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This pictorial essay presents and discusses the imaging findings of patients with hepatocellular carcinoma recurrence post liver resection. A broad range of recurrence patterns is reviewed including intrahepatic and extrahepatic recurrences.
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, representing about 75–90% of liver cancers worldwide. It is the fifth most common cancer and the third most common cause of cancer-related death. HCC incidence in Australia has been on the rise over the last 30 years due to an increase in hepatitis C and hepatitis B cases. Common risk factors for HCC include chronic viral hepatitis, alcohol-related liver disease and increasingly non-alcoholic fatty liver disease.
Potentially curative treatment options for hepatocellular carcinoma include ablation therapy, surgical resection and liver transplantation. Hepatic resection is categorised as ‘typical’ when it adheres to the segmental anatomy and as ‘atypical’ when minor resections are carried out. Perioperative mortality rates after liver resection are reported to be around 5–8% with more unfavourable rates for patients with underlying diffuse liver disease. Survival rates have markedly improved in the last two decades and today 5-year survival after resection can exceed 50%. Hepatic resection is generally limited to patients with good background liver function, Child Pugh A classification and no portal hypertension. Ablation therapy has been shown to be effective in achieving complete tumour necrosis in tumours smaller than 3.5 cm in diameter with more limited success in larger tumours.[6, 7] It has lower perioperative mortality and its use is not restricted to patients with good liver function reserve and normal portal pressure. It is a potentially curative treatment option for both primary tumour and recurrences. The survival rate following ablation therapy has been reported to be 33% at five years following treatment.
Tumour recurrence remains the major cause of death after curative resection for HCC. Prospective studies of patients post liver resection have shown a tumour recurrence rate of 50% at 3 years and over 70% at 5 years. Tumour size, the presence of cirrhosis, satellite nodules, vascular invasion, a positive surgical margin and the absence of capsule formation are all positively correlated with a higher intrahepatic recurrence rate.
Identification of patients with early hepatic recurrence is important as they might benefit from potentially curative treatment with either repeat resection or targeted ablation therapy. The factors influencing the treatment selection are complex and include residual liver volume, liver function as well as the size and location of the recurrent lesion. Factors that impact on prognosis following second hepatectomy include: portal vein invasion, size of the tumour recurrence, recurrence-free interval since the first hepatectomy and liver function performance.
In most cases, however, intrahepatic HCC recurrence will be multifocal from intrahepatic dissemination with a more aggressive biological pattern than the primary tumour. The options available for treatment of multifocal intrahepatic recurrence include multifocal ablation therapy, transarterial embolisation, transarterial chemo-embolisation and systemic therapy such as Sorafenib. Extrahepatic metastases in general are not favourable for locoregional treatment with systemic therapy being the mainstay of treatment.
Imaging of HCC recurrence
Multi-detector CT and MRI have acquired important roles in the assessment of the pre- and postoperative liver. Although the ideal imaging interval is unknown, a 3–4 month interval is commonly recommended to monitor HCC lesions after initial treatment with less frequent intervals after 2 years of recurrence-free survival. Whilst there is no current standardized recommendation for the frequency of extrahepatic imaging, rising alpha-foetal protein without intrahepatic recurrence, previous nodule rupture and histological features of microvascular invasion, extrahepatic extension and positive surgical margin should prompt additional contrast enhanced CT imaging of the chest and pelvis during follow-up. If the patient is being considered for liver transplantation following liver resection, complete imaging of the whole body is vital to exclude extrahepatic recurrence and other malignancies.
Imaging protocol for post-resection liver at our institution is with CT examination with pre-contrast, arterial, portal venous and 5-minute delayed phases through the liver. Reformats are generated in axial and coronal planes. The arterial phase is optimised for late arterial phase using bolus tracking technique with the region of interest placed in the upper abdominal aorta and the use of additional 7 seconds of peak to scan delay.
In difficult cases, MRI or CT catheter hepatic angiogram (CTHA) and CT arterial portography (CTAP) can help to define the extent of the disease for treatment planning. In recent years, liver-specific MRI contrast agents including Gd-EOB-DTPA and Gd-BOPTA have been introduced. Whilst hepatobiliary phase imaging in cirrhosis is limited by the heterogeneity of the background liver and poor hepatocyte function, this is less of an issue in post hepatic resection imaging. The majority of post-resection patients have good hepatocyte function due to the surgical selection requirement. Our experience is that hepatobiliary phase imaging supplements the conventional MRI assessment of intrinsic T1 and T2 lesion signal and lesion enhancement characteristics.
CTHA and CTAP have been in use for decades in liver imaging with sensitive detection of the hemodynamic disturbance intrinsic to typical HCCs. Their use is limited by the invasiveness and the high false-positive rates due to background liver perfusion variation. CTHA and CTAP may still have a role in problem solving and in surgical planning by delineating the extent of the recurrence and excluding further lesions.
Contrast enhanced ultrasound, another emerging new technique, is less suited for surveillance in the post-resection period but is useful in focal lesion characterisation and in the guidance of ablation treatment of small lesions (Fig. 1).
Surgical margin recurrence
The recurrence along the surgical margin often follows the contour of the cut-surface of the liver (Fig. 2). Recurrences along the surgical margin usually demonstrate similar enhancement characteristics as resected HCCs with arterial enhancement and portal venous/delayed phase washout. However, HCC recurrence may also show atypical enhancement characteristics, especially if the resected primary had an atypical appearance (Fig. 3). Surgical clips at the resection site can limit the assessment for small recurrences. Direct comparison between the pre-contrast and the arterial phase is helpful to detect small areas of arterial enhancement adjacent to the clips. A newly developed lesion since the baseline postoperative imaging would also be suspicious especially when the enhancement pattern is atypical (Fig. 3).
Recurrence within the liver
New nodules within the remaining liver are due to either intrahepatic metastases via the portal vein or metachronous multicentric hepato-carcinogenesis. The residual liver undergoes hypertrophy following a lobar resection. This is particularly seen with the left lobe following a right hemihepatectomy. Due to the increased amount of liver parenchyma that juxtaposes the diaphragm and the spleen, the coronal reformats can help to detect lesions that closely abut these structures (Fig. 4). Coronal reformats are also helpful for identification of disease that abuts the hilar vessels (Fig. 5).
Recurrence in portal vein
Rarely, the recurrence may occur within, and is restricted to, the portal vein (Fig. 6). It is unusual to have a thrombus within the stump of the portal vein branches adjacent to the surgical site. Finding of a thrombus should raise the suspicion for tumour recurrence.
Imaging features that suggest tumoural thrombus rather than bland thrombus include enhancement, expansion of the portal vein or a bulging mass-like appearance to the leading edge of the thrombus. In our experience, arterial enhancement of tumour thrombus often occurs early and may not be captured by the standard late arterial phase imaging. Contrast enhanced ultrasound may have a role for focused assessment of the thrombus with real time continuous imaging.
The liver segments supplied by the involved branch will show arterialisation with diffusely increased arterial enhancement which is not necessarily due to underlying parenchymal tumour.
The extrahepatic recurrence following resection can be due to direct invasion, lymphatic, retroperitoneal, transcoelomic or hematogenous metastases. Whilst the extrahepatic tumour deposits are similar to the primary tumour with increased vascularity and increased arterial supply, the arterial enhancement may not be identified on the conventional multiphasic imaging when the background organ has a different perfusion timing as the liver.
Involvement of the diaphragm can be seen following resection of HCC within the right lobe of the liver (Fig. 7). The resected tumour tends to be subcapsular and peripheral in location. Involvement of the diaphragm may be due to incomplete resection of an invasive primary tumour, subsequent invasion from an intrahepatic recurrence or peritoneal spread. In cases where the diaphragm involvement is immediately adjacent to the surgical site, direct invasion is favoured as the aetiology over peritoneal transcoelomic seeding.
On imaging, the involved diaphragm is thickened with extension into the adjacent surgical margin. The blood supply to the tumour is from the inferior phrenic arteries when it is central in the diaphragm and from the intercostal arteries when peripheral. There are case reports of successful resection of diaphragmatic recurrences.
Lymphatic spread of HCC (Fig. 8) commonly occurs within the regional nodes which include the hilar, hepatoduodenal ligament lymph nodes and caval lymph nodes. Non-regional lymph nodes that may be involved include the anterior cardiophrenic and posterior mediastinal lymph nodes. Enlarged reactive lymph nodes are common in chronic liver disease. Features that suggest tumoural lymph node involvement include arterial enhancement and enlargement over time.
Peritoneal spread occurs following rupture of the tumour into the peritoneal cavity and subsequent intraperitoneal dissemination (Fig. 9). The rupture of the original tumour often precedes the resection and rarely occurs intraoperatively. Tumours that rupture tend to be subcapsular, exophytic and haemorrhagic. A past history of rupture should prompt routine follow-up studies that include the pelvis and careful examination of peritoneum including the omentum, paracolic gutters, rectouterine and rectoprostatic recesses.
Retroperitoneal metastases of HCC (Fig. 10) are very uncommon and have previously been described in only two case reports. The described location in both cases is posterior to the duodenum and anterior to the right kidney. Curative resection has been achieved in one case. The proposed aetiology for involvement of the retroperitoneum is via direct seeding rather than hematogenous spread. Alternatively, the retroperitoneum may be involved by direct extension from the diaphragmatic involvement.
Hematogenous metastases are the most common pattern of extrahepatic recurrence. The most common sites are the lungs (Fig. 4), adrenal glands (Fig. 11) and bone. Within the lungs, the lower lobes are more commonly involved than the upper lobes. Close review of the nodules on soft tissue windows may reveal a similar morphology to the primary HCC tumour with heterogeneity, areas of fat density or mosaic appearance (Fig. 4). These metastases also demonstrate similar biological behaviour as the original primary tumour with a propensity for needle tract seeding (Fig. 12).
Follow-up imaging with multiphasic CT/MRI is important after hepatic resection for hepatocellular carcinoma. Detection of tumour recurrence in and outside of the liver has an impact on subsequent management which can sometimes be curative. An understanding of the common patterns of recurrence and review of the characteristics of the resected tumour can help to guide the imaging protocol and interpretation.