Hepatocellular cancer: what if the AFP is rising but no lesion seen on imaging?

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1 Hepatocellular cancer: what if the AFP is rising but no lesion seen on imaging? Arun J Sanyal M.B.B.S., M.D. Charles Caravati Professor of Medicine Virginia Commonwealth University CONFLICTS: US principal investigator for treatment trial of HCC-Gideon (BAYER) What if the AFP is rising but no lesion seen? AFP is coming from outside the liver The imaging technique is incorrect HCC present but imaging unable to detect Rise in AFP due to regenerative activity What you need to know about AFP Normally produced in the fetus-fetal equivalent of albumin Elevated levels occurs due to: Neonatal period Pregnancy Pregnancy-related disorders (omphalocele) Germ cell tumors (testes and ovary) Hepatocellular carcinoma Hepatic regenerative activity 1

2 Imaging features used to diagnose HCC Presence of a visible mass with or without involvement of blood vessels etc Changes seen over time after injection of an intravenous contrast agent Tissue characteristics based on its content HCC and mass effect Small:tumors < 2 cm in diameter Nodular: single or multiple discrete nodules (2-5 cm) Massive: > 5 cm with or without satellite lesions Diffuse: multiple minute indistinct nodules Size matters Type of lesion Regenerative nodule Low grade dysplastic nodule High grade dysplastic nodule Well differentiated HCC Classic HCC Mean size (cm) < Matsui O. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:S136 S140 2

3 Phases of blood flow in the liver Precontrast Arterial peak Venous peak washout seconds Regenerative nodule Main blood supply from portal vein Mild arterial enhancement Strong venous enhancement Hepatocellular cancer Hepatic artery and portal vein supply lost Arterial neovascularization Early enhancement Washout in venous/delayed phase 3

4 HCC: CT scan imaging Pre-contrast arterial venous Characteristic features of HCC on contrast imaging Courtesy of Claude Sirlin M.D., UCSD Additional MRI features of HCC Variable intensity on T1-image Hyperintensity on T2-image 4

5 Imaging criteria for diagnosis of HCC Finding Sensitivity Specificity Arterial enhancement > 90% 80% Delayed washout Delayed enhancing capsule Bright lesion on T2 images 80% 89% 80% 95% 96% 95% Multiple sources Utility of imaging modalities for diagnosis of HCC Modality Sensitivity Specificity Conventional US 45-92% 40-90% Contrast-enhanced US CT scan MRI 60-90% 68% 81% > 90% > 95% > 95% Multiple sources AFP elevated but imaging inconclusive No lesion identified: HCC in very early stage of development small HCC (< 2 cm in diameter) diffuse HCC Lesion seen difficult to characterize: small lesions (< 2 cm) dysplastic nodule infarction (with regenerative activity making AFP rise) Alternate cause of high AFP: regenerative activity non-hepatic source (germ cell tumors) 5

6 Diffuse hepatocellular cancer Bright lesion in T2 weighted image Arterial enhancement with malignant Portal vein thrombosis Willat et al, Radiology, 2008, 247: Confluent scar vs tumor: progressive enhancement in scar Approach to elevated AFP without diagnostic imaging Ensure correct technique is used Repeat imaging to leverage differences in doubling time Use 2 modalities to improve diagnostic accuracy Additional biomarkers Use additional technology 6

7 Very small HCC: diagnosis with MRI Malignant tumors grow faster than benign tumors Doubling time Malignant tumors: Median doubling time days Benign tumors: > 1 yr Taouli et al J Comput Assist Tomogr 2005;29: Benign nodule masquerading as cancer: arterial enhancement without washout Pre contrast Arterial phase Venous phase Delayed phase 7

8 Similar findings on two modalities allow HCC diagnosis to be made with high specificity N= 89 Nodules 1-2 cm in size in cirrhotic subjects Modality sensitivity specificity PPV NPV CEUS MRI CEUS + MRI Forner et al, HEPATOLOGY 2008;47: Alternate biomarkers AFP-L3 (lectin-bound AFP), descarboxylprothrombin (DCP), glypican-3 Relevant only when AFP > 10 or < 200 If AFP-L3 > 10%, then: sensitivity: 70% specificity: 63% If AFP-L3 > 35%, then: sensitivity: 33% specificity: 100% Natural history of HCC development Matsui et al, Clin Gastroenterol Hepatol, 2005, 3:S136-S140 8

9 Dysplastic nodules Isointense on T1 and T2 like regenerative nodules Low grade dysplasia: retain portal vein supply High grade dysplasia: increasing arterial enhancement and decreased venous enhancement T2 image bright if infarcted Nodule within nodule CT scan during arterial or venous angiography CTAP CTAH Portal supply intact decreased arterial supply CT arterial portography (CTAP): evaluates portal supply of lesion CT hepatic arteriography (CTHA): evaluates arterial attenuation of lesion CT-arteriography for diagnosis of very small or indeterminate nodules Pattern Findings correlate I Nodule not seen, arterial and venous supply Low grade intact Dysplasia II Nodule hypodense-indicating decrease in arterial supply High grade Dysplasia III IV Partial Hyperdense area in a nodule (neoarterialization) + loss of portal supply Diffusely hyperdense lesion with loss of portal supply Early HCC in a nodule Classic HCC 9

10 Super-paramegnetic iron oxide (SPIO)-MRI Fe is taken up by Kupffer cells and make the liver look darker and making the tumor which lacks Kupffer cells stand out as a bright signal Macarini et al, Radiol med (2009) 114: Is PET scanning useful? T2 weighted MRI MRI with gadopentate FDG-PET of same lesion PET: False negative rates of 40-50% Nuclear medicine fusion study Contrast-CT scan Octreotide-SPECT +CT scan Outwater et al, Cancer Control, April

11 A suggested algorithm for management Repeat Imaging + labs 3 months High AFP, imaging inconclusive Perform contrast imaging (CEUS, CT or MRI) HIGH RISK SUBJECT High AFP Multiple risk factors Use 2 nd modality CTA?AFP-L3 REFER TO A TRANSPLANT CENTER EARLY Lesion confirmed No YES MODERATE RISK SUBJECT Modest AFP, cirrhosis Indeterminate Lesion Lesion Not seen seen AFP-L3 Use 2 nd modality AFP-L3 Lesion confirmed YES No Repeat Imaging + labs 3 months THANK YOU FOR YOUR ATTENTION 11