SA–CME Information

SA-CME

SA–CME Information

MRI Screening for Hepatocellular Carcinoma

Description Target Audience Screening for hepatocellular carcinoma (HCC) has been • Radiologists shown to improve overall survival by detecting earlier stage, • Related Imaging Professionals more treatable disease. For some patients with HCC, liver transplant is the preferred treatment. However, donor livers System Requirements are a scarce resource. Accurate identification and description In order to complete this program, you must have a com- of HCC with MRI is important in the determination of which puter with a recently updated browser and a printer. For as- patients will receive a liver transplant. sistance accessing this course online or printing a certificate, email [email protected]. This article reviews background information about cirrhosis and hepatocellular carcinoma, the role of screening, transplant Instructions priority determination, and diagnostic criteria for HCC. This activity is designed to be completed within the des- ignated time period. To successfully earn credit, participants Learning Objectives must complete the activity during the valid credit period. To After completing this activity, the participant will be able to: receive SA–CME credit, you must: • Explain the Milan criteria and how these criteria impact liver allocation; 1. Review this article in its entirety. • Describe imaging findings of HCC; and, 2. Visit www.appliedradiology.org/SAM2. • Develop appropriate imaging protocols for HCC 3. Login to your account or create an account (new users). screening. 4. Complete the posttest and review the discussion and references. Accreditation/Designation Statement 5. Complete the evaluation. The Institute for Advanced Medical Education is accredited 6. Print your certificate. by the Accreditation Council for Continuing Medical Educa- tion (ACCME) to provide continuing medical education for Estimated time for completion: 1 hour physicians. Date of release and review: July 1, 2020 The Institute for Advanced Medical Education designates this Expiration date: June 30, 2022 journal-based CME activity for a maximum of 1 AMA PRA Cat- egory 1 Credit™. Physicians should only claim credit commen- Disclosures surate with the extent of their participation in the activity. These No authors, faculty, or any individuals at IAME or Applied credits qualify as SA-CME credits. Radiology who had control over the content of this program have any relationships with commercial supporters. Authors Courtney C. Moreno, MD, is an Associate Professor in the Department of Radiology and Imaging Sciences; Thuy-Van P. Hang, MD, is a gastroenterology Fellow in the Division of Di- gestive Diseases; and Joel P. Wedd is an Assistant Professor in the Division of Digestive Diseases; all at the Emory University School of Medicine, Atlanta, GA.

DETAILS ON PAGE 9

MRI Screening for Hepatocellular Carcinoma

Courtney C Moreno, MD; Thuy-Van P Hang, MD; Joel P Wedd, MD, MPH

rimary liver cancer is the fifth- American Association for the Study of Computed tomography (CT) or leading cause of cancer-related Liver Diseases (AASLD), surveillance magnetic resonance (MR) imaging is death in men and seventh-leading ultrasound imaging should be per- recommended where a nondiagnostic Pcause of cancer-related death in women formed every 6 months.5 Surveillance ultrasound is highly likely, such as in in the U.S.1 Worldwide, the most com- should be offered to cirrhosis patients obese patients. In addition, follow-up mon risk factors for hepatocellular car- when risk of HCC is ≥1.5%/year, and imaging with multiphase abdominal CT cinoma (HCC) are chronic hepatitis B to hepatitis B carriers without cirrhosis or MRI should be pursued when sur- infection (44%) and chronic hepatitis C when HCC risk is ≥0.2%/year.5 Hep- veillance ultrasound is positive for a ≥ infection (21%).2 In North America, the atitis B carriers are at risk of develop- 10 mm lesion or AFP is > 20 ng/mL.5 fraction of cases attributable to major ing HCC even without the presence of HCC risk factors are alcohol (32%), obe- cirrhosis. Therefore, surveillance is Liver Transplant and HCC sity (24%), and chronic hepatitis C infec- recommended for Asian male hepatitis Tumor Size Criteria for Transplant tion (17%).2 All patients with cirrhosis B carriers over age 40, Asian female Most HCCs develop in patients with are at risk for HCC. Patients with smaller carriers over age 50, African and Afri- underlying cirrhosis.6 In such patients, tumors can undergo potentially curative can-Americans with hepatitis B, and tumor resection is typically not pos- surgery, including liver transplantation, hepatitis B carriers with a family history sible, as the patient’s remnant liver whereas patients with larger, unresect- of HCC.5 Although the risk of HCC is would be too poorly functioning to be able tumors or extrahepatic tumor spread reduced in hepatitis C patients who ex- life sustaining. A landmark 1996 pub- have a poor prognosis. perience a sustained virologic response lication by Mazzaferro et al of the Na- with newer antiviral therapy agents, tional Cancer Institute in Milan, Italy, Role of Screening those patients with cirrhosis remain at reported 83% recurrence free survival Surveillance is associated with ear- risk for HCC and should continue imag- at 4 years for patients with unresectable lier HCC detection, higher rates of ing surveillance.5 “small” HCCs, specifically one tumor ≤ cure, and higher overall survival in pa- According to the AASLD, 6-month 5 cm in diameter or up to three tumors ≤ tients with cirrhosis.3,4 According to the imaging surveillance can be performed 3 cm without extrahepatic involvement 2018 guidance document issued by the with or without monitoring of serum al- or macrovascular invasion.7 These pha-fetoprotein (AFP) levels.5 A serum thresholds are now known as the Milan Affiliations: Emory University School of AFP level > 20 ng/mL is considered criteria. Larger tumors can potentially Medicine, Atlanta, GA. Disclosures: Dr. positive and has a sensitivity of approx- be downstaged to within Milan crite- Moreno has a research agreement with imately 60% and a specificity of approxi- ria using locoregional therapy. Other GE Healthcare. mately 90% for HCC.5 classification systems also are utilized,

A B

FIGURE 1. Hepatocellular carcinoma. (A) Late arterial-phase T1 contrast-enhanced (CE) MR image demonstrates a lesion (arrow) with signal intensity greater than background liver parenchyma compatible with arterial phase hyperenhancement. (B) 3-minute delayed image after administration of an extracellular contrast agent demonstrates lower signal intensity in the lesion as compared with the background liver parenchyma compatible with washout. Image also demonstrates enhancing capsule or pseudocapsule (arrow).

A B

FIGURE 2. Hepatocellular carcinoma. (A) Late arterial-phase T1 CE MR image demonstrates a lesion (arrow) with signal intensity greater than background liver parenchyma, compatible with arterial phase hyperenhancement. (B) 3-minute delayed image after administration of an extracellular contrast agent demonstrates lower signal intensity in the lesion compared to background liver parenchyma compatible with washout. Image also demonstrates enhancing capsule or pseudocapsule (arrow). such as the University of California San were performed in the United States in Factors typically considered include the Francisco criteria (one lesion 5 - 6.5 cm 2018 while more than 13,000 candi- patient’s overall health status and non- in diameter, or up to three lesions, each dates were on the liver transplant wait hepatic comorbidities, surgical complex- measuring ≤ 4.5 cm with a total tumor list.9 Eligibility for the transplant list ity, recent or active substance use, and diameter of ≤ 8 cm).8 relies on the judgement of a multidisci- psychosocial barriers. Transplant livers plinary committee, typically consisting are allocated according to the Model of Transplant Priority of hepatologists, transplant surgeons, co- End Stage Liver Disease (MELD) score, Donor livers are a scare resource. ordinators, and social workers who meet which is based upon serum bilirubin, Approximately 8,000 liver transplants regularly to discuss patient candidacy. International Normalized Ratio (INR),

DETAILS ON PAGE 9

A B

FIGURE 3. Nodule-in-nodule appearance. (A) Late arterial-phase image demonstrates arterial phase hyperenhancement involving the lesion in the posterior segment right hepatic lobe (arrow). (B) Delayed phase CE MR image demonstrates lower signal intensity in the lesion compared to the background liver, compatible with washout, as well as a nodule-in-nodule appearance (arrows). sodium, and creatinine values.10 Donor quiring tissue confirmation. MRI with and Transplantation Network (OPTN) livers go to patients with the highest optimized techniques has high (> 90%) and by the American College of Ra- MELD score; these patients are usually diagnostic sensitivity and specificity for diology-sponsored Liver Imaging Re- gravely ill. HCCs ≥ 2 cm.12 When imaging is con- porting And Data System (LI-RADS) Based on MELD scores, many pa- clusive, treatment (eg, liver transplant group.15,16 Both sets of criteria consider tients with cirrhosis and HCC who fall for cirrhotic patients within the Milan suspicious features to be arterial phase within the Milan criteria would not criteria or locoregional therapy for pa- hyperenhancement, washout in the lat- qualify for a donor liver; these patients tients outside the criteria) proceeds ter phases of imaging, the presence of a may then become eligible for “MELD without biopsy, owing to the potential capsule or pseudocapsule around the le- exception points” to better reflect their risk, albeit low (0 - 0.13%), for track sion, and interval growth (Figures 1,2). risk of poor outcomes from HCC and seeding with biopsy.13,14 Cirrhotic pa- Neoangiogenesis is thought to be re- their urgency for transplant. MELD tients with liver masses not definitively sponsible for HCC hyperenhancement exception points permit access to trans- diagnosed as HCC at imaging should in the arterial phase.17 This type of hy- plantation that would otherwise not be undergo biopsy, as risks associated with perenhancement is defined as non-rim available for HCC patients with pre- inappropriate treatment (eg, liver trans- enhancement of the lesion (or “observa- served liver function. Based on the most plant and lifelong immunosuppresion tion,” if using LI-RADS terminology) current policy created by the United for lesions other than HCC) outweigh that exceeds the signal intensity of the Network for Organ Sharing (UNOS), those of biopsy track seeding. It is also surrounding liver parenchyma (Figures HCC patients who meet the Milan crite- important to note that a diagnosis of 1,2).17 Arterial phase hyperenhance- ria are initially listed for transplant with HCC cannot be made with noninvasive ment has a sensitivity of 65-98%, spec- their laboratory MELD score. After imaging alone in the absence of cir- ificity of 62-97%, positive predictive a 6-month waiting period, they are rhosis, except in the setting of hepatitis value of 67-99%, and negative predic- awarded their MELD exception score, B. Biopsy is typically required in such tive value of 54-89% for HCC.17 which is 3 points lower than the median cases; benign hyperplastic nodules can Washout is defined as decreased en- patient MELD score at transplant in the have imaging features similar to HCC hancement of a liver lesion between local distribution area during the previ- in non-cirrhotic, non-hepatitis B livers.5 the earlier and later phases and lower ous 365 days .11 signal intensity in the lesion than in the Imaging Characteristics background liver parenchyma (Figures Diagnostic Criteria As imaging plays a critical role in 1,2).17 The later phases of contrast en- Imaging vs Biopsy diagnosing and managing HCC cases, hancement should be the portal venous Hepatocellular carcinoma is one of accurate image interpretation is para- and delayed phases when using extra- the few malignancies that can be diag- mount. Diagnostic criteria have been cellular contrast agents, and the portal nosed based on imaging without re- established by the Organ Procurement venous, transitional, and hepatobiliary

A B

C D

FIGURE 4. Hepatocellular carcinoma with intralesional fat. (A) Late arterial-phase T1 CE MR image demonstrates a lesion (arrow) with signal intensity greater than background liver parenchyma compatible with arterial phase hyperenhancement. (B) 3-minute delayed image after administration of an extracellular contrast agent demonstrates lower signal intensity in the lesion compared to the background liver parenchyma, compatible with washout. Also enhancing capsule or pseudocapsule (arrow). (C) Opposed-phase image demonstrates signal loss compared to the in-phase image (D), compatible with intralesional fat. phases when administering gadoxetate To be diagnosed as HCC based on phase hyperenhancement and wash- disodium.17 Washout has 50-79% sen- OPTN criteria, for example, lesions out or a capsule or pseudocapsule are sitivity, 62-100% specificity, 55-100% ≥ 1 cm and < 2 cm must demonstrate diagnostic of HCC also under OPTN positive predictive value, and 49-83% late hepatic arterial phase hyperen- criteria.15 The assignment of LI-RADS negative predictive value for HCC.17 hancement, washout, and a capsule or categories is similarly based on lesion A capsule appearance is defined as an pseudocapsule; or demonstrate late he- size, presence or absence of non-rim ar- enhancing rim that surrounds a lesion, patic arterial phase hyperenhancement terial phase hyperenhancement, number owing either to a true capsule or com- and growth by ≥ 50% documented with of major features (eg, enhancing cap- pressed liver parenchyma (ie, pseudo- serial MR images ≤ 6 months apart.15 sule, nonperipheral washout, threshold capsule) (Figures 1,2).17 A capsule has Also under OPTN criteria, a lesion growth), and presence or absence of an- 42-64% sensitivity, 86-96% specificity, with a maximum diameter ≥ 2 cm and cillary features. 89-96% positive predictive value, and ≤ 5 cm can be diagnosed as HCC if it 47-87% negative predictive value for demonstrates late hepatic arterial phase OPTN vs LI-RADS HCC.17 hyperenhancement and washout or a There are differences in the OPTN More than one suspicious feature capsule or pseudocapsule or growth by and LI-RADS criteria. For example, is required to diagnose HCC noninva- ≥ 50% documented on serial MR im- the OPTN criteria are generally binary sively with imaging; the number re- ages ≤ 6 months apart.15 Lesions with a (eg, HCC yes or no) and specifically quired declines as lesion size increases. maximum diameter > 5 cm, late arterial characterize HCC for liver transplant

DETAILS ON PAGE 9

A B

FIGURE 5. Blood products in lesion. (A) Axial T1 precontrast image demonstrates intrinsic T1 signal intensity (arrow) within the lesion, indicat- ing blood products. (B) Delayed postcontrast image demonstrates active extravasation of intravenous contrast material (arrow) with surrounding perihepatic blood products. priority assignment. By comparison, dated approximately every 3-4 years. hyperenhancement and non-rim wash- the LI-RADS system classifies obser- Those practices contemplating a transi- out, but without enhancing capsule or vations on a sliding scale consisting of tion to LI-RADS are encouraged to read threshold growth), and effectively treat- LR-5 (definitely HCC), LR-4 (probably the current version of the LI-RADS ing a lesion prior to demonstration of HCC), LR-3 (intermediate probability core document, which is freely avail- OPTN criteria surrenders candidacy for of malignancy), LR-2 (probably benign), able on the American College of Ra- HCC MELD exceptions.16 LR-1 (definitely benign), LR-M (proba- diology website. bly or definitely malignant but not HCC The next steps in patient manage- MRI Technique specific), and LR-TIV (tumor in vein).14 ment vary based on LI-RADS category. Imaging is the primary screening tool This classification is based on the pres- For example, an LR-5 lesion is assumed for HCC, and accurate description of ence or absence of major features and to be an HCC without requiring a bi- tumor size in a cirrhotic liver determines ancillary features and the use of a table to opsy. By comparison, an LR-4 lesion a patient’s eligibility for liver transplant. assign a final LI-RADS category. should undergo multidisciplinary dis- Therefore, high-quality MR images are Ancillary features are divided into cussion, and potentially a biopsy, to es- paramount. Images should be acquired three categories: those favoring HCC, tablish a diagnosis.14 In a retrospective with ≥ 1.5 T field strength using a surface including nodule-in-nodule architec- review of 181 patients with 146 HCCs, coil.15,16 Required MR sequences ac- ture (Figure 3), fat located within the 94.4% of observations categorized as cording to both the 2011 OPTN/UNOS mass more than in adjacent liver (Figure LR-5 were found to be HCC at final policy for liver transplant allocation and 4), and blood in mass (Figure 5); those pathology; 47.6% of observations cat- LI-RADS version 2018 consist of pre- favoring malignancy not specific for egorized as LR-4 were HCC; 25% of and postcontrast T1 images in the late ar- HCC, including restricted diffusion; observations categorized as LR-3 were terial, portal venous, and delayed phases, and features favoring benignity, includ- HCC; and no observations categorized as well as T2 images, and T1 in- and ing size stability ≥2 years, size reduc- as LR-1 or 2 were HCC.18 opposed-phase images.15,16 LI-RADS tion, greater iron level in the lesion than Care must be taken not to confuse version 2018 also suggests subtraction in background liver, and marked T2-hy- OPTN and LI-RADS in the setting of and diffusion weighted imaging.16 Sec- perintensity.16 possible liver transplant because OPTN tion thickness should be ≤ 5 mm for Physician practices using OPTN or is exclusively used for determining can- dynamic imaging and ≤ 8 mm for other LI-RADS criteria are encouraged to didacy for HCC MELD exceptions. It sequences.15 remain up-to-date on the most recent is also possible for LR-5 lesions not to The development of abbreviated MR version of each diagnostic criteria. The meet OPTN criteria (eg, 10-19 mm ob- protocols for HCC screening is an area LI-RADS criteria, for example, are up- servations with non-rim arterial phase of active research, as these could result in

© 14 n APPLIED RADIOLOGY www.appliedradiology.com July–August 2020 MRI SCREENING FOR HEPATOCELLULAR CARCINOMA SA-CME DETAILS ON PAGE 9 cost-savings, although the ideal abbrevi- early tumor detection and improved survival 14. Maturen KE, Nghiem HV, Marrero JA, Hus- Am J Med ated protocol is a source of debate in the among patients with cirrhosis in the US. . sain HK, Higgins EG, Fox GA, Francis IR. Lack of 2017;130(9):1099-1106. tumor seeding of hepatocellular carcinoma after imaging community; some groups advo- 5. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, percutaneous needle biopsy using coaxial cut- cate coronal T2 images and axial dynamic staging, and management of hepatocellular car- ting needle technique. AJR Am J Roentgenol. contrast-enhanced T1 fat-suppressed se- cinoma: 2018 practice guidance by the American 2006;187(5):1184-1187. Association for the study of liver diseases Hepatol- 15. Wald C, Russo MW, Heimbach JK, Hussain 19 quences, while others prefer T1pre-and ogy. 2018;68(2):723-750. HK, Pomfret EA, Bruix J. New OPTN/UNOS pol- postcontrast imaging alone or diffusion 6. Greten TF, Papendorf F, Bleck JS, et al. Survival icy for liver transplant allocation: standardization weighted images combined with T1im- rate in patients with hepatocellular carcinoma: a of liver imaging, diagnosis, classification, and retrospective analysis of 389 patients. Br J Cancer. reporting of hepatocellular carcinoma. Radiology. ages obtained during the hepatobiliary 2005;92(10):1862-1868. 2013;266(2):376-382. phase of contrast enhancement.20,21 7. Mazzaferro V, Regalia E, Doci R, et al. Liver 16. LI-RADS Steering Committee. CT/MRI transplantation for the treatment of small hepatocel- LI-RADS®v2018 CORE. https://www.acr.org/-/ lular carcinomas in patients with cirrhosis. N Engl J media/ACR/Files/RADS/LI-RADS/LI-RADS-2018- Summary Med. 1996;334(11):693-699. Core.pdf?la=en Accessed August 28, 2019. MR screening is an established tech- 8. Yao FY. Liver transplantation for hepatocellular 17. Tang A, Bashir MR, Corwin MT, et al. Evi- nique for early detection of hepatocellu- carcinoma: beyond the Milan criteria. Am J Trans- dence supporting LI-RADS major features for plant. 2008;8(10):1982-1989. CT- and MR imaging-based diagnosis of hepato- lar carcinoma, a unique tumor that can 9. National Data Organ Procurement and Trans- cellular carcinoma: a systematic review. Radiology. be diagnosed non-invasively based on plantation Network. U.S. Department of Health & 2018;286(1):29-48. MR features using established diagnos- Human Services. https://optn.transplant.hrsa.gov/ 18. Ren A-H, Zhao P-F, Yang D-W, et al. Diagnos- data/view-data-reports/national-data/ Accessed tic performance of MR for hepatocellular carcinoma tic criteria. Early detection with MRI, in August 19, 2019. based on LI-RADS v2018, compared with v2017. J turn, improves HCC patient outcomes 10. Kamath PS, Wiesner RH, Malinchoc M, et al. A Magn Reson Imaging 2019;50(3):746-755. by identifying potential candidates for model to predict survival in patients with end-stage 19. Khatri G, Pedrosa I, Ananthakrishnan L, et al. liver disease. Hepatology 2001;33(2):464-470. Abbreviated-protocol screening MRI vs. complete curative liver transplant. 11. Organ Procurement and Transplantation protocol diagnostic MRI for detection of hepatocel- Network. Policies. U.S. Department of Health & lular carcinoma in patients with cirrhosis: An equiv- References Human Services. https://optn.transplant.hrsa.gov/ alence study using LI-RADS 2018 J Magn Reson 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, media/1200/optn_policies.pdf Accessed Septem- Imaging. 2019 June 18 doi: 10.1002/jmri.26835. 2019. CA Cancer J Clin 2019;69(1):7-34. ber 7, 2019. [Epub ahead of print] 2. Baecker A, Liu X, La Vecchia C, Zhang Z-F. 12. Becker-Weidman DJS, Kalb B, Sharma P, et al. 20. Lee JY, Huo EJ, Weinstein S, et al. Evalua- Worldwide incident hepatocellular carcinoma cases Hepatocellular carcinoma lesion characterization: tion of an abbreviated screening MRI protocol attributable to major risk factors. Eur J Cancer Prev single-institution clinical performance review of mul- for patients at risk for hepatocellular carcinoma. 2018;27(3):205-212. tiphase gadolinium-enhanced MR imaging-compar- Abdom Radiol. 2018;43(7):1627-1633. 3. Singal AG, Pillai A, Tiro J. Early detection, cura- ison to prior same-center results after MR systems 21. Besa C, Lewis S, Pandharipande PV, et al. tive treatment, and survival rates for hepatocellular improvements. Radiology. 2011;261(3):824-833. Hepatocellular carcinoma detection: diagnostic carcinoma surveillance in patients with cirrhosis: a 13. Szpakowski J-L, Drasin TE, Lyon LL. Rate of performance of a simulated abbreviated MRI proto- meta-analysis. PLoS Med. 2014;11(4): e1001624 seeding with biopsies and ablations of hepatocellu- col combining diffusion-weighted and T1-weighted 4. Singal AG, Mittal S, Yerokun OA, et al. Hepa- lar carcinoma: A retrospective cohort study. Hepa- imaging at the delayed phase post gadoxetic acid. tocellular carcinoma screening associated with tol Commun. 2017;1(9):841-851. Abdom Radiol. 2017;42(1):179-190.