Extrahepatic metastasis of HCC occurs in about 30-50% of HCC cases [1
]. The most common metastatic sites are lung, and less frequently in the lymph nodes and bones [1
]. In autopsy series, Sawabe et al [1
] examined extrahepatic metastases of HCC in 98 autopsy cases, and found that 64% had extrahepatic metastases, and most of them (97%) were pulmonary metastases. In living patients, Katyal et al [2
] found extrahepatic metastasis in 148 (32%) of the 463 patients with HCC. The most common sites were lung (55%), followed by lymph nodes (41%) and bones (28%); the percentage was that of positive cases [2
]. Natsuizaka et al [3
] reported that 65 (13%) of the 482 patients with HCC had extrahepatic metastases. The most common location was lung, followed by bone and lymph nodes [3
]. Watanabe et al [4
] demonstrated that abdominal regional lympho node metastasis of HCC was found in 168 (26%) of the 660 autopsy cases of HCC. He et al [5
] reported 205 cases of HCC with bone metastasis. Fukutomi et al [6
] collected 673 patients with HCC and reported that the site of bone metastases from HCC was most frequent in vertebra, followed in order by pelvis, rib, and skull. These extrahepatic metastases of lung, bones and lymph nodes are more frequent in the advanced stages than in the early stages [1
In the present autopsy cases, extrahepatic metastases were present in 21 of the 31 cases (68%). The most common metastatic sites were lung (n=18). Regional lymph nodes metastases were found in 6 cases (19%), and bone metastases were found in 5 cases (16%). In the present surgical cases, lung metastases were 16 cases, and bone metastases were 2 cases. These findings indicate that the most common extrahepatic metastasis site is lung, as in the previous studies [1
]. In the present case, bone and lymph nodes metastases were relatively infrequent, indicating that bone and lymph nodes are unusual sites of extrahepatic metastasis of HCC.
In the present, unusual metastatic sites from HCC were recognized. They were diaphragma (n=2), pancreas (n=2), gall bladder (n=1), stomach (n=1), colon (n=1), adrenal gland (n=1), pleura (n=1), peritoneum (n=1), cervical lymph nodes (n=1), shoulder soft tissue (n=1), brain (n=1), skin (n=1), and oral cavity (n=1). These data indicate that HCC can metastasize in any locations.
There are only a few case reports of each unusual metastatic site from HCC; in the diaphragma [7
], in the pancreas [8
], in the gall bladder [9
], in the stomach [10
], in the colon [11
], in the adrenal gland [12
], in the pleura [13
], in the peritoneum [14
], in the cervical lymph node [15
], in the soft tissue [16
], in the brain [17
], in the skin [18
], and in the oral cavity [20
]. It was very interesting that the metastatic sites of the present 2 cases (skin and oral cavity) were the first manifestations of HCC.
The pathological diagnosis of metastatic HCC in extrahepatic metastatic site can be made relatively easily in patients with HCC. The histologies of HCC show trabecular and pseudoglandular patterns composed of acidophilic cells. Detection of bile is confirmative for HCC. Mallory bodies strongly suggest HCC. However, immunohistochemical studies are of great value. HepPar1 is a relatively specific marker of hepatocytes and HCC [29
]. AFP is a specific marker of HCC and York sac tumor. As is well known, cytokeratins 8 and 18 are hepatocyte cytokeratins, but they are expressed in other tumors. P53 expression indicated p53 mutations, and a marker of malignancy [30
]. Ki-67 labeling indicates cell proliferative activity. In the present study, HepPar1 and AFP were very useful in the adjunct diagnosis of HCC. Cytokeratins 8 and 18 were helpful in HCC diagnosis. P53 expression and high Ki67 labeling were useful tools of malignant nature of HCC.
In summary, the present data shows that HCC can metastasize in various organs other than the lung, and HepPar1 and AFP were good markers of extrahepatic metastases of these unusual sites of metastatic foci from hepatic HCC.