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ManagementHepatocellular Carcinoma Tugas program pendidikan dokter spesialis IIIlmu bedah DigestifUniv. hasanudin RS. Wahidin SudirohusodoMakasar

IntisariKarsinoma hepatoseluler (HCC) adalah neoplasia yang sering terjadi dan angka kematian yang tinggi.Peningkatan manajemen secara signifikan selama beberapa tahun terakhirBCLC (Barcelona Clinic Liver Cancer) sistem, untuk prediksi, prognosis dan pendekatan pengobatan yang lebih baikTerapi kuratif (reseksi, transplantasi, ablasi) dapat meningkatkan kelangsungan hidup pada pasien yang didiagnosis HCC stadium awal. DefinisiKarsinoma Hati Primer (Primary Hepatocellular Carcinoma) adalah tumor primer hati yang biasanya berkembang pada penyakit hati kronis terutama pada hepatitis viralInsidensiLiver cancer penyebab kematian karena kanker urutan ke-4 di dunia dan urutan ke-3 pada pria.Insidensi berbeda secara geografis.Indonesia termasuk negara dengan insidensi intermediate untuk Hepatitis B

Age-specific incidence of hepatocellular carcinoma

6Age-specific incidence of hepatocellular carcinoma Age-specific incidence of hepatocellular carcinoma (HCC) in Taiwan and the United States. HCC is one of the most common malignant tumors worldwide. It occurs most commonly in the Far East and in sub-Saharan Africa where it accounts for the greatest number of cancer deaths. In the United States, the incidence is generally much lower and the mean age at presentation is higher [8].Hepatocellular carcinoma occurs against the background of cirrhosis. The underlying liver disease is most often caused by viral hepatitis or by alcohol, although the exact form of liver injury may vary in different areas. Thus, in countries such as China, Taiwan, Hong Kong, North and South Korea, and Vietnam and in sub-Saharan Africa, most cases are related to chronic infection with hepatitis B virus whereas in southern Europe and Japan, hepatitis C is more of a problem [9], [10]. In the United States, both of these forms of hepatitis are related to HCC as well as to alcoholic cirrhosis. (Adapted from Beasley [11].)

Faktor ResikoViral hepatitis B dan C.Toksin: aflatoksin dan toksin yang terkandung pada air minum.Hepatitis kronis dan sirosis hati Screening & SurveillanceHCC has poor prognosis if diagnosed at advanced stage (5 yr survival rate 0 10%) compared if is treated in the early stages (5 yr survival rate up to 70%) need to screening & surveillance for high risk populationStrategy of surveillance aimed to detecting early diseaseSurveillance for HCC in high risk population is recommended cirrhotic patients with HBV and HCV

Screening & SurveillanceSurveillance for HCC should be performed by Ultrasonography (US) and -fetoprotein (AFP) every 6 monthsAFP alone not recommended for diagnosis of HCCSmall HCC ( 3 cm) do not secrete AFP to achieve a diagnostic levelAFP elevated in patients with both HCC and chronic liver diseaseUS is a screening test and not a diagnostic test for confirmation

Surveillance Recommendation

SurveillanceThe incidence and mortality of hepatocellular carcinoma (HCC) is highThe main risk of HCC in Asia is chronic infection of HBVThe best strategy is prevent infection of HBV through universal vaccination and Public health-education to educate about viral transmission protectionOther strategy are :Prevent and detect alcohol dependence syndrome, and toreduce contamination of food by aflatoxinTherapy which have beneficial to reduce disease progression in HBV & HCV patientsScreening & surveillance in high risk populationMain risk factors for HCC

EASLEORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma

European Association for the Study of the Liver*, European Organisation for Research and Treatment of Cancer(European Journal of Cancer(2012)48, 599641)

Hepatitis B: the primary cause of HCC in AsiaPacific

Chronic HBV infection associated with 100 fold increase risk of HCC compared to non infectedHBV associated cirrhosis, increased risk 1000 fold

Frequency of Complications in Patients with Compensated Liver Cirrhosis

Development of Liver Cirrhosis

ETIOLOGI

anatomi

Hepatitis B dan HCCTaiwan: HBsAg (+) resiko utk menjadi HCC 223 x dibanding HBsAg (-).Canada & Austria: Resiko utk populasi Asia > nonAsia.HBeAg (+) menambah resiko utk HCC (RR 60,2 dgn 95% CI 35.5-102.1), dibandingkan hanya HBsAg (+) saja (RR 9.6 dgn 95% CI 6.0-15.2).Beban HBV DNA sebanding dgn resiko HCC.Koinfeksi dgn HCV meningkatkan resiko HCCAflatoksinSuatu mycotoxin yang sering mengkontaminasi jagung, kedelai dan kacang tanah. Asupan aflatoxin yang tinggi dari makanan berhubungan dengan timbulnya HCC. Tempe?Aflatoksin mutasi pada codon 249 tumor supressor gen p53.Potensiasi karsinogenik dgn infeksi HBVPatogenesis

Histopathological progression and molecular features of HCC

PatogenesisHepatocarcinogenesis bisa memakan waktu 30 tahun setelah infeksi HBV / HCV.Sitokin dari selsel inflamasi, proses regenerasi sel dan transaktivasi virus hepatitis peningkatan ekspresi Transforming Growth Factor (TGF) dan Insulin Growth Factor-2 (IGF-2) melalui mekanisme epigenetik meningkatkan proliferasi hepatocyte.Gejala KlinisGejala = gejala sirosis hati.Curigai pada yang semula sirosis hati kompensata asites, hepatik ensefalopati, jaundice, perdarahan varises.Massa tumor icterus, nyeri.Tumor ruptur perdarahan intraperitoneal: distensi dan nyeri abdomen, pucat.Gejala metastase: paru; dyspnoe, tulang ; nyeri tulang.Paraneoplastic syndrome.Clinical PresentationAged > 40 years and men more likelySymptoms (only present in advanced disease) :Pain in the right upper quadrant of the abdomenWeight lossSymptom of cirrhosis and / or liver failure Liver mass in examinationMetastases causes sign and symptom extrahepatic :Bone painDiarrheaDyspnoeCutaneous sign

DiagnosisUSGCTscanMRIAFPDes-gamma-carboxy prothrombin (prothrombin produced by vitamin K absence or antagonism II [PIVKA II])Biopsi perkutan hanya dilakukan bila diagnosanya tidak jelasKalau lesinya hypervascular, dengan peningkatan intensitas sinyal T2 pada MRI, adanya invasi vena, or is disertai dengan peningkatan AFPDiagnosa HCCDiagnostic algorithm for the diagnosis of liver malignancy depending on tumor size

Diagnosis of HCCMedical history & Physical ExaminationLaboratory tests (with visible mass on US in screening test) AFP Cutoff value is different among literature (range 200 500 ng/mL) APASL recommendation is 200 ng/mL AFP-L3 or DCP may also be used Imaging studiesCTMRI BiopsyOnly performed if diagnosis is in doubt due to potential complicationsDiagnosis HCCGuidelines of the APASL and the AASLD on the definition of imaging features of classical HCC.The presence of arterial hypervascularity and washout on portal vein or delay phaseHCC receives predominant vascular supply via the hepatic arteryDiagnosis HCCDiagnosis Liver Nodule Clinical Features , Age , GenderMorphology and enhancement characteristic : mosaic patern ,nodule in nodule appearance, central scar, ring, pseudocapsuleBackground liver : cirhosis Patient History Imaging StudiesUS is generally used in screening, guiding percutaneous biopsies and interventional therapyDynamic CT / MRI useful for diagnosis assessment, characterization and staging of tumorHCC tumors grow, they need supply from hepatic artery, whereas normal liver have supply from hepatic portal venous typical pattern with arterial enhancement and portal venous washout on dynamic CT / MRIImaging useful for assess the extent of disease within liver (invasion of vascular structure) or distant metastases

Multiphasic contrast protocol 1. Hepatic arterial phase : 25 sEarly arterial : 5-10 sLate arterial : 15-25 s2. Portal venous phase : 60 s3. Interstitial phase (hepatic venous phase ): 90 s4. Delayed phaseEarly delayed : 3-5 minutesLate delayed : 10-15 minutes

BiopsyBeneficial to confirm the HCC diagnosis, especially in lesion < 2 cmUnfortunately Biopsy carries :Risk of bleeding (particularly in patients with advanced cirrhosis)Slight risk of tumor seeding along the needle track ( 1%)

Diferential DiagnosisShould be remember that hypervascularity on arterial phase and washout in portal vein phase not only found on HCC Hepatic adenoma Focal Nodular HypertrophyHypervascular metastasisSTAGING OF HCCThere are many staging systems for HCC none are universally acceptedIn Europe & USA Tumour Node Metastasis (TNM) Model for End Stage Liver Disease (MELD) Cancer of the Liver Italian Program (CLIP) Barcelona Cancer of the Liver Clinic (BCLC)In Japan Okuda System StagingStatus Child-Pugh one of the best predictor of outcome of HCCTNM stagingPrimary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Solitary tumor without vascular invasion T2 Solitary tumor with vascular invasion, or multiple tumors none more than 5 cm T3 Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s) T4 Tumors with invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis N1 Regional lymph node metastasis Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Fibrosis score (F)* F0 Fibrosis score 0-4 (none to moderate fibrosis) F1 Fibrosis score 5-6 (severe fibrosis or cirrhosis) Stage grouping Stage I T1 N0 M0 Stage II T2 N0 M0 Stage IIIA T3 N0 M0 Stage IIIB T4 N0 M0 Stage IIIC Any T N1 M0 Stage IV Any T Any N M139

Staging in HCC

BCLC Staging

PenatalaksanaanMedian survival 6-20 bulan.Reseksi bedah, namun mayoritas tak bisa dilakukan.Pilihan terapi: Liver transplantation Radiofrequency ablation (RFA) Percutaneous ethanol or acetic acid ablation Transarterial chemoembolization (TACE) Cryoablation Radiation therapy Systemic chemotherapyGuide TreatmentPenyebaran tumor atau stagingKeterlibatan pembuluh darah heparAda tidaknya kapsul tumor Ada tidaknya penyebaran diluar heparVaskularisasi pembuluh darah tumor

KRETERIA TUMOR UNRESECTABLEAdanya kelainan extrahepatikAdanya disfungsi heparExtensi tumor yang luas dimana hanya sedikit hepar yang disisakansetelah reseksiTerbukti adanya metastasis/ekstensi extrahepatikTumor melibatkan vena hepatik vena porta

Ahmad, Syed A. Hepatobiliary Cancers. 2010`

Partial hepatectomyBerpotensi kuratif. Reseksi ideal: solitary HCC tanpa bukti radiologis adanya invasi vaskularisasi liver, tidak ada hipertensi dan dengan cadangan fungsi hati yang baik. Long-term relapse-free survival 40%, dan five-year survival 90%.

Resected specimen of cirrhotic liver

Copyright Science Press Internet Services58Resected specimen of cirrhotic liver Resected specimen of cirrhotic liver with a small (2.5 cm diameter) hepatocellular carcinoma (HCC). Therapy of HCC is difficult and the prognosis is poor. The best chance of cure or long-term survival appears to be with resection. Because of the associated cirrhosis, extensive resection is usually not possible and the usual operation is a "segmentectomy" or enucleation of the tumor. Even so, a high rate of tumor recurrence exists within the first few years after surgery. Liver transplantation appears to be a suitable modality of therapy for HCC less than 5 cm in diameter with no evidence of extrahepatic spread [29]. Again, there is a high rate of recurrence (although less than resection) and attempts to prevent this complication have used adjuvant chemotherapy before and after transplantation. The value of this approach is currently being evaluated.Other approaches that may be used for small tumors include ablation by injection with absolute alcohol or cryoablation. For large unresectable tumors, chemoembolization has been used in an attempt to shrink the tumor. The rationale for this approach is based on the fact that, whereas the liver as a whole has a dual blood supply (from the hepatic artery and portal vein), HCC derives its supply exclusively from the hepatic artery. Thus, when this blood supply is cut off, tumor necrosis and shrinking can be seen. The use of systemic chemotherapy and external radiation appear to be of little benefit in HCC. Chemotherapy directed to the tumor by intra-arterial infusion of targeting with Lipiodol (Therapex, Canada) may be more helpful. (From Di Bisceglie [18]; with permission.)

LIVER TRANSPLANTATIONMilan Criteria :Single HCC 5 cm or Up to three nodules 3 cmNo extra hepatic spread( 5 years survival : 70% dengan rekuren 5 15% )

Radio Frequency AblationRFA = aplikasi lokal energi thermal dari gelombang radiofrequency melalui elektroda peningkatan suhu lokal lesi > 60C nekrosis. Sebaiknya dengan single tumor diameter 4mg/dl3. Portal vein trombosis4. Uncorrectable coagulopathy5. Poor general healthy6. Significant A-V shunt through the tumour7. Encephalopathy

RadioterapiHCC merupakan tumor yang radiosensitive, yang hanya sanggup menerima rata-rata 20 Gy, stereotactic body radiation therapy (terarah) atau selective internal RT dengan iodine-131 [131I]- labeled lipiodol atau yttrium-90 [90Y]-tagged glass Microspheres)KemoterapiHCC dianggap suatu tumor yang relatif chemorefrakter. Karena tingginya ekspresi drug resistance gene seperti p-glycoprotein, glutathione-S-transferase, heat shock proteins dan mutasi p53.DRUGS Cysplatin Doxorubicin Mytomycin 5-FUTargeted TherapySorafenib = multitargeted tyrosine kinase inhibitor.SHARP trial sorafenib monotherapy sebagai standar monoterapi untuk advanced HCC.

SummaryFirst line diagnostic tools for HCC are Dynamic CT or MRI when screening test results is abnormalTo get a better of prognosis & outcome of treatment, recommended to include; tumor stage, liver function (Child Pugh), patients physical status, effects of treatment in the staging HCCProvide a multidisciplinary and individualized approach for each patient

TERIMA KASIH