Hepatocellular carcinoma C22.0

Hepatocellular carcinoma (HCC) is a highly malignant tumor with rapid progression, significantly different geographical incidences and limited therapeutic options and prognosis.

TNM Classification: The TNM staging system classifies on the basis of tumour-associated characteristics and is recognised worldwide as the standard for oncological staging. Like the American classification of the AJCC (Edge SB et al. 2010), the TNM classification is based on data obtained through the pathological assessment of resected or explanted tissue and includes parameters such as microvascular tumor invasion that cannot be clinically and radiologically detected. It is therefore primarily suitable for the morphological classification of the tumor as pTNM staging (Llovet JM et al. 1998).

• T1 Soliary, without vascular invasion
• T2 Solitaire with vessel invasion or multiple (≤5cm)
• T3a Multipel >5cm
• T3b Invasion of larger branches of V-portae or Vv hepaticae
• T4 Invasion of neighbouring organs, except gallbladder, perforation of the visceral peritoneum
• N0 Without regional lymph node metastases (LK)
• N1 With regional lymph nodes
• M0 Without distant metastases
• M1 With remote metastases

Incidence: 5/100.000 inhabitants/year. Over the last 20 years, the incidence of HCC has increased significantly with a time lag to the occurrence of chronic hepatitis C infection [El-Serag HB et al. 2003). In the tropics (Africa, Asia), hepatocellular carcinoma is partly the most frequent malignoma in men (incidence: 100/100,000 per year). Worldwide, between 500,00 - 600,000 people contract HCC every year (Jemal A et al. 2011). This makes HCC the fifth most common malignant tumor disease globally.

HCC develops only exceptionally in a healthy liver. In the main countries, chronic viral hepatitis(HBV, HCB) and liver cirrhosis are the most important underlying diseases (liver cirrhosis is to be considered as precancerous). Less frequent are aflatoxins, nitrosamines, possibly long-term androgen - estrogen therapy. In detail versch. Constellations are evaluated as follows:

Viral hepatitis and HCC: For the development of HCC in chronic hepatitis, the general rule is: the higher the viral load of the organism, the more frequent HCCs are to be expected (Tseng TC et al. 2012). CLDN1 (Claudin1 receptor) acts as a co-receptor for hepatitis C virus (HCV) in hepatocytes. Associated with CD81, it forms a CLDN1-CD81 receptor complex that is essential for HCV entry into the host cell. Thus, these proteins occupy an important role in the biology of liver disease and in their function as cell entry receptors for HCV-one of the most common causes of hepatocellular carcinoma (Zeisel MB et al. 2019).

Liver cirrhosis and HCC: Patients with liver cirrhosis have a significantly increased risk of developing HCC; up to 4% of patients with liver cirrhosis develop hepatocellular carcinoma.

HV infections and HCC: The greatest risk of HCC affects patients with cirrhosis on the floor of chronic hepatitis B/C. If Child-Pugh A stage cirrhosis is present, the annual incidence of HCC is approximately 4% (Sangiovanni A et al. 2006; Lok AS et al. 2009).

Alcohol and HCC: Regular alcohol consumption is an important cofactor for the development of HCC. In chronic HCV infection, concomitant high alcohol consumption (>80 g/day) significantly increases HCC risk. Up to 1/3 (4%-38%) of HCC disease can be attributed to alcohol consumption (Fattovich G et al 2004).

Non-alcoholicfatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH): NAFLD represents the hepatic manifestation of the metabolic syndrome and can progress from simple steatosis to steatohepatitis, as well as hepatic hirrosis and hepatocarcinogenesis.

Diabetes and HCC: The presence of diabetes concomitant with high alcohol consumption significantly increases the risk of HCC.

Hemochromatosis and HCC: For symptomatic hemochromatosis, HCC is a major complication (Olynyk JK 1999).

Obesity and HCC: In cases of marked obesity (body mass index > 35), the risk of dying from HCC is increased by a factor of 4.52 in men and by a factor of 1.68 in women (Calle EE et al 2003).

m: w=3:1; frequency peaks in Europe and USA: 5-6th decade of life; in Africa and Asia: 3-4th decade of life.

Pressure pain in the upper abdomen, weight loss, hepatosplenomegaly, possibly palpable coarse lumps, possibly ascites. At the time of diagnosis, in 50% of the cases usually already multilocular growth, in 25% portal vein thrombosis and in 10% infiltration of liver veins and V.cava inferior.

Staging of HCC must be performed according to the current TNM classification. For this purpose, all macroscopically definable tumor-suspect nodes are measured, localized and histologically evaluated (for the evaluation of different tumor entities: e.g. intrahepatic cholangiocarcinoma or HCC/CC). In principle, nodules up to 2 cm in size should be examined completely in their maximum diameter. For all larger nodules, one paraffin block per cm diameter is recommended. Spreading (e.g. hilus area, gallbladder, any locoregional lymph nodes included) should be examined macroscopically and taken into account in the TNM classification

Abdominal sonography: This method is the preferred method for early detection of HCC as it is risk-free, non-invasive, ubiquitously available and well accepted by patients.

CE-US: For the characterization of a specific liver focus, contrast enhanced ultrasound (CE-US) is an important complementary diagnostic measure in the detection of arterial hypervascularization and subsequent wash-out (it is considered equivalent to MRI and CT (Forner A et al. 2008). Remark: The pathophysiological basis for this is the arterialisation, which increases with tumour size and de-differentiation and which can be reliably detected by imaging from tumour diameters of about 1 cm, as well as the presence of arterioportals and arteriovenous shunts. In comparison to normal liver tissue, these shunts lead to a characteristic "washing out" of the contrast agent in the tumor in the parenchymatous and late hepatocytic perfusion phase after contrast agent application, which results in a "contrast inversion".

CT: The CT examination is able to detect and characterize HCC with high accuracy as HCC.

CE-CT: The detection of the typical contrast behaviour of a tumour node > 3cm with arterial hypervascularisation and subsequent wash-out phenomenon is considered as proof of HCC.

MRI: Due to the superior tissue characterization, MRI allows a more differentiated diagnosis of HCC-suspected lesions. In the native MRI, a T2-weighted image is hyperintense, and a T1-weighted image is hypointense and highly suspect for a malignant tumor. The administration of contrast media with hepatocyte-specific Gd-containing contrast media provides a diagnostic gain. The absence of the contrast agent in the clearly late images (approx. 20 minutes after KM application) is considered evidence of a de-differentiation of the tumor.

Nuclear medical examination procedures: The classical nuclear medical examination procedures such as gallium scintigraphy or sulfur colloid scintigraphy are no longer relevant in the diagnosis of HCC. According to the available data, there is no indication for PET-CT for the primary diagnosis of HCC (Lee JE et al. 2012).

Biopsy and histopathology:

Biopsy procedures should only be used if the findings can lead to a therapeutic consequence. The processing and diagnosis of a biopsy should determine the extent of the tumor (staging) according to the current TNM classification, its type (typing) and degree of differentiation (grading) and the status of the resected margin (R-classification) as well as the status of the non-tumorous liver.

In many cases, the diagnosis of HCC can be made using conventional histology. It is important for the detection of fibrolamellar HCC, mixed-differentiated tumors; further for the differentiation of early HCC from progressive HCC; detection of special forms of intrahepatic cholangiocarcinoma, liver metastases and for the differentiation of benign liver tumors. Depending on the histopathological appearance, further, especially immunohistological examinations can be used to confirm the diagnosis.

Localization diagnostics by imaging procedures (abdominal sonography, (angio-)-CT, MRT. Laboratory: in HCC, in about 50% of cases, increase of alpha1-fetoprotein (AFP); in case of strong increase, high specificity! Alpha1-fetoprotein correlates with the success of treatment or the recurrence rate of HCC and can therefore be used to assess the course of the disease. The current American and European guidelines no longer recommend its use in the primary diagnosis of HCC. Histological confirmation by sonographic or CT-guided fine needle biopsy.

Liver tumors should be typed according to the latest WHO classification (Wittekind CH et al.). In typing, moderately and poorly differentiated HCC must be distinguished from the solid variant of intrahepatic cholangiocarcinoma and metastases.

This differentiation is clinically relevant and may require the use of additional differentiating special staining and immunohistological procedures.

Furthermore, HCC should be differentiated from mixed-differentiated tumors, especially HCC/CC [133]. Well differentiated HCC must be distinguished diagnostically from non-malignant tumors (multiazinary regenerative nodules, focal nodular hyperplasia, dysplastic nodules, hepatocellular adenoma). This differentiation can be difficult in individual cases and especially in biopsy, immunohistological analysis is helpful and often required. According to international consensus, early and progressive, well-differentiated HCC should be distinguished from progressive HCC [134]. Especially in the differential diagnosis of well differentiated hepatocellular tumors, precise clinical, serological and radiological information is essential.

Furthermore, HCC must be subtyped. This is prognostically relevant in the differentiation of fibrolamellar hepatocellular carcinoma, although it is unclear whether its better prognosis is due to the tumor itself or to the fact that patients are consistently younger and do not exhibit a cirrhotic remodeling of the non-tumorous liver.

The prognosis of patients suffering from HCC is determined not only by the tumor stage but also by the remaining liver function (e.g. cirrhosis). Cirrhosis and liver function also significantly determine the patients' ability to receive therapy. Liver transplantation is a curative treatment for both the tumor and the underlying liver disease (Mazzaferro V et al.1996).

Non-surgical procedures: Several ablation techniques can be used as non-surgical procedures in HCC. The use of these techniques has been described in the literature, but no comparative data exist to date with resection as the current gold standard of local therapy.

Non-surgical ablation techniques include: percutaneous alcohol injection - PEI, local in situ thermoablation techniques such as cryosurgery, laser induced thermotherapy, percutaneous microwave ablation - MWA, high intensity focused ultrasound-HIFUS, radiofrequency thermoablation -RFA, transarterial chemoembolization-TACE.

Radio Frequency Ablation (RFA), which can be performed via percutaneous, laparoscopic or open access, is generally considered the standard method of local ablation of HCC. According to the available data, it seems to be superior to MWA for local ablation of HCC. The percutaneous access route is the most common procedure. RFA represents the least invasive approach for performing RFA and should be considered especially in patients who are not suitable for open tumor resection or who have an increased surgical risk (e.g. due to advanced liver cirrhosis) (Ohmoto K et al. 2009). Percutaneous access is to be favoured in patients with tumours smaller than 5 cm, which are visible in ultrasound, CT or MRI. Based on the available clinical data, RFA should therefore be considered the standard method of percutaneous local ablation.

Depending on the size, location and number of tumours, residual liver function or the general condition and, if necessary, comorbidities, the individual therapy should be determined in an interdisciplinary conference. In principle, there are three curative therapy methods available for the treatment of HCC:

• surgical resection
• orthotopic liver transplantation
• Tumor ablation.

Resection: According to the current guidelines primarily resectable hepatocellular carcinomas should be resected. Criteria for non-resectability are non-resectable extrahepatic tumor manifestation, general inoperability due to patient co-morbidity, tumor involvement of all three hepatic veins and lack of functional reserve (Benson AB et al. 2009). In particular, the size of the tumour alone is only an exclusion criterion in exceptional cases; the location of the tumour in relation to the vessels is decisive. Especially in the case of large tumours, atypical resections can be performed well, leaving as much liver tissue as possible and the patient losing only little functional liver tissue. In non-cirrhotic livers, however, the 5-year survival rate is only 40-60%, as the tumor biology is usually more aggressive. Prognostic factors for recurrence in non-cirrhotic livers are residual tumor status, vascular invasion and tumor grading.

Potentially resectable tumors can be treated neoadjuvantly (e.g., transarterial chemoembolization [TACE]) in the primary diagnosis due to limited functional reserve or impossible R0 resection. The assessment of surgical resectability must be performed in an interdisciplinary conference with a surgeon experienced in hepatobiliary surgery.

Liver Transplantation: Liver transplantation is basically a therapeutic option that treats not only HCC but also the underlying liver cirrhosis. All patients with HCC in cirrhosis and potentially resectable / ablatable tumors within the Milan criteria (1 focus < 5 cm, maximum 3 focus < 3 cm) are generally indicated for liver transplantation and should therefore be presented at a liver transplant center. According to the current AASLD guideline, the absolute exclusion criteria are advanced tumor diseases, tumor spread across the liver, macrovascular infiltration or distant metastasis. Furthermore, the basic suitability for liver transplantation must be considered against the background of the candidate's general morbidity profile.

Liver resection in cirrhosis: Resection of HCC in cirrhosis requires careful patient evaluation. In a healthy liver, 25-30% of the liver parenchyma is functionally sufficient for this purpose, but more than 40% is required for CHILD-A cirrhosis. Analogous to the NCCN guideline, patients in good clinical general condition with CHILD-A cirrhosis are eligible for resection of HCC (BCLC stage 0). However, especially the presence of ascites preoperatively indicates a protracted and thus complicated postoperative course. Functional resectability should take into account adequate postoperative liver function and portal hypertension.

Bridging: In patients with non-resectable HCC and an existing indication for transplantation but lack of an adequate donor organ, the waiting period before liver transplantation represents a high risk of tumor progression and thus of falling out of the narrow Milan criteria (drop-out). Due to limited availability and the simultaneously increasing demand for donor organs, the waiting time of patients on the transplant list in Europe is approx. 6 to 12 months and is associated with a drop-out rate of 30-40% (Llovet JM et al. 2002). In order to bridge the waiting period and to keep the tumour within the transplantation criteria, ablative procedures and transarterial chemoembolization (TACE) have become established in recent years. They have the advantage of low invasiveness, are considered safe, gentle on the parenchyma and can be repeated several times. The most frequently used locoregional therapy procedure for bridging before liver transplantation is TACE followed by RFA.

HCC tends to locally infiltrate or cross-organ growth without and with remote metastasis only in advanced stages. The determination of the extent of the tumor is crucial for staging and the resulting therapeutic decisions. In this respect, abdominal and thoracic spread diagnostics in HCC is basically no different from other tumors. With curative targeting, the 5-year survival rates depend on the stage of the causal liver disease and HCC as well as on the radicality of the tumor removal:

• After liver transplantation: 40-70%
• After partial resection of the liver: 20-50
• After (local ablative) therapy (RFA or TACE): 20-50
• After palliative therapy the median survival time is 6-12 months
• If HCC is diagnosed only after the onset of symptoms, 5-year survival rates are 0-10% (Llovet JM et al. 2003)
• If HCC is diagnosed at screening, the 5-year survival rate is > 50% (Bruix J et al. 2011).

Prognosis after therapy: Patients with HCC have an increased risk of tumor recurrence after successful resection and/or ablation. This is either an intrahepatic metastasis (true recurrence) or de novo HCC in the same liver. The risk of recurrence depends on the tumor stage at the time of resection/ablation and the underlying liver disease and is about 70%. For this reason, many adjuvant systemic therapy studies have been conducted to investigate how the prognosis can be improved. These include:

• interferon alpha
• Calcineurin inhibitors
• mTOR inhibitors

Screening: All patients with cirrhosis of the liver, chronic hepatitis B and fatty liver hepatitis should be offered a screening test every 6 months if they are eligible for HCC therapy. In a multicenter, prospective DEGUM study on liver ultrasound, a diagnostic accuracy of 84.9% was achieved in histologically confirmed HCCs (n=269) (Strobel D et al. 2008).

Follow-up should be performed every 3-6 months for 2 years using multiphase tomography (preferably MRI). After completion of the follow-up, the patients should be reintegrated into the early detection program. Extrahepatic diagnostics in aftercare should be symptom-oriented. If AFP is positive at the time of diagnosis, an AFP control after ablation should be performed every 3 months for 2 years, then every 6 months.

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