4/16/2018

1

Liver Lesions: How to Evaluate?

Laura Kulik MD

Professor of Medicine, Surgery and Interventional Radiology

Northwestern University Finberg School of Medicine

Disclosures

• Consulting: BMS, Bayer, BTG, Eisai

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% 1975-1977 vs. 18%1998-2007

– 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;80:827-41. World Health Organization; Sangiovanni A et al. Hepatology. 2006;43(6):1303-10;

El-Serag HB et al. N Engl J Med 1999;340:745-50; Calle EE. NEJM 2003;348:1625-38.Altekruse SF et al. Hepatology 2012;55:476-82

www.cancer.org/cancer ; www.wcrf.org/cancer_statistics/world_cancer_statistics.php.

Risk of HCC• Inflammation leading to scar tissue

• Prospective study identified risk for HCC:

– Platelet < 75,000

– > 55 y/o

– + HCV

– PT > 75% baseline

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%

Liver stiffness α with risk of HCC

El Serag et al Hepatology 2014 Singh S et al Clin Gastroenterol Hepatol 2013 2013 ;11(12):1573-84.

Velazquez RF et al. Hepatology 2003;37:520-7.

Diagnosis of HCCIn Cirrhosis

Arterial Enhancement Venous Washout

4/16/2018

2

Alteration in Blood Supply in HCC

Andreana L. et al World J Hepatol. 2009 October 31; 1(1): 48-61.

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

Diagnosis of HCC

< 1 cm > 1 cm

*4 phase CT/contrast enhanced MRIarterial hypervascuarity

AND venous or delayed phase washout

YES

Low likelihood of HCCUS q 3 months

No growth up to 2 yrs.Resume q 6 month US

HCC

NO

Characteristic on other contrast

enhanced study

NOBiopsyIf neg, cont. to follow q 3-6 mo, consider repeat BX

“Because performance of the study is so crucial to non-invasive diagnosis of HCC, it is

recommended that these studies be performed in expert centers”.

Bruix J et al. Hepatology 2011;53: 1020-22.

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

IL1 BENIGNL2 PROBABLY BENIGNL3 INTERMEDIATEL4 PROBABLE HCCL5 DEFINITIVE HCC

Mitchell DG. et al. Hepatology 2015;61:1056-65.

5A = ≥ 1 cm & < 2 cm5B = ≥ 2 cm & ≤ 5 cm

Ancillary Imaging Features

Mosaic Architecture

Purysko AS et al. Radiographics 2012;32:1977-95.

*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

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 0.018 – 0.040)

• 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

Chhieng DC et al. World J Surg Oncol 2004;2:5. Silva MA et al. Gut 2008;57:1592‐96.

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

• 1983- 1990: 23.5%• 1991-1996: 44.4%• 1997 – 2005: 67.8%

Mazzoferro et al N Engl J Med 1996;334(11):693-9. Onaca N. et al. Liver Transpl. 2009 Jun;15(6):574-80.

3 lesions, none > 3 cm

1 lesion < 5 cm

S. Cook ‘97

4/16/2018

3

Listing for Liver Transplant

HCC MELD Upgrade:

OLD NEW as of 10/08/15

Initial Score 22 Calculated MELD Score

Extension 1 25 Calculated MELD score

Extension 2 28 28

Extension 3 29 30

Extension 4 31 31

Extension 5 33 33

Extension 6+ 35 Cap of 34

6 mo. Waiting until HCC MELD upgrade applies

Native MELD-Na: 6-40

Limited Resource

End stage Liver disease HCC patients

Waiting list for liver transplant: 15,000-16,000

Liver transplants in 2016: 7841

Post Transplant Outcomes

DAAs Reduce Incident HCC

Kanwal et al. Gastroenterology 2017Kanwal et al. Gastroenterology 2017

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.

• 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

16Rimola et al Hepatology 2009;50:791-798. Rana A et al. Curr Opin Gastroenterol.2012 May;28(3):258-65.

Hepatic Abscess• Most pyogenic: portal or biliary origin

• More common in right lobe, majority solitary

• 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

Mavilla MG et al. J of Clin Transplational Hepatol. 2016;4:158-68.

Benign Lesions in Cirrhosis

*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”

Purysko AS. Radiographics 2012;:1977-95.

L1 BENIGNL2 PROBABLY BENIGNL3 INTERMEDIATEL4 PROBABLE HCCL5 DEFINITIVE HCC

4/16/2018

4

Benign Lesions in Cirrhosis

Confluent Fibrosis Perfusional Variants

Ronot M et al. European J of Rdiol. 2017;93:157-68.

Fatty Infiltration and Sparing• 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

• 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

Kim TK et al. Clinical and Molecular Hepatology 2015;21:326-43.

US Non Contrast CT

Arterial Phase CT T1 Out of Phase

Fatty Infiltration

Kim TK et al. Clinical and Molecular Hepatology 2015;21:326-43.

CT Venous T1 MRI Out of Phase

T1 Venous T1 In Phase T1 Out of Phase

Lesions in Cirrhotic Liver

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; 3rd 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

MillianM et al. Int J Surg Case Rep. 2016; 28:165‐68.

4/16/2018

5

Hepatic Epithelioid Hemangioendothelioma(HEHE)

• Rare tumor: vascular origin

• 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

Hepatic Epithelioid Hemangioendothelioma

Peripheral coalescing masses with capsular retraction

Multiple peripheral masses w/ capsular Retraction & more confluent lesions Centrally w/calcification.

Peripheral confluent mass with capsular retraction is the hallmark feature

Histological Classification

Benign Tumors

Epithelial Non‐epithelial Tumor‐like lesions

• 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

Key Points in History

• Constitutional symptoms: anorexia, weight loss

• Prior history of malignancy

• 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?

• MRI is preferred imaging modality

– No radiation

– Provides more detail of tissue

• Mutidisciplinary team: hepatologist, hepatobiliary

surgeon, interventional radiologist and pathologist

2016

4/16/2018

6

Hemangioma

• Most common benign liver lesion; 1-20% population

• Classic appearance: peripheral nodular enhancement with gradual central fill-in

• 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

• 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

Hemangioma

Kim TK et al. Clinical and Molecular Hepatology 2015;21:326-43.

Sclerosing Hemangioma: fibrous replacement

T1 Arterial Portal

Hepatobiliary T2

T1 Early Arterial

Late Arterial T2

Typical Hemangioma

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

• Pregnancy & OCP NOT contraindicated with stable, asymptomatic hemangioma

• Symptomatic or giant hemangioma uncommon; refer to multidisciplinary team

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

Clinical Manifestations: Hemangioma• Cardiac failure

• 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

• Hemobilia

• Rupture: large, peripherally located

• Innumerable hemaniomas– Associated with Osler Weber Rendu

Rare manifestations

Focal Nodular Hyperplasia (FNH)• 2ND most common benign hepatic lesion; in autopsy series prevalence 0.4 – 3%

• 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:

• 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

Central scar

4/16/2018

7

Imaging Characteristic: FNH

Pre contrast                25s post contrast          40s post contrast

60s post contrast           Delayed phase            10 min post contrast

FNH

• 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 0.007 – 0.012% population

– Increased incidence in estrogen & androgen use

• Most common in females 35-40 years old: 10:1 F:M

– Usually solitary

• Size: mm to 30 cm: increase with OCP/pregnancy

• 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

Plates of hepatocytes 2-3 cells thick, no bile ducts

HCA

• Estrogen: dose dependent

• Obesity, steatosis, & metabolic syndrome, often multiple (incidence RISING)

• 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 J of Hepatol 2016

Almost exclusively in females

Expression of serum amyloid A &CRP

MRI can identify HNF‐1 and inflammatory subtype with > 90% specificity 

EASL Guidelines: Adenoma

Klompenhouwer AJ et al. BJS 2017;104:1695‐03.

Non surgical candidates: Embolization or ablation depending on size

Bx proven β-catenin(irrespective of size)

4/16/2018

8

EASL Guidelines: Adenoma

Non surgical candidates: Embolization or ablation depending on size

EASL J Hep 2016

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

- 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

Klompenhouwer AJ et al. BJS 2017;104:1695‐03.

Regression with Time

Regression to ≤ 5 cm, by baseline diameter Regression to ≤ 5 cm, by HCA subtype

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.

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

Hepatobiliary Agents in MRI

• 2 different hepatobiliary agents:

– gadobenate dimeglumine (Gd-BOPTA)

– gadoxetic acid (Gd-EOB)

• Benefits:

– Can help distinguish FNH vs. Adenoma

– May be used to help suggest diagnosis of small HCC w/o washout

– Helpful detecting metastatic disease

• 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

Korean J Radiol. 2011 Jul-Aug; 12(4): 403–415.

Facilitates uptake of hepatobiliary agent

FNH & Adenoma

T2 ADC T1

Arterial Phase Venous Phase Hepatobilary Phase

Albiin N. et al Current Medical Imaging Review 2012;8:107-16.

FNHadenoma

4/16/2018

9

Simple Hepatic Cyst

• No communication with biliary tree

• 1% of autopsy

• 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

• Symptoms or increase in size raises concern for cystadenoma/cystadenocarcinoma

Regev et al. J Am Coll Surg 2001; 193:36

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

Regev et al. J Am Coll Surg 2001; 193:36.Normal CEA < 3 ng/ml Normal CA19-9 < 33 U/LKoffron A et al Surgery 2004; 136(4):926-36.

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