Liver Lesions: How to Evaluate?

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1 Liver Lesions: How to Evaluate? Disclosures Consulting: BMS, Bayer, BTG, Eisai Laura Kulik MD Professor of Medicine, Surgery and Interventional Radiology Northwestern University Finberg School of Medicine Malignant Lesions Hepatocellular Carcinoma (HCC) Intrahepatic Cholangiocarcinoma (ICCA) Metastatic lesions Hepatic Angiosarcoma Hepatic Epithelioid Hemangioendothelioma (HEHE) Cirrhosis Unrelated to Cirrhosis Burden of Hepatocellular Carcinoma Increased incidence Peak incidence of HCV induced HCC in 2020 In US rising faster than all other cancer except lung cancer Main cause of death in patients with cirrhosis 1/3 of cirrhotic pts. develop HCC over their lifetime HCC is the indication for OLT in 15-50% of centers DM is an independent risk factor for HCC Males with BMI > 40 have a 5x increased mortality Novel therapies are needed to treat HCC at various stages 5-yr cause specific HCC survival: 3% vs. 18% Attributed to diagnosis and treatment at earlier stage 5-yr. OS: Localized 31% vs. 3% in metastatic Parkin DM et al. Int J Cancer 1999;80: World Health Organization; Sangiovanni A et al. Hepatology. 2006;43(6): ; El-Serag HB et al. N Engl J Med 1999;340:745-50; Calle EE. NEJM 2003;348: Altekruse SF et al. Hepatology 2012;55: ; Inflammation leading to scar tissue Risk of HCC Liver stiffness α with risk of HCC Diagnosis of HCC In Cirrhosis Prospective study identified risk for HCC: Platelet < 75,000 > 55 y/o + HCV PT > 75% baseline Arterial Enhancement Venous Washout 5 year risk of HCC: HCV cirrhosis 17% West; 30% East Hemochromatosis 21% HBV cirrhosis 10% West; 15% East ETOH cirrhosis 8-12% Biliary cirrhosis 4% El Serag et al Hepatology 2014 Singh S et al Clin Gastroenterol Hepatol ;11(12): Velazquez RF et al. Hepatology 2003;37:

2 Alteration in Blood Supply in HCC Diagnosis of HCC < 1 cm > 1 cm Small HCC may be Hypovascular: 38% of 1-2 cm Bx proven HCC did not meet radiographic criteria with lack of arterial enhancement Bolondi L et al Hepatology 2005;42(1):27-34 Low likelihood of HCC US q 3 months No growth up to 2 yrs. Resume q 6 month US Because *4 performance phase CT/contrast of enhanced the study MRIis so crucial to non-invasive arterial hypervascuarity diagnosis of HCC, it is recommended that these AND studies be performed venous in or expert delayed centers. phase washout NO YES HCC Characteristic on other contrast enhanced study Andreana L. et al World J Hepatol October 31; 1(1): If neg, cont. to follow q 3-6 mo, consider repeat BX Biopsy NO Bruix J et al. Hepatology 2011;53: LI-RADS: Liver Imaging Reporting and Data System Increased contrast enhancement on LATE arterial images AND Washout on portal venous phase AND/OR Pseudocapsule enhancement OR Increased contrast enhancement on LATE arterial images AND Growth of 50% on serial CT or MRI obtained 6 months apart L1 BENIGN L2 PROBABLY BENIGN L3 INTERMEDIATE L4 PROBABLE HCC L5 DEFINITIVE HCC 5A = 1 cm & < 2 cm 5B = 2 cm & 5 cm I Mitchell DG. et al. Hepatology 2015;61: Ancillary Imaging Features *Discrete ring along the lesion, margin that is thicker or of greater conspicuity than the ring along the margin of regenerative nodules Includes nodule in nodule Purysko AS et al. Radiographics 2012;32: Mosaic Architecture Arterial Venous Is a Liver Biopsy Needed? Risk of needle track seeding Reported rates vary: 3 9% Variation based on Diameter of needle # of passes Amount of normal liver parenchyma transversed FNA reported less than tru cut needle Meta- Analysis of 8 studies, all published prior to 2007 Overall incidence 2.7% (95% CI ) Median time to seeding 17 months N= 26 confirmed needle tract seeding, none impacted OS All treated with resection or ablation; none had OLT Risk of false negative continue imaging to monitor 1 lesion < 5 cm 3 lesions, none > 3 cm Milan Criteria No evidence of VI/mets Based on pre-transplant imaging 4 year survival : 74% Recurrence rate: <10% Studies with > 1000 Validated in several patients 5 yr survival: >70% Recurrence: < 15% International registry: 5 yr OS 902 pts s/p OLT : 23.5% : 44.4% : 67.8% Chhieng DC et al. World J Surg Oncol 2004;2:5. Silva MA et al. Gut 2008;57: S. Cook 97 Mazzoferro et al N Engl J Med 1996;334(11): Onaca N. et al. Liver Transpl Jun;15(6):

3 Listing for Liver Transplant Native MELD-Na: 6-40 Limited Resource Waiting list for liver transplant: 15,000-16,000 Liver transplants in 2016: 7841 HCC MELD OLD NEW as of 10/08/15 Upgrade: Initial Score 22 Calculated MELD Score Extension 1 25 Calculated MELD score Extension Extension Extension mo. Waiting until HCC MELD upgrade applies End stage Liver disease Post Transplant Outcomes HCC patients Extension Extension Cap of 34 DAAs Reduce Incident HCC Intrahepatic Cholangiocarcinoma Poor outcomes 5-yr. OS < 5% Increase in Incidence worldwide age-adjusted 0.32 per 100,000 to 0.85 per 100,000 over 30 yrs. Kanwal et al. Gastroenterology 2017 Risk factor: Chronic biliary stasis/inflammation PSC (present at younger age) Intrahepatic stones Liver flukes HCV/HBV Cirrhosis Chemical exposure: thorium dioxide, dioxin, asbestos, and radon. Congenital abnormalities of bile ducts (Caroli s, choledochal cysts) DM ETOH/smoking Distinction between icca and HCC needed Poor prognosis w/ ICCA w/ high recurrence rates Can distinguish from HCC on imaging No MELD upgrade due to reduced OS c/w HCC in OLT Rimola et al Hepatology 2009;50: Rana A et al. Curr Opin Gastroenterol.2012 May;28(3): Most pyogenic: portal or biliary origin More common in right lobe, majority solitary Hepatic Abscess Benign Lesions in Cirrhosis Risk factors: DM, cirrhosis, immunocompromised, advanced age, PPI Imaging characteristics variable depending on stage of disease Can mimic a solid mass Rim- like enhancement with central non-enhancing area Can have no non-enhancing areas -Transient enhancement on arterial PVT or HV thrombosis Clinical signs of infection are key: fever, chills, RUQ pain -50% + Blood culture L1 BENIGN L2 PROBABLY BENIGN L3 INTERMEDIATE L4 PROBABLE HCC L5 DEFINITIVE HCC *Arterial phase nonhyperenhancing atypical nodules may be categorized as LR-2 at the discretion of the radiologist. Teaching Point: Note that hepatocellular adenoma and focal nodular hyperplasia, both of which are benign and are usually hyperenhancing during the arte- rial phase, are purposely omitted from the pro- vided list of differential diagnoses for LR-1 and LR-2, since these conditions rarely occur in cirrhotic livers Mavilla MG et al. J of Clin Transplational Hepatol. 2016;4: Purysko AS. Radiographics 2012;:

4 Benign Lesions in Cirrhosis Fatty Infiltration and Sparing Confluent Fibrosis Perfusional Variants Typical areas of focal fatty sparing are around the gallbladder & hepatic hilum Direct splanchnic venous supply results in a local decrease in lipid rich PV flow US Non Contrast CT Focal fatty deposit or sparring in atypical sites can appear nodular Distinguishing features of fatty pseudotumor vs. mass containing fat No mass effect on vessels and structures Geographic configuration as opposed to round/oval shape Contrast enhancement similar to normal liver Arterial Phase CT T1 Out of Phase Ronot M et al. European J of Rdiol. 2017;93: Kim TK et al. Clinical and Molecular Hepatology 2015;21: Fatty Infiltration CT Venous T1 MRI Out of Phase Lesions in Cirrhotic Liver Kim TK et al. Clinical and Molecular Hepatology 2015;21: T1 Venous T1 In Phase T1 Out of Phase Metastatic lesions Rare in cirrhosis Alterations in portal flow 1 neoplasms can spread to a cirrhotic liver, particularity colorectal adenocarcinoma Hypervascular Metastatic Dz Melanoma Renal Cell Choriocarcinoma Thyroid Carcinoid Pancreas Breast Hepatic Angiosarcoma Rare tumor; 3 rd most common liver tumor Single mass with satellite lesions of infiltrative mass with atypical proliferation of endothelial cells in sinusoids High mortality: 2 rupture/ liver failure 2 year OS 3% Risk factors: vinyl chloride, arsenic, cyclophosphamide, anabolic steroids, OCP Therapy: resection + chemotherapy OLT contraindicated; poor outcomes Millian M et al. Int J Surg Case Rep. 2016; 28:

5 Hepatic Epithelioid Hemangioendothelioma (HEHE) Rare tumor: vascular origin Hepatic Epithelioid Hemangioendothelioma Peripheral confluent mass with capsular retraction is the hallmark feature Non specific sx: RUQ pain, wt loss, BCS, abnormal liver function Generally low to intermediate grade More favorable prognosis than other hepatic malignancies Commonly middle age female, median age 41 Stains: + for 1 of the following endothelial markers: Factor VIII-related Ag, CD34, CD31 Negative for epithelial markers: cytokeratin and CEA: MUST distinguish from adenocarcinoma or sarcoma Course: prolonged survival to rapidly progressive course Treatment: Resection OLT: >10 nodules or >4 involved hepatic segments Anti VEGF therapy Peripheral coalescing masses with capsular retraction Multiple peripheral masses w/ capsular Retraction & more confluent lesions Centrally w/calcification. Histological Classification Benign Tumors Epithelial Non epithelial Tumor like lesions Constitutional symptoms: anorexia, weight loss Prior history of malignancy Key Points in History Liver cell adenoma Bile duct adenoma Bile duct cystadenoma Biliary papillomatosis Hemangioma Infantile hemangioendothelioma Lymphangioma Angiomyolipoma Pseudolipoma Fibroma Leiomyoma Cysts Fibropolycystic disease Focal nodular hyperplasia Nodular regenerative hyperplasia Mesenchymal hamartoma Biliary hamatoma (von Meyenburg complex) Inflammatory pseudotumor Risk factors for chronic liver disease History of foreign travel Medications: steroids, OCP Resection in a Suspected Benign Lesion Has there been growth in the lesion? Is the lesion atypical or is the diagnosis in question? enhancement pattern Is it causing symptoms? Is the lesion in a location amendable for resection? 2016 MRI is preferred imaging modality No radiation Provides more detail of tissue Mutidisciplinary team: hepatologist, hepatobiliary surgeon, interventional radiologist and pathologist 5

6 Hemangioma Hemangioma Most common benign liver lesion; 1-20% population Classic appearance: peripheral nodular enhancement with gradual central fill-in Typical Hemangioma T1 Arterial Portal Sclerosing Hemangioma: fibrous replacement T1 Early Arterial Bright on T2-weighted images is helpful for confident diagnosis of hemangiomas. Can mimic HCC; especially when small and lack centripetal enhancement filling in Larger lesions may show an avascular zone MUST distinguish from malignancy Predominant prevalence in woman Female to male 3:1 Hepatobiliary T2 Late Arterial T2 Size generally remains stable Hormonal influence has been documented to increase size Single or multiple: most solitary Size varies from millimeters to 20 cm: most < 5 cm > 10 cm giant hemangioma Kim TK et al. Clinical and Molecular Hepatology 2015;21: Management Biopsy not contraindicated if can not make Dx with imaging Must have normal parenchyma between the capsule and margin of hemangioma Biopsy 96% accurate Often asymptomatic; may increase in size over time Follow up is not required for typical hemangioma NO correlation with size and complication Hemangioma vs. ICCA Not seen with similar frequency in cirrhosis often shrink & become sclerosed in cirrhosis generally not seen in advanced cirrhosis therefore follow up on lesions read as hemangioma Atypical hemangioma may represent an intrahepatic cholangiocarcinoma Pregnancy & OCP NOT contraindicated with stable, asymptomatic hemangioma Symptomatic or giant hemangioma uncommon; refer to multidisciplinary team Clinical Manifestations: Hemangioma Cardiac failure Focal Nodular Hyperplasia (FNH) 2 ND most common benign hepatic lesion; in autopsy series prevalence 0.4 3% Hypothyroidism 2 to high levels of enzyme activity Kasabach Meritt syndrome: consumptive coagulopathy, more common in > 5 cm Breaches in EC integrity exposure of sub-endothelial collegen & tissue factors platelet aggregation (low platelets) and activation of coagulation cascade Reports of development of KMS w/ pregnancy in > 5 cm lesions Steroid resistant polymylagia rheumatica Contains bile ducts and Kuffer cells; distinguishing from adenoma Features: More frequent in right lobe 90% female 80-95% solitary Usually < 5 cm, only 3% > 10 cm generally stable in size but can see slow growth MRI is nearly 100% specific: CEUS is more accurate than MRI in FNH <3 cm Congenital vascular anomaly: Central scar Hemobilia Rupture: large, peripherally located Innumerable hemaniomas Associated with Osler Weber Rendu Rare manifestations Associated with Osler Weber Rendu and hemangiomas Hallmark is central scar : Feeding artery- corkscrew artery 15% no central scar present; generally in lesions < 3 cm 20 30% multiple: more seen in pts. w/ vascular liver diseases, i.e. Budd-Chiari syndrome, obliterative portal venopathy and congenital disorders Livderatlas.org 6

7 Imaging Characteristic: FNH FNH Pre contrast 25s post contrast 40s post contrast 60s post contrast Delayed phase 10 min post contrast No evidence is pre-malignant lesion Need to differentiate from fibrolamellar cancer (calcified central scar seen in 55%) Management: conservative regardless of size if patient asymptomatic poor correlation between FNH & symptoms, so even with symptoms, treatment is rarely indicated. Resection rarely indicated: pedunculated, expanding, exophytic lesions Pregnancy & OCPs not shown to play a role in development or progression When to refer: Symptomatic patients hepatic artery embolization or resection Pedunculated, expanding, exophytic lesions * *unless there is underlying vascular liver disease Hepatic Adenoma (HCA) True incidence not clear: 10x < common than FNH Estimated prevalence % population Increased incidence in estrogen & androgen use Estrogen: dose dependent HCA Obesity, steatosis, & metabolic syndrome, often multiple (incidence RISING) Most common in females years old: 10:1 F:M Usually solitary Size: mm to 30 cm: increase with OCP/pregnancy Plates of hepatocytes 2-3 cells thick, no bile ducts Complications: Hemorrhage: 5 cm, exophytic lesions higher risk risk factors: inflammatory subtype, pregnancy, OCP in last 6 months, increasing size Treatment: selective embolization Emergent resection: 5-10% mortality vs.. delayed resection < risk, blood loss, complications Degeneration to HCC Anabolic androgenic steroids Imbalance of hormones: Klinefelter s, PCOS Genetic syndromes: Familial adenomatous polyposis (associated with β-catenin) Glycogen storage disease: seen in 75% of pts. GSD 1a Guidelines: annual US age 0-10, biannual > 10 Adenoma size/# decreases with optimal metabolic control of GSD Maturity onset DM Abnormalities of hepatic vasculature & intra hepatic shunt Subtype Classification of Adenomas EASL Guidelines: Adenoma Almost exclusively in females Expression of serum amyloid A &CRP Bx proven β-catenin (irrespective of size) Non surgical candidates: Embolization or ablation depending on size MRI can identify HNF 1 and inflammatory subtype with > 90% specificity EASL J of Hepatol 2016 Klompenhouwer AJ et al. BJS 2017;104:

8 EASL Guidelines: Adenoma HCA: Resection after 6 Months? Retrospective study: 194 pts. (194 female) with HCA > 5 cm Surveillance N= 86 Treatment N = 108 Higher BMI (P=0.029) -Smaller baseline HCA (P<0.001) -Centrally located (P<0.001) -Multiple lesions (P=0.001) 87% Resection -8.3% TAE -4.6% RFA Non surgical candidates: Embolization or ablation depending on size - Time-to-event analysis: - -HCA measured at 4 time points: Time of DX, 6 mo., 12 mo., last available scan - n=118 n=108 n=79 n=68 EASL J Hep 2016 Klompenhouwer AJ et al. BJS 2017;104: Regression with Time Regression to 5 cm, by baseline diameter Regression to 5 cm, by HCA subtype Pregnancy with HCA Not discouraged in lesions < 5 cm In pregnancy follow with US q 6-12 wks. In lesions < 5 cm, not exophytic or growing, no data to support C- section over vaginal delivery For growing lesions embolization can be considered Prior to 24 wks., surgery may be preferred, especially if peripheral lesion to avoid radiation & IV contrast 58.5% showed regression to < 5 cm after a median of 104 wks. 6-month cut-off for assessment of regression of HCA > 5 cm is too early In females with typical, non-β-catenin HCA could be prolonged to 12 mo. Irrespective of baseline size. Hepatobiliary Agents in MRI FNH & Adenoma 2 different hepatobiliary agents: gadobenate dimeglumine (Gd-BOPTA) gadoxetic acid (Gd-EOB) FNH adenoma Benefits: Can help distinguish FNH vs. Adenoma May be used to help suggest diagnosis of small HCC w/o washout Helpful detecting metastatic disease T2 ADC T1 Concerns: Approved at lower dose, so may have less robust arterial phase Reported to induce transient hypoxemia Need long enough delayed phase to capture biliary excretion Facilitates uptake of hepatobiliary agent Korean J Radiol Jul-Aug; 12(4): Arterial Phase Venous Phase Hepatobilary Phase Albiin N. et al Current Medical Imaging Review 2012;8:

9 No communication with biliary tree 1% of autopsy Simple Hepatic Cyst More common right lobe in female; large cysts almost exclusively in female > 50 Generally no septations Hemorrhage can cause appearance of septa No treatment for asymptomatic cysts Laproscopic unroofing symptomatic cysts Monitor large cysts > 4 cm for growth for stability Cystadenoma/Cystadenocarcinoma Cystadenoma More common in females Present with abdominal fullness/anorexia Malignant transformation in 15% Treatment: enuclueation Cystadenmacarcinoma Generally in elderly Treatment : formal resection Better prognosis than CCA Symptoms or increase in size raises concern for cystadenoma/cystadenocarcinoma Regev et al. J Am Coll Surg 2001; 193:36 Regev et al. J Normal Am Coll CEA < Surg 3 ng/ml 2001; 193:36. Koffron A et al Surgery 2004; 136(4): Normal CA19-9 < 33 U/L Conclusion The presence of cirrhosis or chronic liver disease is important when a liver lesion is identified increased risk of HCC Surveillance for HCC has improved outcomes due to identification of early HCC and curative options Liver biopsy is not needed to make a diagnosis of HCC Distinguishing HCC from other malignant lesions is crucial Most benign liver lesions can be managed conservatively Key radiographic features can help distinguish the various benign lesions 9