph nodes, portal vein, hepatic vein, diaphragm, gallbladder, and serosa. Frequent sites for distant metastases include the lung (39%), adrenal gland (6%), and bone marrow (8%) [4]. HCC rarely metastasizes to the brain. In autopsy series, brain metastases were found in 0.3% of 382 cases of HCC in Taiwan [2] and 0.5% of 5,208 cases [6] and 1.3% of 227 cases in Japan [4]. It is by virtue of its 0 1991 Wiley-Liss, Inc.

prevalence in Asia that HCC accounts for 0.8% of all central nervous system tumors in Japan [6] and 1.8% in Taiwan [2]. In contrast, an American survey of 482 consecutive cases of intracranial metastases from the University of Maryland and John Hopkins University did not include a single case of metastatic HCC [7]. PRESENTATION OF A CASE Clinical History

The patient was a 65-year-old white male and a veteran of the Second World War, during which he served in Europe. He worked as a factory foreman for 25 years, until degenerative joint disease and a pulmonary embolus led to early retirement 7 years ago. He had long-standing arterial hypertension and obesity; alcohol abuse was not reported. Suicidal and aggressive behavior, with a dramatic loss of recent memory, brought the patient to psychiatric attention 4 years ago. The patient was diagnosed with schizophrenia and progressive dementia (presumed secondary to Alzheimer’s disease) and required long-term care in a mental health facility. His neurologic and psychiatric problems were stable until the current illness. The malignancy probably first manifested in late From the Department of Pathology, State University of New YorkHealth Science Center at Syracuse. Received November 13, 1990. Address reprint requests to Henry D. Friedman, SUNY-Health Science Center, 750 East Adams Street, Syracuse, NY 13210.

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Fig. 1, Microscopic appearance of the HCC in the liver; several nests of tumor are present in this field. The gross appearance of the liver is shown in the inset. Much of the parenchyma had an abnormal soft, loose texture and a large hemorrhagic necrotic area was present in the right lobe. X 2 5 0 (with current reduction)

October 1987 as vague, intermittent abdominal discomfort. Though he became withdrawn and lost weight, it was not until mid-December that his general physical and mental status noticeably deteriorated. He was transferred to our acute-care facility at the beginning of January 1988. At admission, the jaundiced patient was in no apparent distress and was oriented to his person but not to time and place. The patient had ascites, was bedridden, and showed little spontaneous activity; focal neurologic symptoms were not appreciated. The laboratory examination was remarkable for hyperbilirubinemia (212 kmol/liter or 12.4 mg/dl of which 93%was direct reacting), moderately elevated transaminases (AST [660], ALT [120], and GGT [660 U/liter]), LDH (550 U/ liter), BUN (14 mmol/liter or 40 mg/dl), creatinine (194 FmoUliter or 2.2 mg/dl), hypoproteinemia (50 g/ liter), hypoalbuminemia (20 glliter), and slightly prolonged prothrombin and activated partial thromboplastin times. Arterial blood gases, peripheral blood cell counts, serum electrolytes, lipids, and glucose were normal; serology for hepatitis B surface and core antigens was negative. No pulmonary lesions were seen on chest x-ray. While ascites hindered an accurate abdominal palpation, sonogram showed hepatomegaly and suggested a hepatic mass lesion. Further tumor workup was

postponed however, because of worsening medical problems. The patient became lethargic and then comatose and hypotensive. He expired in cardiopulmonary failure complicated by renal failure on the tenth hospital day, 2.5 months after initial symptoms. Necropsy Findings

The liver was markedly enlarged and weighed 4,500 g (normal is a1,600 8). Approximatelly 70% of the parenchyma had an abnormal soft, necrotic, or hemorrhagic appearance (Fig. 1). Microscopic examination showed that much of the liver was replaced by HCC. The tumor consisted of epithelioid cells with centrally placed round nuclei and eosinophilic cytoplasm that grew as both tiny expansile nodules and infiltrating cords; bile-filled canaliculi were identified between tumor cells. There was no evidence of preexisting hepatic cirrhosis. Although some parahepatic lymph nodes contained metastatic HCC and were enlarged, the extrahepatic biliary ducts were patent. The brain was of normal size and contained five separate foci of metastatic HCC. The two largest metastases were situated in the right parietal cortex and in the left posterior thalamus and were associated with focal fresh hemorrhage and tumor necrosis (Fig. 2). The

Hepatocellular Carcinoma With CNS Metastasis

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Fig. 2. Brain in coronal section, at the level of the posterior thalamus. Three metastases are labeled (arrows). The large metastasis in the left posterior thalamus extends into the rostral midbrain and shifts midline structures; its microscopic appearance is shown in the inset. Bar = 1 cm.

thalamic metastasis appeared to be the most significant cerebral lesion; it measured 2.5 cm in diameter, extended into the subthalamus and rostral midbrain, and caused a midline shift. Three smaller metastases, measuring approximately 0.7 cm each, were located in the left temporal lobe cortex and the parasagittal parietal white matter. Mild lacunar change was found in the basal ganglia. No other disease-specific changes were found in the hippocampi ,mammillary bodies, cortex, or cerebellum. The primary and metastatic tumor reacted with antibody against a1-chymotrypsin, which further supports the diagnosis of HCC [8]. Cytoplasmic mucin, whose presence would be indicative of hepatobilliary differentiation, was not identified in either the primary or metastatic tumor (PAS-diastase and Alcian blue stain). A large ascitic effusion and moderate-sized pleural effusions were present. Both lungs were edematous and congested (combined weight, 1,550 g); microscopic tumor emboli were present within small pulmonary vessels.

risk factors for primary liver cancer, HCC may give rise to significant cerebral metastases. The most significant of this patient’s brain metastases was the 2.5 cm thalamicmesencephalic lesion. Although no symptomatology directly attributable to this lesion was documented, it is likely that 1) it contributed to the terminal deterioration in this patient’s mental state, 2) it was present for weeks or longer, and 3) the neurologic deficit expected with such a lesion was masked by the patient’s mental illness and progressive incapacitation. I did not find a morphological explanation for the patient’s long-standing neuropsychiatric illness [9]. In view of the subacute progression of most cases of HCC [lo], the two illnesses are most likely independent of one another. HCC and the Central Nervous System

HCC may effect the central nervous system (CNS) in several ways. Tumor-induced liver failure is probably most frequent. Pulmonary dysfunction secondary to pulmonary metastases, malignant pleural effusions, asDISCUSSION cites, or invasion of the diaphragm is also common in Present Case advanced disease. Rarely, metastases invade or compress I have presented a case that illustrates that even in a the CNS directly. Paraneoplastic syndromes are not nonendemic area, in a subject who had no identifiable uncommon, and some of these such as hypoglycemia

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TABLE I. Cases of Hepatocellular Carcinoma That Manifested Themselves as Brain Metastases* Age/ Patient gender

Symptoms (Time to dx)

tLiver/ lung nodule

Intracerebral metastasis without history of HCC a 25M Abdominal pain (3w), headache/hemiparesis (7d), subarachnoid hemorrhage (0) 3 1M Headache (5d) b hemiplegia (Id) C 3 1M Hemiplegia (0) d 40M Convulsion/hemiplegia (0) e 42M Chronic hepatitis (IOy), loss of consciousness (1 w), coma (0) f 44M Hemiplegia (1d) g 47M Liver cirrhosis (5y), unconsciousness (0) h 57F Headachelataxia ( I .7m) 1 59M Neck mass (3m), focal sensomotoric defect (1 w), headacheihemiparesis (0) Intracerebral metastasis with history of HCC j 45M HCC resecton (1.5y), cranial nerve paresis (0) k 56M HCC embolization (2y), pulmonary metastasis (1 Om), hemiparesis (0) I 66M HCC resection (1Sy), HCC ligation (4m), hemiparesis (2m) m 7 IM HCC ligation, chemo (5y); hemiparesis (0) n 74M Hemiulegia . - (0) Primary metastasis to structures neighboring the brain 0 5 IF Hemicrania (6m), epistaxidnasal mass (3m), cranial nerve palsy (1 m) P 57M Liver cirrhosis, hand weakness (3m), scalp mass (2m) q 58F Scalp mass (2m), leg weakness (2m) r 65M Diplopia/ptosis/pain (3w) S

50M

HCC resection (3y), scalp m a d l e g weakness (3m), seizure (0) -

Metastasis location

CNS bleed Prognosis Country

Author

ns 1 ns

Cerebral cortex

Id

Taiwan

Chang and Chen [2]

-I+

Cerebral cortex

lm

Senegal

Collomb et al. 191

+I+ nsl-

Cerebral cortex Cerebral cortex Cerebral cortex

lm 2m 9m

Senegal Senegal Japan

Collomb et al. 191 Collomb et al. 191 Todo et al. [6]

+I+ fl-

Cerebral cortex Subcortical mass

lm 4d

Senegal Collomb et al. [ 191 Japan Ohno et al. [ 131

-1ns(+

Cerebellum Cerebral cortex

ns 2m

USA Taiwan

Brunner et al. [7] Lee and Lee [ 121

ns(+

Pons

8m

Japan

Uchino et al. [ 181

+I+

Cerebral cortex

3m

Japan

Matsuo et al. [ 151

nsl+

Cerebral cortex

16m

Japan

Yoshikawa et al. [ 161

+I+

Cerebral cortex

1.5m

Japan

Otsuka et al. [ 171

-I-

Cerebral cortex

4m

Senegal

Collomb et al. [I91

+Ins

Skull base

ns

Taiwan

Chang and Chen [2]

+I+

Dura/ skull

Im

Japan

Kobayashi and Sakurai [ 141

-Ins

Dura/ skull

3m

Taiwan

Lee and Lee [12]

+Ins

Orbit/skull

9d

nsl+

Dura/skull

ns

England Phadke and Hughes [23] Taiwan Chang and Chen [2]

-Ins

+,

*Age in years; M, male, F, female; ns, not stated; positive; -, negative; time to dx, time before the diagnosis of brain metastases in years (y), months(m), weeks(w),or days (d); tliver/lung nodule, whether the liver was palpably enlarged or there was a lung nodule on chest x-ray at the diagnosis of brain metastasis; CNS bleed, tumor related central nervous system hemorrhage; prognosis, survival following the diagnosis of brain metastasis.

may adversely effect CNS function [ I l l . A specific neurologic paraneoplastic syndrome has only been described once in HCC and consisted of cerebellar atrophy 1111.

tumor recurrence. A total of 19 such cases are summarized in Table I [2,6,7,12-191. Their ages ranged from 25-74 years (average, 51 years), with a male to female ratio of 16:3. Many of these patients manifested nonneurologic signs of disease prior to their neurologic HCC and Brain Metastasis symptoms, and several had a history of liver disease that Exceptionally, neurological symptoms secondary to predisposed them to develop HCC .* brain metastasis can lead to the diagnosis of HCC or In 7 of 11 cases with intracerebral metastasis, intra-

Hepatocellular Carcinoma With CNS Metastasis

cranial hemorrhage was the event that caused the patient to seek medical attention. Some surmise that metastatic HCC may cause intracranial hemorrhage more commonly than most metastatic carcinoma [6]. Its prominent neovascularity, sinusoids, and concomitant hepatic damage with coagulopathy lend a theoretical basis to this clinical impression. In general, the incidence of hemorrhage from cerebral metastases depends on both the type of tumor and which group of patients was analyzed. It is generally accepted that most primary and secondary brain tumors do not bleed [20, pp 452-4541. At the time “metastatic HCC involving the brain” was diagnosed, 5 of 9 patients had a palpably enlarged liver and 8 of 12 patients had lung nodules on plain film chest x-ray. Even in the absence of lung masses, microscopic pulmonary metastasis is expected in these patients. Patient e (Table I) is therefore remarkable in that no pulmonary metastasis was found at autopsy [6]. In several patients, the primary metastasis appeared to first involve the meninges or cranium. Metastatic seeding of the meninges or cranium often occurs in hematogenous tumor spread [20, pp 71-77]. Though the dura mater generally constitutes a barrier to tumor spread, with time a metastasis may spread along it, grow outward into bone, or inward into brain. Often it is not possible to determine the precise anatomical structure from which a metastasis grew [20, pp 71-77]. Patients p, q, and s noted palpable soft tissue masses on their scalps whose appearance roughly coincided with neurologic symptoms; it is possible that they had primary meningeal metastases [2,12,14]. Patient o had a cranial base metastasis that caused epistaxis and an intranasal mass prior to severe neurological symptoms [2]. Of the 14 cases with primary intracerebral metastasis summarized in Table I, 11 were to the cerebral cortex, 1 was to the subcortex, 1 was to the cerebellum, and 1 was to the pons. The cerebral cortical lesions were scattered, though more common in regions supplied by the medial cerebral artery. This distribution of metastases is consistent with that of other carcinomas and hematogenous metastasis in general [20, pp 13-15]. The prognosis of patients with HCC metastatic to the brain is, as one would expect, poor. The survival of 16 patients for whom prognostic data were available ranged from days to 15 months following diagnosis of a brain metastasis. Fatal intracranial hemorrhage was the most common cause of immediate mortality. Patient 1survived for 16 months by undergoing three separate neurosurgical interventions to extirpate different metastases [ 161. Surprisingly, several patients ultimately succumbed to other tumor-related problems, such as pulmonary failure secondary to pulmonary metastases or malignant pleural effusions. The mean survival for HCC ranges from 4 to 6.7 months from the first onset of symptoms, according to data from 502 patients in eight studies [lo].

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HCC and Spinal Cord lesions

In a Senegalese series, metastatic HCC was responsible for 6 of 35 cases of spinal compression [21]. In 37 reported cases of HCC that manifested itself through spinal cord and spinal root compression, 36 of the patients (97%) were male, and the patient age ranged from 9 to 65 years [2,19,21,221. In most of these cases, the metastasis seeded primarily to vertebral bone; only rarely did it seed to the epidural space. Intraspinal or (spinal) meningeal metastasis is extremely rare, if reported at all. Only 3% of HCC metastasized to the skeleton in an African series [ 191. Thus, compared with common carcinomas such as breast, lung, or prostate, HCC does not frequently metastasize to bone. When it does, however, its pattern of spinal involvement is consistent with that of other metastatic tumors [20, pp 121-1 321. Conclusion

This case illustrates that HCC can metastasize to the brain in an American individual who is not at risk for HCC. In the clinical setting of hepatic disease, HCC may be a primary or secondary cause of neurologic symptoms. ACKNOWLEDGMENTS

The author thanks Dr. Catherine Powers and the VA Medical Center Medical Staff for their excellent care of this patient; Dr. Sho Yamauchi of Fukuoka, Japan, for the translation of Japanese case reports; Drs. George C. Collins, Gerald B. Gordon, Victor Casas, and Arthur H. Tatum and Mr. John Daucher for their help and advice. REFERENCES 1. DiBisceglie AM, Rustgi VK, Hoofnagle JH, Dusheiko GM, Lotze MT: Hepatocellular carcinoma. Ann Intern Med 108:39& 401, 1988. 2. Chang YC, Chen RC: Craniospinal and cerebral metastasis of primary hepatomas. J Formosan Med Assoc 78594-604, 1979. 3. Khoo TC, Tan KK, Hanam E: Three cases of hepatocellular carcinoma with unusual presentation. Singapore Med J 10:121126, 1968. 4. Okuda K: Clinical aspects of hepatocellular carcinoma: Analysis of 134 cases. In Okuda K, Peters R (eds): “Hepatocellular Carcinoma.”New York: John Wiley & Sons, 1976, pp. 387436. 5 . Wolff H, Winkler H, Lippert H: Liver transplantation for malignant liver disease. Transplant Proc 21:2406, 1989. 6. Todo T, Noguchi M, Manaka S: Metastatic hepatoma presenting as intracreanial hemorrhage. No To Shinkei 40:919-924, 1988. 7. Brunner DR, Dunne MG, Rao KC: Hepatoma presenting as a cerebellar metastasis. J Cornput Tomogr 6:65-68, 1982. 8. Taylor C: “Immunomicroscopy: A Diagnostic Tool for the Surgical Pathologist.” Philadelphia: WB Saunders, 1986, pp. 253-259. 9. Vogal FS: Dementia: A diagnostic and scientific problem for pathologists. Adv Pathol 1:177-299, 1988. 10. Murray-Lyon IM: Primary and secondary cancer of the liver. In

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Brain metastasis of hepatocellular carcinoma presenting with hemorrhage. Neurol Med Chir (Tokyo) 27:654-657, 1987. Uchino A, Miyoshi T, Ohno M: Solitary pontine metastasis form hepatocellular carcinoma-A case report. Radiat Med 5:99-100, 1987. Collomb H, SankalC M, Dumas M, Ancelle JP: Les fonnes neurologiques du cancer primitif du foie. Bull SOCMed Afr Noire Lgue Fr 13577-585, 1968. Henson RA, Urich U: “Cancer and the Nervous System.” Boston: Blackwell Scientific Publications, 1982, pp. 13-15, 71-77, 121-132, 452-454. Carayon A, Courson B, Virieu R, Piquard B: Compression medulaire par mitastase d’un cancer du foie cliniquement inapparent (A propos de dix observations). Bull SOCAfr Noire Lgue Fr 13:58&593, 1968. Byrne MJ, Scheinberg MA, Mavligit G, Dawkins RL: Hepatocellular carcinoma: Presentation with vertebral metastases and radicular compression. Cancer 30:202-204, 1972. Phadke JG, Hughes RC: Hepatocellular carcinoma with cranial metastasis and hyperglobulinaemia. J Neurol Neurosurg Psychiatry 44:1171-1172, 1981.