European Journal of Neurology 2007, 14: 408–412
doi:10.1111/j.1468-1331.2006.01681.x
Hepatocellular carcinoma presenting as nervous system involvement S.-F. Chena, N.-W. Tsaia, C.-C. Luib, C.-H. Lua, C.-R. Huanga, Y.-C. Chuanga, Y.-F. Chengb, C.-H. Kuoc and W.-N. Changa a
Departments of Neurology, bRadiology, and cInternal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung
University College of Medicine, Kaohsiung, Taiwan
Keywords:
hepatocellular carcinoma, nervous system involvement Received 7 March 2006 Accepted 18 October 2006
To analyze the clinical features of hepatocellular carcinoma (HCC) in patients with signs and symptoms of nervous system involvement as the initial presentation. Over a period of 11 years (January 1993 to December 2003), 15 008 HCC patients were identified at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan. Amongst them, 42 cases had nervous system involvement, of which six had nervous system involvement as their initial presentation. These six cases were enrolled in this study and their clinical and laboratory data were analyzed. The clinical features of the other 36 HCC cases with nervous system involvement were also analyzed for comparison. The six cases were all males, aged 36–68 years old. The involved parts of the nervous system were the cerebellar hemisphere (one), the frontal lobe (one), the sphenoid sinus, sellar turcica, and cavernous sinus (one), the cervical spine (one), and the thoracic spine (two). Their corresponding neurologic presentations were back pain, headache, consciousness disturbance, visual disturbance, and limb weakness. Whilst three out of six patients presenting with nervous system manifestations were found to have concurrent systemic metastases in other expected sites (lung, bone), three had isolated nervous system involvement even after extensive work up. The associated medical conditions of the six cases included hepatitis B (three), hepatitis C (one), liver cirrhosis (two), portal vein thrombosis (three), and diabetes mellitus (two). All the six died within 9 months after the detection of nervous system involvement. The prevalence of nervous system involvement in HCC patients is 0.28% (42/15088), with 0.04% (6/15088) having this as their initial presentation. The prognosis of HCC with nervous system involvement is grave. Their clinical and laboratory data are not unique but the diagnosis could only be confirmed by hepatic and nervous system imaging studies, histopathologic examination, and serum alpha-fetoprotein detection. This consideration should be emphasized especially in areas that are hyperendemic for HCC and if the original focus of metastatic lesion is obscure.
Introduction Hepatocellular carcinoma (HCC) is a common cancer in Asia and South Africa [1–4] and ranks as one of the most lethal malignancies in Taiwan [5]. In endemic areas, the annual incidence is up to 500 cases per 100 000 population [1,6], which may be correlated with the high infection rate of hepatitis virus [7]. Local metastasis of HCC is common and usually involves the regional lymph nodes, portal vein, hepatic vein, diaphragm, gallbladder, and serosa [8–12]. The frequent sites for distant metastases include the lungs, adrenal glands, and bone marrow [8–12]. Correspondence: Wen-Neng Chang, MD, Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung, 123, Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan (tel.: +886 7 7317123 ext 2283; fax: +886 7 7333816; e-mail:
[email protected]).
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Hepatocellular carcinoma metastasis to the nervous system is still an uncommon condition [8–13]. Because of the rapid clinical course, most patients without active treatment die within few months after the diagnosis is made [6]. Recently, advancements in both medical and surgical therapies have significantly prolonged the survival time [14]. In Taiwan, the incidences of HCC with nervous system metastasis were reported in two autopsy studies, one in 1979 [2] and another in 1997 [1], with reported figures of incidence of 0.3% and 6.2%, respectively. Thus, the incidence of HCC metastasis to nervous system is expected to increase, which is also noted in other reports [15,16]. However, HCC patients with distant metastasis but without abdominal discomfort or a palpable liver mass are quite uncommon. Furthermore, nervous system involvement as the initial presentation is rarely reported. In this study, we analyzed the clinical
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58/M
68/M
58/M
54/M
36/M
2
3
4
5
6
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ALK-P, alkaline-phosphatase (normal range: 28–94 U/L); a-FP detection, alpha-fetoprotein detection; normal range of AST 0–37 U/L; normal range of ALT 0–40 U/L; AST, ????; ALT, ????; T-bilirubin, total bilirubin (normal range: 0.2–1.4 mg/dl).
1 3.1 416 129 384 19 860 Lung
7 Not done Not done Not done 25 219 Lung, bone
9 0.8 101 84 98 500
Mental change, right hemiparesis (28 days) Sphenoid sinus, sella turcica, bilateral Headache, ptosis, cavernous sinus, supra-sellar extension diplopia (21 days) Cervical spine (C7) with cord Neck pain, left upper None compression limb weakness (21 days) Multiple T-spine (T3–T7) with cord Paraparesis (5 days) Hepatitis B, diabetes compression, paravertebral mass mellitus with intraspinal extension Thoracic (T3) spine Paraparesis (4 days) Portal vein thrombosis with cord compression
Not done
4 1.3 205 177 6.85 108
2 1.3 104 69 89 50 000
1.4 170 132 100 Left cerebellar hemisphere 59/M 1
Age Case (years)/ no. sex Location of involvement
The clinical characteristics of the six enrolled cases are listed in Table 1. They were all male, aged 36–68 years old. The diagnosis of HCC-related nervous system metastasis was confirmed by lesion site biopsy in five cases (patients: 1, 2, and 4–6) and by both liver and lesion site biopsy in one (patient 3). The associated medical conditions of the study cases were hepatitis B (three), hepatitis C (one), liver cirrhosis (two), portal vein thrombosis (three), and diabetes mellitus (two). Their clinical presentations included hemiparesis (two), paraparesis (two), headache (two), monoparesis (one), ptosis and extra-ocular motor palsy (one), altered consciousness (one), and dizziness (one). The locations of nervous system involvement are shown in Fig. 1.
Table 1 Clinical characteristics and laboratory data
Results
Left frontal lobe
Underlying conditions Clinical presentations (duration)
800
AST ALT (U/l) (U/l) Other metastasis a-FP (lg/ml) sites
Biochemistry data
ALK-P (U/l)
From January 1993 to December 2003, the medical records of 15 088 HCC patients diagnosed at the Chang Gung Memorial Hospital, Kaohsiung, a 2482-bed acute- and tertiary-care referral teaching hospital in southern Taiwan, were reviewed. Amongst these, 42 had HCC-related nervous system metastasis, six of whom had nervous system involvement as their initial presentation. These six cases were enrolled and their clinical and laboratory data were analyzed. All of the 42 patients underwent cranial and/or spinal computed tomography (CT) (GE LightSpeed Plus, Siemens Somatom Plus 4, Milwaukee, WI, USA) and/ or magnetic resonance imaging (MRI) (Signa, Horizon GE Medical system, Milwaukee) studies to confirm the existence of nervous system involvement. The diagnosis of metastatic HCC was confirmed by the following criteria: (i) positive liver biopsy characterized by the similarity of tumor cells to hepatic cord cells [17,18], (ii) brain or skull biopsy, or (iii) spinal biopsy. The results of extrahepatic biopsy had histopathologic characteristics of HCC. Patients without tissue proof were confirmed by the radiographic criteria of HCC [19], which included: (i) a mass >2 cm in diameter in a cirrhotic liver in two imaging modalities, and (ii) contrast enhancement on CT, MRI, or angiography. A mass lesion within a cirrhotic liver in the presence of serum alpha-fetoprotein (a-FP) level >400 ng/ml is also diagnostic. For a comparison, the clinical and laboratory data of the other 36 patients with HCC-related nervous system metastasis but not as their initial presentation were also analyzed.
Hepatitis B, liver cirrhosis, Not done portal vein thrombosis, diabetes mellitus Hepatitis C, portal Not done vein thrombosis Hepatitis B, liver cirrhosis Lung, skull base
Materials and methods
Headache, dizziness (60 days)
Survival T-bilirubin time (mg/dl) (months)
features of six HCC patients with nervous system metastasis as the initial presentation.
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Hepatocellular carcinoma with nervous system involvement
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Figure 1 (a) Brain computed tomography (CT) axial view shows an irregular wall enhancement and mass in the left cerebellum (arrows); the fourth ventricle is displaced to the right. (b) Brain CT axial view shows a ring enhancement lesion in the left frontal region (arrow) with obvious perilesional edema. (c) Brain CT axial view with contrast enhancement shows lateral bulging of the cavernous sinus on both sides (arrows). (d) Post-myelographic CT at the cervical level, transverse view shows destructive bone lesion of the posterior element with soft tissue component compressing the spinal cord. (e) Thoracic spine CT transverse view shows osteolytic lesions involving the vertebral body, transverse process, and left rib with spinal cord compression. (f) Contrast enhancement with fat suppression T1W1 axial view magnetic resonance imaging at thoracic level that shows a heterogeneous enhanced mass in the spinal canal and left side, posterior element, with spinal cord compression.
Aside from the nervous system involvement, pulmonary metastasis was found in three cases (patients: 3, 5, and 6), multiple bone metastasis in one (patient 5),
and skull base involvement in one (patient 3). Despite combined surgical intervention and radiotherapy, all six patients died within 9 months after diagnosis.
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Hepatocellular carcinoma with nervous system involvement
Except for patient 3, the initial serum a-FP levels were markedly elevated in the other five cases. Patient 3 received a follow-up study of serum a-FP level 3 months later, which showed an elevation of 154 ng/ ml. Except for patient 5, asparate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase were elevated in the other five cases. All cases had an elevated total bilirubin (T-bilirubin) levels except for patient 6. As to the clinical data of the other 36 HCC patients with nervous system involvement (though not as the initial presentation), 33 were male and three female, with age range from 25 to 78 years. The involved locations were as follows: intracranial metastasis in 29 cases (20 with brain parenchyma involvement and nine with both brain parenchyma and bony skull involvement), four spinal involvement (bony spine, root, and cord), and three with both spinal and intracranial involvement. Hepatitis was found in 27 cases, liver cirrhosis in 24, portal vein thrombosis in 15, and esophageal varices in 11. Aside from nervous system involvement, lung metastasis was found in six cases, bone metastasis in 11, and both lung and bone metastasis in six. The clinical manifestations of the 36 cases were hemiparesis in nine, monoplegia in three, headache in eight, consciousness disturbance in six, visual disturbance in four, dizziness in two, seizure in two, dysphagia in two, back pain in two, and dysphasia in one. The biochemical data were as follows: a-FP, 3.0– 12740 (lg/ml); AST, 24–371 (U/L); ALT, 15–173 (U/ L); and T-bilirubin, 0.38–3.6 (mg/dl). Except for one patient who died 25 months after nervous system involvement was detected, the other 35 died within 11 months of detection.
Discussion Patients with HCC usually have constitutional manifestations, including abdominal fullness and pain, anorexia, and general malaise [1]. The spectrum of clinical presentation and laboratory data of our six cases were not unique. Because of the different study designs, the exact incidence of nervous system involvement (intracranial and spinal involvement) of HCC patients varies in different reports [6,20–24]. In this study, more than 62% (26/42) of cases had concomitant bone and/or lung involvement. Thus, in HCC patients with nervous system involvement, additional bone and lung involvement is also expected and should be investigated. Moreover, our results showed nervous system involvement in 0.28% (42/15088) of the total number of HCC patients, although only 0.04% (6/ 15088) had the concomitant signs and symptoms on presentation.
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The incidence of HCC-related nervous system metastasis is lower than those of HCC metastasis to other organs [13], which may be due to the rapid course and short survival time of HCC itself, thereby limiting the development of nervous metastasis [20]. The low affinity of HCC to the nervous system is also implicated as one of the causes of the low incidence [20]. At the same time, the signs and symptoms of HCC-related nervous system involvement can be masked by many other clinical features, including hepatic encephalopathy, an important course in the late stages of HCC. For these reasons, the exact incidence of HCC patients with nervous system involvement is underestimated. Nervous system involvement as the initial presentation of HCC is occasionally mentioned in the Englishlanguage medical literature [6,20–22,24–31]. The reported locations include the spine, skull, and intracranial areas, whilst the corresponding neurologic features are radiculopathy, myelopathy, cranial neuropathy, intracranial mass-related signs and symptoms, and cerebral hemorrhage. Our cases had similar clinical features. The locations and clinical manifestations of our six HCC cases were similar to those of the other 36 cases with nervous system involvement. Aside from similar clinical features, all of these HCC patients had a short survival time and their clinical features were consistent with those of other reported HCC patients with nervous system involvement [6,21,22,24,25]. The diagnosis of HCC with nervous system involvement in this particular group of patients can only be made by hepatic and nervous system imaging studies, histopathologic examination, and serum a-FP detection. If there is a high index of suspicion and there is a concomitant viral hepatitis and/or elevated serum a-FP, the possibility of HCC-related nervous system metastasis should not be ignored. This consideration should be emphasized especially in HCC hyperendemic areas, such as Taiwan, if the original focus of metastatic lesion is obscure. However, the study has only a small number of cases, which limits the analysis. Further large-scale studies of this specific group of patients should be conducted to delineate the clinical and laboratory characteristics of HCC patients with nervous system involvement as their initial presentation. This is also necessary to ensure an earlier diagnosis and a better therapeutic outcome. In conclusion, at least 0.28% of HCC patients have nervous system involvement, which is the initial presentation in 0.04% of cases. In this group, the areas of nervous system involvement are protean and the diagnosis can only be made by hepatic and nervous system imaging studies, histopathologic examination, and serum a-FP detection. These considerations should be emphasized, especially in HCC hyperendemic areas
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such as Taiwan, if the original focus of the metastatic lesion is obscure.
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