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Gastrointestinal Imaging |
1 From the Departments of Radiology (S.K., J.H.O., M.S.P., J.V.F., R.L.B.) and Transplantation Medicine (B.S.C.), University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213. Received November 11, 1999; revision requested December 15; revision received January 7, 2000; accepted January 12. Address correspondence to S.K. (e-mail: katyal@pitt.edu)
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: CT findings in 403 consecutive patients with HCC at our institution since 1992 were reviewed retrospectively. One hundred forty-eight patients with extrahepatic metastatic HCC were identified, and the locations, sizes, and attenuation and enhancement characteristics of the lesions were recorded.
RESULTS: A majority (128 [86%] of 148) of patients with extrahepatic HCC foci had either intrahepatic stage IVA tumor (112 [76%] patients) or an intrahepatic stage III tumor (16 [11%] patients) at the occurrence of metastases. The most frequent site of the first detectable metastasis was the lung (58 [39%] patients). Tabulation of all extrahepatic metastatic sites showed the most common to be the lung in 81 (55%) patients, the abdominal lymph nodes in 60 (41%) patients, and the bone in 41 (28%) patients.
CONCLUSION: The lung, abdominal lymph nodes, and bone are the most common sites of extrahepatic metastatic HCC. Most extrahepatic HCC occurs in patients with advanced intrahepatic tumor stage (stage IVA). Incidental extrahepatic lesions at CT in patients with stage I or II intrahepatic HCC are unlikely to represent metastatic HCC.
Index terms: Liver, CT, 761.12111, 761.12112, 761.12115 • Liver neoplasms, metastases, 761.323 • Liver neoplasms, staging, 761.323
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The frequent sites of extrahepatic metastases have been reported (3–11) previously only in autopsy studies and isolated case reports. To our knowledge, the true incidence and radiologic appearance of extrahepatic HCC in patients with extrahepatic metastases remains unknown. In addition, it is also not known whether the intrahepatic tumor stage of HCC may be useful in predicting the likelihood of extrahepatic occurrences of HCC.
The purpose of this study was to determine the incidence, locations, and relative frequency of extrahepatic metastases and to determine the computed tomographic (CT) manifestations of these lesions. Extrahepatic metastases were also correlated with intrahepatic tumor staging.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Of the 148 patients with metastatic disease, 43 patients had recurrent extrahepatic HCC after orthotopic liver transplantation. The 96 male patients and 52 female patients with extrahepatic HCC were 17–82 years of age (mean age, 57 years). The causes of liver disease included cryptogenic cirrhosis (49 patients), hepatitis B (26 patients), hepatitis C (31 patients), alcoholism (22 patients), hemochromatosis (eight patients), hepatitis B and C (five patients), hepatitis B and alcoholism (one patient), hepatitis C and alcoholism (one patient), hepatitis B and C and alcoholism (one patient); primary sclerosing cholangitis (one patient); primary biliary cirrhosis (one patient); autoimmune hepatitis (one patient); and glycogen storage disease type 2 (one patient).
CT scans were retrospectively reviewed independently at separate sessions by two of four experienced gastrointestinal radiologists (including J.H.O., K.L.B., and M.S.P.). All extrahepatic HCC lesions were identified, and the size, number, location, and radiographic appearance of each lesion were documented. The radiographic appearance included the CT attenuation and enhancement characteristics. The intrahepatic tumor stage at the time that the first metastasis was detected, in accordance with the TNM classification (Table 1), was recorded (12). The site of the initial manifestation of extrahepatic metastatic disease, the first detectable metastasis, also was recorded.
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Patients receiving intravenously administered contrast material each received 150 mL of either Conray 60 (iothalamate meglumine; Mallinckrodt Medical, St Louis, Mo) or Optiray 320 (ioversol; Mallinckrodt Medical) with a mechanical power injector (OP 100; Medrad, Pittsburgh, Pa). The intravenous contrast material was injected at 2.5–5.0 mL/sec for both ionic and nonionic contrast material. For injection rates of 2.5–3.5 mL/sec, 28- and 70-second delays were used for arterial and portal venous phase imaging, respectively. For injection rates of 4.0–5.0 mL/sec, delays of 20 and 60 seconds were used for arterial and portal venous phase imaging, respectively.
Regional lymphadenopathy was classified separately in accordance with location—periceliac, portohepatic, paraaortic, portocaval, peripancreatic, aortocaval, or retrocaval. Since distant sites may have had different seeding mechanisms, these sites were classified separately.
In patients with extrahepatic HCC, lung nodules were counted as a single site of metastatic disease, whether a single nodule or multiple nodules were identified initially, because all lung metastases progressed to multiple bilateral nodules in patients who underwent follow-up imaging. Bilateral adrenal metastases were considered to be a single site. All bone lesions were classified separately in accordance with location. Bone and lung CT reconstruction algorithms and window displays were reviewed in all cases.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Intrahepatic HCC Stage
The majority (112 [76%] of 148) of patients with extrahepatic HCC foci had intrahepatic stage IV tumor. Sixteen (10%) patients had intrahepatic stage III tumor, 16 (10%) patients had intrahepatic stage II tumor, and one (1%) patient had intrahepatic stage I tumor. There were three patients with uncertain tumor stage: Two patients underwent partial hepatic resection and one patient underwent orthotopic liver transplantation at outside hospitals, and preoperative images could not be obtained.
Of the 43 patients with extrahepatic HCC after orthotopic liver transplantation, 36 (84%) had intrahepatic stage IV disease, five (12%) patients had intrahepatic stage III disease, and two (5%) had intrahepatic stage II disease.
Extrahepatic Metastases
All sites of extrahepatic HCC metastases are shown in Table 2. Fifteen patients had widespread, diffuse metastatic disease as their initial manifestation of extrahepatic HCC. The most frequent site of metastasis was the lung, in 81 (55%) patients. The most frequent site of the first detectable metastasis also was the lung, in 58 (39%) patients. The metastatic HCC lesions were noncalcified soft-tissue nodules with the same CT appearance as lung metastases from other primary tumors (Fig 1). In 48 of these 58 patients, all pulmonary nodules were less than or equal to 1.0 cm in greatest diameter. In the remaining 10 patients, the largest pulmonary nodule measured up to 3.0 cm. The lower lobes of the lung were involved more often with metastases than were the upper lobes. Of the 81 patients with lung metastases, 23 (28%) had additional extrapulmonary sites of metastatic disease at the initial manifestation of extrahepatic HCC.
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Forty-one (28%) of 148 patients had musculoskeletal metastases. In all cases, the osseous metastases were lytic (Fig 3). In 14 (9%) of 148 patients with extrahepatic HCC, lytic metastases to the transverse skeleton were the first manifestation of extrahepatic HCC. More than two thirds of these involved the lumbosacral (seven metastases) or the thoracic (three metastases) spine.
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Adrenal metastases were identified in 16 (11%) of 148 patients, with lesions of 1.5–4.0 cm in greatest diameter. Contrast material enhancement characteristics ranged from the typical hypoattenuation of soft tissue seen in adrenal metastases from other primary tumors to the marked hyperattenuating enhancement, as seen in four (25%) patients (Fig 4). Two of these four patients with marked arterial phase–enhancing adrenal masses had proof of metastatic HCC at biopsy. The remaining two patients had interval growth of adrenal masses. Unilateral adrenal metastases were seen in 12 (75%) of 16 patients, and bilateral lesions were identified in the remaining four (25%) patients. The right and left adrenal glands were affected equally by unilateral metastases in six patients. Of the 16 patients with metastatic disease in the adrenal gland, nine (56%) patients had adrenal metastases as their first manifestation of extrahepatic HCC.
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There were three (2%) patients with brain lesions. In all three patients, multiple 1.0–1.5-cm enhancing masses at the gray matter–white matter junction were observed after an initial manifestation of extrahepatic HCC at other more common sites.
Splenic lesions (small, hypoattenuating, nonenhancing masses of 1–2 cm) were seen in two (1%) patients. There were two (1%) patients with diaphragmatic invasion by HCC, both of whom also had peritoneal and/or omental metastases. A 7-cm pancreatic mass (soft-tissue attenuating, with enhancement) was the initial manifestation in one patient with metastatic HCC. A 2-cm enhancing soft-tissue nodule involving the superior aspect of the seminal vesicle was seen in one patient. In another patient, a 3-cm enhancing soft-tissue mass in the bladder wall represented biopsy-proved HCC.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The most frequent location for metastatic HCC in our study population was the lung, seen in 81 (55%) patients with extrahepatic HCC. Hematogenous dissemination to the pulmonary capillary network is the presumed mechanism of spread. As with hematogenous metastases from other extrathoracic malignancies, the lower lung zones were involved more frequently than the upper lung zones (14). The frequency of lung lesions (55%) seen in our study correlated well with the findings of a previous autopsy meta-analysis, in which lung metastases were found to be the most common sites of extrahepatic disease (median, 44%; range, 34%–58%) (3).
Most patients with HCC in the United States have cirrhosis. It is well documented that patients who have cirrhosis also have benign enlarged lymph nodes (15). These benign enlarged lymph nodes are seen commonly in patients with viral hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and other underlying liver disorders that predispose patients to HCC (15). In patients who have undergone orthotopic liver transplantation, the differential diagnosis also includes posttransplantation lymphoproliferative disorder and opportunistic infections. This makes the staging of HCC difficult.
Lymphatic spread of HCC was common, seen in 78 (53%) of 148 patients with extrahepatic HCC. Sixty (77%) of these 78 patients had involvement of the regional lymph nodes, and the remaining 18 (23%) had distant lymph node involvement. This correlates well with prior autopsy meta-analysis findings (3), which show involvement of HCC in regional lymphadenopathy cases (the second most common site of metastatic disease after the lung) in 10%–42% of autopsy cases. Regional lymphadenopathy included portohepatic, peripancreatic, gastroduodenal, portocaval, aortocaval, and paraaortic nodal groups. The aortocaval and paraaortic nodal sites within the upper part of the abdomen were included as regional lymphadenopathy, because 20% of the normal lymphatic drainage of the liver typically occurs through the lymphatic vessels along the inferior vena cava (12). Most regional lymphadenopathy was seen in the periceliac (33%) and the portohepatic lymph nodes (23%).
Helical biphasic CT scanning can be helpful in differentiating malignant from benign lymphadenopathy when arterial phase enhancement of the lymph nodes is seen. All cases of arterial phase–enhancing lymph nodes (seen in 8% of patients with lymphatic spread of HCC) were malignant. The size of the malignant lymph nodes (1.5–4.0 cm) was not a reliable criterion of malignancy, as also reported by Dodd et al (15). Therefore, arterial phase enhancement, interval size increase, or proof of malignant cells within lymph nodes at biopsy should be the only criterion used to document malignant lymph node involvement.
Systemic hematogenous metastases to sites other than the lung were documented in the bone (28%) and in the adrenal glands (11%). All bone metastases were lytic, as observed in prior case reports (5–7). The frequency of bone metastases was higher than in prior autopsy studies (3,6), in which investigators reported a median involvement of 8% (range, 4%–20%). This may have been due to current treatment regimens of chemotherapy and/or to chemoembolization that resulted in the longer survival of patients with diagnoses of HCC in our study compared with older autopsy populations.
Similar to the problem of differentiating benign from malignant lymphadenopathy, the presence of an enlarged adrenal mass does not always imply malignancy. Adrenal adenomas statistically are a more common cause of an enlarged adrenal gland, even in patients with known extraadrenal primary tumors. However, arterial phase enhancement in an adrenal mass, seen in 25% of patients with HCC and adrenal metastases, is not seen in adenomas and should suggest metastatic disease. The frequency of adrenal metastases (11%) correlated well with that in prior autopsy studies (median, 8%; range, 6%–27%) (3).
While peritoneal and/or omental tumors are seen more commonly in patients with ovarian or gastrointestinal malignancies, they also were seen in 16 (11%) patients with extrahepatic HCC in our study. The tumor cells within peritoneal implants may have disseminated through tumor cells within the ascites in the peritoneal cavity; through direct invasion from an exophytic tumor; or hematogenously, through variceal collateral pathways (9).
In our study, a distinction was made between the first detectable metastasis and the metastatic sites detected at any time during the patient’s life. Lungs were both the most common site of metastases and the most common site of the first detectable metastasis. Conversely, the less common metastatic sites (the brain, bladder, gastrointestinal tract, diaphragm, seminal vesicles, and pancreas) almost never represented the initial manifestation of extrahepatic HCC but occurred only after metastatic involvement was documented at more common sites (Table 2). These findings suggest that incidental extrahepatic lesions in the more uncommon sites should be viewed less confidently as potential metastases if metastatic disease in the more common sites (lung, lymph nodes, and bone) is not seen. In fact, some sites (the brain and the gastrointestinal tract) are so unlikely to have metastatic HCC if extrahepatic disease in more common locations is not seen that another primary tumor probably should be presumed unless proved otherwise.
The intrahepatic stage of the tumor is important in determining the clinical importance of an extrahepatic lesion. In our study, a majority of patients (87%) with extrahepatic HCC had intrahepatic stage III (10%) and stage IVA (76%) tumors. Ten percent of the patients had intrahepatic stage II tumor, and one patient had stage I tumor. We recognize that the majority of patients who undergo imaging and who are treated at our institution have advanced HCC (bilobar disease and/or macrovascular invasion) and are referred mainly for palliative transcatheter chemoembolization. This referral bias precludes the evaluation of a large number of patients with early-stage HCC tumors. Because of the small number of patients with stage I or II HCC in our study population, we could not achieve statistical meaningfulness with regard to the incidence of metastatic HCC in this subgroup. However, all of these patients had chest, abdominal, and pelvic CT scans that showed no suspected metastatic disease prior to surgical resection or liver transplantation. More than three quarters of the patients with metastatic HCC in our study had stage IV disease. This suggests that the likelihood and degree of suspicion that an extrahepatic lesion represents metastatic HCC is greater with more advanced intrahepatic tumor stages.
We included 43 patients with extrahepatic HCC after orthotopic liver transplantation. We recognize that these patients were immunosuppressed and that the time course for occult tumor present at the time of transplantation to grow and spread may have been accelerated. As in the patients who did not undergo transplantation, a majority (41 of 43 [95%]) of patients who had extrahepatic HCC after orthotopic liver transplantation had advanced stage III and IV disease at the time of the diagnosis of their extrahepatic metastases. While orthotopic liver transplantation is used as a curative surgical procedure in patients with stage I or II HCC, the poor sensitivity in the detection of HCC during pretransplantation CT (approximately 65%) may result in missed occult tumors or in inadequate disease staging in patients with known small HCCs (2).
There were limitations to our study. First, it was a retrospective analysis. Second, we recognize that not all of the extrahepatic lesions had proof of metastatic HCC at biopsy. However, in a patient with known HCC and with no other primary tumor, the development of a new lesion (ie, a new bone lesion) or the interval increase of previously noted extrahepatic lesions (Fig 1) strongly suggests metastatic HCC. These criteria for metastatic disease are used by oncologists and surgeons in planning therapy.
In conclusion, the detection of extrahepatic HCC is crucial for patients with HCC to receive appropriate therapy, which ultimately determines patient survival. The lung, abdominal lymph nodes, and bone are the three most common sites of extrahepatic HCC. Arterial phase enhancement, when present, can and should be used to differentiate malignant lymphadenopathy and adrenal masses from benign causes. It is not unexpected that most extrahepatic HCC occurs in patients with an advanced intrahepatic stage of tumor (stage IVA). Incidental extrahepatic lesions seen at CT in less common sites (the brain and the gastrointestinal tract) in patients with HCC who do not have metastatic disease at the more common sites are unlikely to represent metastatic HCC.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, S.K., J.H.O., R.L.B.; study concepts, R.L.B., J.H.O., J.V.F.; study design, S.K., J.H.O., M.S.P., R.L.B.; definition of intellectual content, R.L.B., J.H.O.; literature research, S.K., B.S.C., J.V.F.; clinical studies, S.K., J.H.O., J.V.F.; data acquisition, S.K., J.H.O., M.S.P., R.L.B., J.V.F.; data analysis, S.K., J.H.O., M.S.P.; manuscript preparation, editing, and review, S.K., J.H.O., M.S.P., R.L.B.
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REFERENCES |
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