BENIGN SOLID SOL IN LIVER

Benign solid SOL in the liver

1. Benign solid SOL in the liver Dr Pukar Thapa DM Resident ( Hepatology ) March 20 th , 2020

2. Background Focal liver lesions are solid or cystic masses or areas of tissue that are identified as an abnormal part of the liver. The term “ lesion ” rather than “mass ” was chosen because “ lesion ” is a term that has a wider application, including solid and cystic masses. Because of the widespread clinical use of imaging modalities such as US, CT, and MRI, previously unsuspected liver lesions are increasingly being discovered in otherwise asymptomatic pts. Benign liver tumors are a heterogeneous group of nodular lesions originating from different cell lines.

3. Classification of benign tumors of liver Courtesy: Dr PST

4. Prevalences of benign tumors of liver Benign tumors Prevalence Hepatic hemangioma 0.1 to 20% Hepatic cysts 0.06 to 17.8% FNH 0.8 to 3.8% Hepatic adenoma 0.4 to 1.5% Focal fatty sparing 7.2 to 19.8% NRH 2.6 % Focal fatty change 9.2 % Mesenchymal hamartoma Rare/undefined Hepatic angiomyolipoma Rare/undefined Hepatic pseudolymphoma Rare/undefined 1. Khosa F, Warraich H, Khan A, Mahmood F, Markson L, Clouse ME, Manning WJ. Prevalence of non-cardiac pathology on clinical transthoracic echocardiography. J Am Soc Echocardiogr . 2012;25:553–557. 2. Moschetta M, Telegrafo M, Rella L, Stabile Ianora AA, Angelelli G. Let’s go out of the breast: prevalence of extra-mammary findings and their characterization on breast MRI. Eur J Radiol . 2014;83:930–934. 3. Marin D, Galluzzo A, Plessier A, Brancatelli G, Valla D, Vilgrain V. Focal nodular hyperplasia-like lesions in patients with cavernous transformation of the portal vein: prevalence, MR findings and natural history. Eur Radiol . 2011;21:2074–2082.

5. Hepatic hemangiomas : Introduction / Epidemiology Hepatic hemangiomas are benign, vascular tumors of the liver, accounts for 73% of all benign liver tumors [1] and is the second most common tumor seen in the liver after metastases [2]. The prevalence of hemangiomas in autopsy series is 0.4%-20%.[2] The age at diagnosis is typically between 30 - 50 yrs but hemangiomas can be diagnosed in all age groups. The reported female : male ratios range from 1.2 : 1 to 6 : 1. Most hemangiomas are small (< 4 cm) predominantly identified in the right lobe are usually solitary (90%). Some consider >4 cm as large and >10 as Giant Hemangioma ,however some consider >5 cm as Giant hemangiomas . 1.Zhang WJ, Ye LY, Wu LQ, Xin YL, Gu F, Niu JX, et al. Morphologic, phenotypic and functional characteristics of endothelial cells derived from human hepatic cavernous hemangioma . J Vasc Res 2006;43:522–532. 2.Mortele KJ, Ros PR. Benign liver neoplasms . Clin Liver Dis 2002;6:119–145. 3.Karhunen PJ: Benign hepatic tumours and tumour like conditions in men. J Clin Pathol 39:183–188, 1986.

6. Pathogenesis HH are congenital vascular malformations. They enlarge by ectasia rather than hyperplasia or hypertrophy and are considered to be hamartomas . They compress, rather than infiltrate the surrounding liver parenchyma. A pathogenic role of sex hormones has been postulated, because of consistent female predominance in larger tumors and tumor enlargement/recurrence in hysterectomized women under estrogen replacement therapy and in pts with a long-term use of oral contraceptives.[1] HH have been observed to ↑ in size during pregnancy and often display estrogen receptors, whereas no direct causal link between OC use and HH was observed in a case-control study.[2] Moreover, tumor growth was also induced or influenced by drugs such as metaclopramide .[3] 1. Trotter JF, Everson GT: Benign focal lesions of the liver. Clin Liver Dis 5:17–42, 2001. 2. Gemer O, et al: Oral contraceptives and liver hemangioma : a casecontrol study. Acta Obstet Gynecol Scand 83:1199–1201, 2004. 3. Feurle GE: Arteriovenous shunting and cholestasis in hepatic hemangiomatosis associated with metoclopramide . Gastroenterology 99:258–262, 1990.

7. Pathology Note: Peliosis hepatis may also form large, blood - filled cavities but the walls do not have the well – developed structure seen in haemangioma [2] . 1. Trotter JF, Everson GT: Benign focal lesions of the liver. Clin Liver Dis 5:17–42, 2001. 2. Wanless IR . Vascular disorders . In: Burt AD , Portmann BC , Ferrell L , eds. MacSween ’ s Pathology of the Liver , 5th edn . Edinburgh : Churchill - Livingstone - Elsevier , 2007 , p.613 – 648 . The tumors are ovoid, soft, reddish-purple or blue masses separated from the surrounding parenchyma by a fibrous pseudocapsule . Various degrees of fibrosis, hyalinization, calcification, thrombosis, and shrinking are seen. Extensive fibrosis and hyalinization, with narrowing or obliteration of vessels, are typical for sclerosed hemangiomas . Microscopically, HH are vascular abnormalities characterized by multiple blood-filled sinusoidal spaces and vascular lakes lined by endothelial cells. Vascular channels are separated by a fibrous tissue. They are fed by hepatic artery branches, and their internal circulation is slow.[1] Macroscopically Microscopically

8. Macrospcopic /microscopic view Laparoscopic appearance of a giant hemangioma showing a wellcircumscribed soft lesion with dark colored areas. Histologic examination exhibits numerous dilated vascular channels containing blood.

9. Microspcopic appearance Multiple vascular channels of various sizes lined by a single layer of flattened endothelium and supported by thin fibrous septae (hematoxylin and eosin). Very dilated vascular spaces with irregular shapes, filled with erythrocytes.

10. Clinical manifestations The long-term clinical course of most HHs is benign. The vast majority of pts will never experience any symptoms and HH are typically discovered when the liver is imaged for another reason. Large lesions are more likely to cause symptoms, which usually consist of abdominal discomfort or pain, nausea, or vomiting. Infarction, bleeding, or necrosis may also result in severe and sudden pain. Rare cases of rupture, have been reported. Pressure on bile ducts or the portal vein may also result in obstructive jaundice or portal HTN, respectively.

11. Other manifestations Large HHs (>5 cm) or HHs measuring more than 10cm (“giant hemangiomas ”) may induce a particular disease named Kasabach –Merritt syndrome, referring to the combination of a massive vascular lesion, consumptive coagulopathy , and thrombocytopenia [1]. Although its pathogenesis remains unclear, it is generally presumed to be related to platelet trapping, activation, and consumption within the abnormal vascular structure [1]. 1. Hall GW. Kasabach -Merritt syndrome: pathogenesis and management. Br J Haematol 2001;112:851–62. 2. Farges O, et al: Cavernous hemangiomas of the liver: are there any indications for resection? World J Surg 19:19–24, 1995. 3. Charny CK, et al: Management of 155 patients with benign liver tumours . Br J Surg 88:808–813, 2001. The presence of symptoms correlated with the size of HH in one study[2] but not in another study.[3] In addition, there seems to be no correlation between symptoms and the number of tumors.

12. Hepatic Hemangiomas & Associations HH can occur as part of well-defined clinical syndromes. In Klippel - Trenaunay -Weber syndrome, HH occur in a/with congenital hemi-atrophy and nevus flammeus , with or without hemimegalencephaly. Osler- Rendu -Weber disease is characterized by numerous small hemangiomas of the face, nares , lips, tongue, oral mucosa, GI tract, and liver. Von Hippel-Lindau disease is marked by cerebellar and retinal angiomas , with lesions also in the liver and pancreas.

13. Multiple HH have been reported in pts with systemic lupus erythematosus .[1] Infantile hemangioma is a common tumor in infancy. It may be seen in 5-10% of children aged 1 yr. The hemangiomas typically regress during childhood.[2] Typically, the tumors affect the skin and subcutaneous tissue. Occasionally, they affect the liver. Case reports have described the regression of infantile hemangiomas after RX with propranolol .[3,4] Reports have described infants with massive HH and hypothyroidism.[5] 1. Suzuki T, Tsuchiya N, Ito K. Multiple cavernous hemangiomas of the liver in patients with systemic lupus erythematosus . J Rheumatol . 1997 Apr. 24(4):810-1. 2. Dong KR, Zheng S, Xiao X. Conservative management of neonatal hepatic hemangioma : a report from one institute. Pediatr Surg Int. 2009 Jun. 25(6):493-8. 3. Tan ST, Itinteang T, Leadbitter P. Low-dose propranolol for multiple hepatic and cutaneous hemangiomas with deranged liver function. Pediatrics. 2011 Mar. 127(3):e772-6. 4. Starkey E, Shahidullah H. Propranolol for infantile haemangiomas : a review. Arch Dis Child. 2011 Sep. 96(9):890-3. 5. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas . N Engl J Med. 2000 Jul 20. 343(3):185-9. Hepatic Hemangiomas & Associations

14. Diagnosis Hepatic biochemical tests are usually normal and are therefore of little help in the diagnosis of hepatic hemangioma . On rare occasions, serum aminotransferases or alkaline phosphatase level may be mildly elevated. Serum levels of tumor biomarkers are invariably normal. Use of needle aspiration or biopsy in the evaluation of a possible hemangioma is not recommended.

15. Imaging : Ultrasonography and CEUS The USG appearance is that of a sharply demarcated lesion with uniformly increased echogenicity relative to normal liver. This pattern is observed in approx 70% of HH detected by USG.[1,2] Posterior acoustic enhancement is a common feature. Doppler does not usually detect flow because of the slow blood flow. (Larger HH are more heterogenous & occasionally contain central fibrosis due to a previous hemorrhage. ) 1. Moody AR, Wilson SR: Atypical hepatic hemangioma : a suggestive sonographic morphology. Radiology 188:413–417, 1993. 2. Quaia E, et al: Characterization of focal liver lesions with contrastspecific US modes and a sulfur hexafluoridefilled microbubble contrast agent: diagnostic performance and confidence. Radiology 232:420–430, 2004.

16. In one study, the addition of a contrast agent to routine USG improved the SN from 78% to 100% and SP from 23% to 92 %. (1) During the early phase of the contrast-enhanced study: most HH(78%-93%) show peripheral nodular enhancement, with progressive centripetal fillin during the portal venous phase. With delayed imaging, the lesion may completely " fill in”. (However, complete enhancement might not occur in large lesions where central thrombosis or scarring may be present.) Imaging : Ultrasonography and CEUS 1.Shaked O, et al: Biologic and clinical features of benign solid and cystic lesions of the liver. Clin Gastroenterol Hepatol 9:547–562, 2011.

17. HH: Contrast enhanced US Description: After contrast agent intravenous administration, the lesion demonstrates peripheral enhancement in arterial phase with slow and complete filling in venous phase.

18. Computed Tomography: HH Most HH are relatively well defined. The dynamic enhancement pattern is related to the size of its vascular space . Features of typical lesions include: Noncontrast : often hypoattenuating relative to liver parenchyma. Arterial phase : typically show discontinuous, nodular, peripheral enhancement (small lesions may show uniform enhancement) Portal venous phase : progressive peripheral enhancement with more centripetal fill-in. Delayed phase : further irregular fill-in and therefore iso - or hyper-attenuating to liver parenchyma. This pattern has a SN of 67%-86% and a SP of 99%-100% for the DX of hemangioma .

19. Hepatic hemangioma : CECT Precontrast phase (A), arterial phase (B), portal-venous phase (C) and equilibrium phase (D). Note the peripheral, globular uptake with centripetal distribution.

20. Magnetic Resonance Imaging: HH HH appears as a homogeneous focal lesion with smooth, well-defined margins. The lesion is hypointense compared with liver parenchyma on T1-weighted MRIs and strongly hyperintense on T2-weighted MRIs. The high signal intensity on T2-weighted MRIs gives hemangiomas a consistent light-bulb pattern with 100% SN and 92% SP.[1] Dynamic CE MRI shows a quite typical perfusion pattern in HH; that is, discontinuous peripheral nodular enhancement in the early phase with centripetal progression to uniform or almost uniform enhancement during the portal venous and the delayed phase . Such a characteristic enhancement pattern has a SN of 77-91% and a SP of 100% for the diagnosis of HH.[2,3] 1. McFarland EG, et al: Hepatic hemangiomas and malignant tumors: improved differentiation with heavily T2-weighted conventional spin-echo MR imaging. Radiology 193:43–47, 1994. 2. Whitney WS, et al: Dynamic breath-hold multiplanar spoiled gradient-recalled MR imaging with gadolinium enhancement for differentiating hepatic hemangiomas from malignancies at 1.5 T.Radiology 189:863–870, 1993. 3. Semelka RC, et al: Hepatic hemangiomas : a multi-institutional study of appearance on T2-weighted and serial gadoliniumenhanced gradient-echo MR images. Radiology 192:401–406,1994.

21. Hemangioma - Magnetic R esonance I maging (MRI) On the baseline T2-weighted MRI : the lesion shows very high signal intensity (Light bulb pattern). On the baseline T1-weighted MRI: the HH is hypointense compared with surrounding liver parenchyma. During the arterial phase of the CE dynamic study, the lesion shows peripheral globular enhancement. In the delayed phase, complete homogeneous enhancement is observed within the lesion.

22. On the baseline T2-weighted MRI, a tiny lesion is detected as a hyperintense nodule ( arrow). On the baseline T1-weighted MRI, the HH is hypointense compared with surrounding liver ( arrow). In the arterial phase of the CE dynamic MR study, the small lesion shows uniform enhancement ( arrow). In the delayed phase the lesion remains hyperintense because of persistent enhancement ( arrow). Hemangioma - Magnetic R esonance I maging (MRI)

23. Natural history of HH Variable results, with progression rates ranging from 18-39 % over 1 to 10 years of f/u [1-3]. In one study that followed the progress of 68 HH in 47 pts over 1-6 yrs, 56 HH (82 %) remained unchanged in size, 3 lesions could not be found, 7 were less obvious, 1 smaller, and only 1 lesion was found to have↑in size [3]. Another series: [150 HH (mean 3.2 cm)], the mean annual volumetric growth rate was 3 %, and 39 % of lesions ↑in size by 5 % or more[2]. Larger lesions were more likely to demonstrate growth. Among the lesions <3 cm at baseline, 19 of 46 (41 %) grew by 5 % or more , whereas among the lesions ≥5 cm, 9 of 16 (56 %) grew by 5 % or more. 1. Gandolfi L, Leo P, Solmi L, et al. Natural history of hepatic haemangiomas : clinical and ultrasound study. Gut 1991; 32:677. 2. Farges O, Daradkeh S, Bismuth H. Cavernous hemangiomas of the liver: are there any indications for resection? World J Surg 1995; 19:19. 3. Mungovan JA, Cronan JJ, Vacarro J. Hepatic cavernous hemangiomas: lack of enlargement over time. Radiology 1994; 191:111.

24. Longitudinal Studies Assessing Changes of Volume of Hemangiomas During Follow-Up Zakim

25. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma Follow up Local ethanol injection therapy Surgical resection, enucleation EBRT and RFA Trans-arterial embolization Monoclonal antibodies, Sorafenib

26. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma Asymptomatic patients, HH < 5 cm : COUNSEL THE DISEASE STATUS WITH THE PATIENT RARELY GROWS, RARELY COMPLICATES, RARELY REQUIRE INTERVENTION HH ≥ 5 cm: Repeat imaging in 6 to 12 months, using the imaging modality that best showed the hemangioma previously. If there is no change in the size of the lesion, no need for additional imaging/tests. Note: In the absence of symptoms, the risk of bleeding is too low to justify prophylactic resection.

27. Radiologic study follow-up Exceptions: Pts with a new onset of abdominal pain deserve a follow-up imaging study. Pts who are undergoing RX with estrogens or have become pregnant. Finally, pts with large HH ( ie , >10 cm) may deserve long-term follow-up radiologic studies, perhaps annually, because of their probable ↑ risk of complications. Pregnancy and the use of OCPs are not contraindicated in the presence of stable asymptomatic HH. ( EASL) Incidental reports described the development of KMS during pregnancy in females with HH > 5cm [1]. 1. Ebina Y, Hazama R, Nishimoto M, Tanimura K, Miyahara Y, Morizane M, et al. Resection of giant liver hemangioma in a pregnant woman with coagulopathy : case report and literature review. J Prenatal Med 2011;5:93–96.

28. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma Until relatively recently, no medical therapy capable of reducing the size of HH had been described. A case report in 2008 demonstrated reduction in the size of HH in a pt treated for colon cancer with bevacizumab. [1] Sorafenib , was used in the MX of a 76-year-old man with a giant HH >20 cm in diameter. Tumor volume ↓ from 1492 mL at baseline to 665 mL after 78 days of treatment with sorafenib 600 mg/day. [2] 1. Mahajan D, Miller C, Hirose K, McCullough A, Yerian L. Incidental reduction in the size of liver hemangioma following use of VEGF inhibitor bevacizumab. J Hepatol. 2008 Nov. 49(5):867-70. 2. Yamashita S, Okita K, Harada K, et al. Giant cavernous hepatic hemangioma shrunk by use of sorafenib . Clin J Gastroenterol . 2013 Feb. 6(1):55-62.

29. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma Danza et al evaluated the feasibility of percutaneous treatment of large HH by producing sclerosis through percutaneous US-guided alcohol injection. Two pts, affected by giant HH were elected for percutaneous treatment to avoid lobar liver resection. The first pt had HH (10 cm), the other pt of 12 cm. A percutaneous needle injection of 95% sterile alcohol was performed under real-time US control. Two different areas of the lesions were injected with 10 and 20 cm3 of alcohol, respectively. CT scans were performed in both pts at 3, 6 and 12 months after procedure in order to evaluate the efficacy of treatment. 1. Danza FM. Percutaneous sclerosis of giant cavernous hepatic hemangioma: Preliminary report of two cases. International Congress Series 1230:1083-1087 · June 2001

30. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma 1. Danza FM. Percutaneous sclerosis of giant cavernous hepatic hemangioma: Preliminary report of two cases. International Congress Series 1230:1083-1087 · June 2001 Results showed Progressive thrombosis of HH in both cases, resulting in a significant volume reduction. Over 95% volume reduction was achieved in the first pt within 6 months and this effect still remains after 3 years. The second pt showed extensive thrombosis in the center of the lesion (>40% in volume) at 8 months control. Conclusions: This demonstrates the effectiveness of percutaneous sclerosis of giant HH in order to reduce the mass effect, the compression on the surrounding liver parenchyma, limiting the risk of rupture. This RX is a good alternative to major surgical liver resections and shows low risk, costs and minimal discomfort for the pt.

31. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma 1. Veriasova NN, Polysalov VN, Tarazov PG. Long-term results of local ethanol injection therapy in the treatment of hemangiomatosis of the liver. Vestn Khir Im I I Grek . 2003;162(3):22-6. When local ethanol injection therapy was delivered to 37 pts with symptomatic hemangiomas, the tumors shrank in 27 of the pts (73%) and pain disappeared in 10 of the 29 pts (35%).[1]

32. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma Arterial embolization ( eg Transarterial catheter embolization ) has been used to control acute bleeding, to manage symptoms, and to shrink hemangiomas prior to surgical resection. However, it may be complicated by abscess formation, and there is no evidence of long-term efficacy.

33. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma Radiotherapy has been used historically in the management of HH but the risks of radiation hepatitis, veno -occlusive disease, and hepatic neoplasia occurs[1,2,3] and the lack of objective evidence of benefit indicate that its use should now be exceptional. RFA may provide some beneficial effects in reducing tumor size in settings in which resection is not technically feasible because of tumor location, size, multiplicity, location or medical conditions. [4] 1. Rubin P. Radiation biology and radiation pathology syllabus. Chicago: Waverley Press, 1975:59-75. 2. Issa P. Cavernous haemangioma of the liver: the role of radiotherapy. Br J Radiol 1968;41:26-32. 3. Park WC, Rhillips R. The role of radiation therapy in the management of hemangiomas of the liver. JAMA 1970;212:1496-8. 4. Gaspar L, Mascarenhas F, da Costa MS, et al. Radiation therapy in the unresectable cavernous hemangioma of the liver. Radiother Oncol 1993; 29:45.

34. Radiofrequency ablation for large HH: Initial experience and lessons Objective : To assess the feasibility, safety, and efficacy of RFA for the treatment of large (≥5 cm in greatest diameter) HHs. Methods : Thirty-six pts (15 m, 21 f; mean age 50 yrs) with 41 HH ≥5 cm in diameter were enrolled and treated with RFA attributable to the presence of enlargement tendency and/or persistent H-associated symptoms. Pts were followed for a period of 15 ± 6 months (6–24 months ). Results: There was no perioperative mortality. No delayed complications, such as local tumor progression, destructive biliary damages, or liver abscess, developed . The mean diameter of ablation zone was ↓ to 8 ±3 cm (4.0–16.0 cm) 1 mnth after ablation and further ↓ to 6 ± 3 cm(2.0–12.0 cm) in last follow-up. • Of the 26 pts with obvious symptoms related to the HH, all patients had a complete disappearance of their symptoms. Gao et al. Surgery 2013;153:78-85

35. Radiofrequency ablation for large HH: Initial experience and lessons. Conclusion : The present study supports RF ablation as an alternative treatment for HH ≥ 5 cm (but smaller than 10 cm) for the low risk of complications and likelihood of complete ablation, but, in contrast, RF ablation appears to be an inappropriate method for HH ≥ 10 cm because of the high occurrence rate of complications. Gao et al. Surgery 2013;153:78-85

36. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma Surgical therapy is indicated only in pts with symptoms, rapid growth, complications, or inconclusive diagnosis . However, it is important that all other causes of pain should have been evaluated and excluded prior to surgery. Liver resection Enucleation Mortality from surgical resection is negligible in specialized hepatobiliary centers. However, some studies suggest Enucleation is a/with less blood loss and transfusion requirements compared with resection.

37. Observation Medical management Locoregional therapy Endovascular management Radiation therapy Surgical management Liver transplantation Management of hepatic hemangioma Orthotopic LT has also been used successfully to treat symptomatic pts with unresectable giant HH and HH associated with Kasabach -Merritt syndrome [1-3]. Case report of a 27-year-old f pt with a giant HH (50 × 40 × 25 cm in size and weighed 15 kg). The patientshowed jaundice, ascites, anemia, and appetite loss. Successful LT was done with survival of more than 7 years. 1. Longeville JH, de la Hall P, Dolan P, et al. Treatment of a giant haemangioma of the liver with Kasabach -Merritt syndrome by orthotopic liver transplant a case report. HPB Surg 1997; 10:159. 2. Tepetes K, Selby R, Webb M, et al. Orthotopic liver transplantation for benign hepatic neoplasms. Arch Surg 1995; 130:153. 3. Russo MW, Johnson MW, Fair JH, Brown RS Jr. Orthotopic liver transplantation for giant hepatic hemangioma . Am J Gastroenterol 1997; 92:1940.

38. Summary P ublished studies from many centers demonstrated that asymptomatic giant hemangiomas can be safely observed, and tumor size alone is not supported as an indication for surgery in asymptomatic lesions. Furthermore, surgical resection or another alternative treatment modality should be considered if symptoms or complications (KMS) occur. Other indications for surgery includes rapid growth of the tumor and inconclusive diagnosis. When surgery is indicated, both liver resection and enucleation can be employed as surgical procedure to resect giant liver hemangiomas with low morbidity and nil mortality rates.

39. FNH (Focal Nodular Hyperplasia)

40. Classification of benign tumors of liver Courtesy: Dr PST

41. Introduction / Epidemiology FNH was first described by Edmondson in 1958 and is the second most frequent benign liver tumor after hemangioma [1] is usually discovered incidentally as a solitary mass(multinodular) but can be multiple in up to 20% of cases.[ 2 ] It is characterized by a strong female predominance (f:m ratio 8 : 1) and usually occurs between the third and fifth decades [3]. (SCHIFF: between 2 :1 and 2.6 :1) FNH has an estimated prevalence of 0.4% to 3% in autopsy series,[3,4] whereas clinically relevant cases of FNH are rare. 1. MacSween RNM, Burt AD, Portmann B, Ferrell LD. In: MacSween’s Pathology of the Liver, 6th edn . Edinburgh: Churchill Livingstone, 2011:1 online resource (v.). 2. Nault JC, Bioulac -Sage P, Zucman -Rossi J. Hepatocellular benign tumors – from molecular classification to personalized clinical care. Gastroenterology 2013;144:888–902. 3. Wanless IR, et al: Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol 2:456–462, 1989. 4. Buscarini L, et al: Laparoscopy integrates ultrasound and ultrasound guided biopsy for diagnosis of benign liver tumors. Acta Endoscopica 23:27–36, 1993. FNH is frequently associated with liver hemangioma (20% of cases), with other FNH (multiple FNH in 20% to 30% of cases), and more rarely with HCA.

42. Pathogenesis FNH appears to be the result of a hyperplastic response of the hepatic parenchyma , mainly composed of reactive polyclonal proliferating hepatocytes, to an arterial lesion and/or portal venous malformation. The consequent formation and enlargement of arterial to venous shunts causes hyperperfusion in local arteries, resulting in oxidative stress that triggers a response from hepatic stellate cells to produce the central scar typically seen in cases of FNH . FNH can be a/with other vascular abnormalities, such as hepatic hemangioma and hereditary hemorrhagic telangiectasia ( Rendu -Osler- Weber disease) or the congenital absence of the portal vein .

43. Molecular features Molecular studies have revealed that several genes involved in angiogenesis has been reported to be strongly dysregulated, with an increase in the ANGPT1:ANGPT2 ratio. As ANGPT1 promotes new vessels formation and ANGPT2 acts as an antagonist of ANGPT1, the increase in the ANGPT1:ANGPT2 ratio thus reflects active neoangiogenesis . FNH also demonstrates activation of the TGF-β ( transforming growth factor ) pathway related to the fibrous features of the lesions and activation of the WNT/β-catenin pathway. Caused by β-catenin activation, FNH exhibits overexpression of glutamine synthetase (GS), a target of β-catenin, with a typical map-like pattern of GS staining at the periphery of the nodules that is very useful for DX.

44. Pathology The size of FNH most often ranges from 1 to 5 cm . Its gross appearance is most often highly characteristic and consists of non-encapsulated, well-demarcated, yellow or brown masses with a multinodular architecture . A central stellate scar from which septa radiate to the periphery is one of the typical gross features.

45. Histologically, FNH is a multinodular mass composed of normal-appearing hepatocytes. Ductular reaction, dystrophic vessels, and inflammatory infiltrates are usually identified within the fibrous septa and/or the central scar . (SPOKE IN WHEEL FIBROUS BANDS) FNH does not contain portal venous supply. Pathology The tumor  is  subdivided into  nodules  by fibrous septa (A, white arrowhead) originating from a central scar (A, white arrow).  The  malformed arteries (B, black arrow) and bile  ductular  proliferation (B, black arrowhead)  is  detected. No  vein is   found.

46. Glutamine synthetase immunostain shows broad bands of hepatocyte staining in a geographic map-like pattern in the lesional tissue (left), whereas the nonneoplastic liver (right) shows only pericentral-venular staining. Pathology 5 to 10 thick plates of hepatocytes stained around the veins without staining around the fibrous scar ( maplike pattern).

47. FNH: Types & Variants FNH is divided into two types: Typical/classic: 80% Atypical/ nonclassic : 20% In classic FNH, all 3 characteristic features are present: abnormal nodular architecture, malformed vessels, and cholangiolar proliferation. In nonclassic FNH, 2 of the 3 characteristic features are present; bile duct proliferation is always present.

48. Variants of Atypical: Some authors also describe division of atypical FNH into several variants which include: Telangiectatic variant: most common M ixed hyperplastic and adenomatous variant L esions with large cell hepatocellular atypia FNH: Types & Variants Multiple FNH may be observed in specific clinical context, especially in patients with underlying vascular liver diseases, such as Budd-Chiari syndrome, obliterative portal venopathy and congenital disorders, including hereditary haemorrhagic telangiectasia, portal vein agenesis. Other atypical forms of FNH: FNH without a central scar is the most common of these; mostly absent in lesions <3 cm. FNH with significant steatosis are also recognized

49. Clinical manifestations In the vast majority of cases, FNH is asymptomatic and incidentally discovered during imaging investigations performed for unrelated reasons. In pts with large nodules, FNH may however be responsible for vague, nonspecific abd discomfort/pain, feelings of fullness, or dyspepsia. Intratumor bleeding may also occur in rare cases.

50. Diagnostic Workup Diagnostic confirmation can rely solely on imaging findings. The mass lesion seen on US and CT is not specific for FNH unless the central scar and feeding artery are seen. Although promising results have been recently reported with the use of CEUS, MRI is the most accurate technique to DX FNH. In unclear cases, or if the clinical context is unusual (men, age >50 years), a liver biopsy is performed to rule out a malignant tumor. The immunohistochemical staining of glutamine synthase may add SN and SP to the histologic DX whenever a liver biopsy is deemed necessary.

51. Diagnostic Workup Diagnostic confirmation can rely solely on imaging findings. The mass lesion seen on US and CT is not specific for FNH unless the central scar and feeding artery are seen. Although promising results have been recently reported with the use of CEUS, MRI is the most accurate technique to DX FNH. In unclear cases, or if the clinical context is unusual (men, age >50 years), a liver biopsy is performed to rule out a malignant tumor. The immunohistochemical staining of glutamine synthase may add SN and SP to the histologic DX whenever a liver biopsy is deemed necessary. When all features are not met, combination of CEUS and MRI yields the highest diagnostic accuracy. (EASL 2018)

52. Imaging: USG On sonography, the lesion usually appears homogenous, mostly isoechoic, however may be hypo/ hyperechoic. The center of the lesion shows a scar as an echogenic and linear structure however which is present in only 18-20 %. Lesion shows a characteristic Doppler vascular pattern, including hypervascularity , centrifugal arterial flow radiating peripherally from a central vessel. In the portal phase the lesion remains hyperechoic relative to normal liver tissue, & becomes isoechoic in the late phase. In general, this typical pattern has been observed in 74% to 100% of cases.

53. USG of FNH

54. FNH – video (CEUS)

55. Imaging: CT features in FNH Non Contrast : FNH is usually isoattenuating or slightly hypoattenuating ( hyperattenuated in fatty liver) compared with surrounding liver. 47-year-old asymptomatic woman with 2-cm FNH in right hepatic lobe. A, Unenhanced CT scan does not show mass that is isodense to liver. B, Arterial phase at same level shows small early homogeneously enhancing mass ( arrow) consistent with FNH.

56. In Arterial Phase FNH shows strong homogeneous enhancement. The central scar is typically hypoattenuating . In the portal venous and delayed phases , FNH becomes isoattenuating compared with the hepatic parenchyma. T he central scar may become hyperattenuating (80%) because of contrast agent distribution within its fibrous stroma . Imaging: CT features in FNH

57. CT features may allow correct characterization of FNH in 78% of cases. The detection rate of the central scar, which appears as a hypoattenuating structure, is related to the size of the lesion. The central scar may be identified in 35% of lesions <3 cm in diameter and in 65% of those > 3 cm. Imaging: CT features in FNH

58. MRI MRI is the most accurate imaging method to characterize FNH. FNH is usually slightly hypointense or isointense with respect to normal liver parenchyma on T1-weighted images and isointense or slightly hyperintense on T2-weighted images. The hallmark of the lesion, the central stellate scar, is usually depicted because of its hypointensity on T1-weighted images and hyperintensity on T2-weighted images, reflecting its pathologic substratum of a vascularized connective tissue. On baseline MRI, however, the mentioned typical features are observed in only 22% of cases.

59. MRI MRI is the most accurate imaging method to characterize FNH. FNH is usually slightly hypointense or isointense with respect to normal liver parenchyma on T1-weighted images and isointense or slightly hyperintense on T2-weighted images. The hallmark of the lesion, the central stellate scar, is usually depicted because of its hypointensity on T1-weighted images and hyperintensity on T2-weighted images, reflecting its pathologic substratum of a vascularized connective tissue. On baseline MRI, however, the mentioned typical features are observed in only 22% of cases.

60. Contrast-enhanced MRI (gadolinium) FNH shows strong, homogeneous enhancement in the arterial phase sparing the central scar, whereas it becomes isointense compared with liver parenchyma in the portal venous and delayed phases. The central scar may show contrast agent uptake in the delayed phase owing to the interstitial distribution of the contrast agent. These features have a specificity of >95% for the DX of FNH.

61. Contrast-enhanced MRI (gadolinium) FNH shows strong, homogeneous enhancement in the arterial phase sparing the central scar, whereas it becomes isointense compared with liver parenchyma in the portal venous and delayed phases. The central scar may show contrast agent uptake in the delayed phase owing to the interstitial distribution of the contrast agent. These features have a specificity of >95% for the DX of FNH. However, even with the administration of gadolinium chelates, the central scar may not be detectable in as many as 22% of FNHs, including 80% of those smaller than 3 cm.

62. Axial T2W MRI shows a well-circumscribed T2 isointense lesion (long arrow ) in the left lobe of the liver with a central T2 hyperintense scar (short arrow). Axial T1W MRI shows a well-circumscribed T1 isointense lesion (long arrow ) in the left lobe of the liver with a central T2 hypointense scar (short arrow). Axial post-contrast MRI in the arterial phase reveals intense enhancement of the lesion (long arrow ) with a non-enhancing central scar (short arrow). Axial post-contrast MRI in the venous (d) and delayed phases (e and f) shows the isointense nature of the lesion (long arrow) with progressive delayed enhancement of the central scar (short arrow)

63. MRI:T1 C+ Gadoxetate disodium Use of a liver-specific MR contrast agent is an alternative strategy to diagnose FNH. Owing to the affinity of its cells with hepatocytes, FNH takes up hepatocyte targeted agents, like normal parenchyma. These agents are then trapped within the lesion because FNH is unable to eliminate the compound via biliary excretion , because of the presence of abnormal bile ductules that fail to communicate with the normal biliary system, possibly resulting in defective or delayed excretion with persistent contrast agent retention. This approach may allow DX of 90% of the FNHs with atypical features on the baseline and conventional contrast-enhanced dynamic study.

64. FNH on Gadoxetic acid–enhanced MRI B, The mass (arrow) is also isointense to adjacent liver on precontrast T1-weighted imaging with the exception of the T1 hypointense central scar (arrowhead). C, Arterial phase postcontrast T1-weighted image demonstrating uniform hyperenhancement of the mass (arrow) apart from its central scar. D, Enhancement persists into delayed phases to a greater degree than the background liver due to the presence of normal hepatocytes and abnormal bile ductules . E, Twenty minute–delayed hepatocyte phase image demonstrating typical retention of contrast by FNH (arrow) with a hypointense central scar.

65. FNH VS HEPATIC ADENOMA • The most common differential consideration for FNH is hepatic adenoma. • These lesions can generally be distinguished on MR imaging on the basis of the presence of a central scar for FNH and, if present, fat and/or hemorrhage seen in adenomas. • More commonly used in the past, radionuclide imaging with 99mTc-labeled sulfur colloid could help support a DX of FNH because of uptake of radiotracer by Kupffer cells. However, in comparison with the adjacent liver, similar or greater uptake is seen in only 50% of FNH, and this may be limited to detection of only large lesions.[1] • Adenomas may contain Kupffer cells but in reduced numbers and with little or no function, therefore usually manifesting themselves as cold defects; however, they can occasionally show uptake that consequently limits the utility of sulfur colloid studies for DX.[1,2]

66. FNH Vs FLC • A central scar is not specific to FNH and can be seen with malignancies including HCC, metastases, and fibrolamellar carcinoma.( Medscape ) • Fibrolamellar carcinoma can have other imaging features that overlap with those of FNH and also usually affects young adults, occurring in an otherwise normal liver. However, fibrolamellar carcinoma tends to be a larger lesion, with an average size of 13 cm (range 5 to 20 cm), more heterogeneous, often contains central calcification rarely seen in FNH, and often appears in pts with advanced disease, including regional adenopathy , at presentation.[1,2] • In addition, fibrolamellar carcinoma is very uncommon, while FNH is a common lesion.

67. Summary of MRI Features

68. Associated Conditions The syndrome of multiple FNH is the presence of at least two FNH, hepatic hemangiomas, and disorders of the CNS such as meningioma, astrocytoma, and arterial malformations. FNH can be a/with other vascular abnormalities, such as hepatic hemangioma and hereditary hemorrhagic telangiectasia ( Rendu -Osler-Weber disease) or the congenital absence of the portal vein .

69. Associations and Complications of FNH

70. FNH, pregnancy and OCP A hospital-based case-control study in women with histologically proven FNH showed increase in the risk of FNH in pts who had ever used oral contraceptives. [1] Their use has been a/with an increase in size and vascularity of FNH nodes, and tumor regression was observed after drug withdrawal.[2 ] However, the association between pregnancy, estrogen, and FNH was negated by an 8-year study in 216 women in Paris.[3] 1. Scalori A, et al: Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case-control study. Am J Obstet Gynecol 186:195–197, 2002. 2. Haber M, et al: Multiple focal nodular hyperplasia of the liver associated with hemihypertrophy and vascular malformations. Gastroenterology 108:1256–1262, 1995. 3. Mathieu D, et al: Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 118:560–564, 2000.

71. Pregnancy and the use of oral contraceptives or anabolic steroids are not contraindicated in pts with FNH ; however, follow-up USG annually for 2 years to 3 years is prudent in women with FNH who wish to continue with oral contraceptive use. Women with a firm diagnosis of FNH who are not using oral contraceptives do not require follow-up imaging. FNH, pregnancy and OCP

72. Prognosis and Natural History FNH is a completely benign condition with the potential of changing in size. Most cases of FNH are asymptomatic and stable over time[1] or even regress or disappear after a long follow-up period. In one study,[2] 4% of the lesions decreased in size, whereas FNH increased in size in 9% of 53 pts who were monitored for 9 years. The risk of bleeding of FNH seems remote ,[3] and neoplastic transformation has never been reported. In a few pts, FNH has been reported to progress to develop clinically important symptoms . In a series of 53 pts observed in Hannover for 3 years, upper abdominal symptoms developed in 21 pts (40%) and were severe in 2 pts (4 %)[4]. 1. Kuo YH, et al: Natural course of hepatic focal nodular hyperplasia: a long-term follow-up study with sonography . J Clin Ultrasound 37:132–137, 2009. 2. Weimann A, et al: Benign liver tumors: differential diagnosis and indication for surgery. World J Surg 21:983–990, 1997. 3. Tan M, et al: Successful outcome after transplantation of a donor liver with focal nodular hyperplasia. Liver Transpl 7:652–655,2001. 4. Sadowski DC, et al: Progressive type of focal nodular hyperplasia characterized by multiple tumors and recurrence. Hepatology 61:210–214, 1995 .

73. Treatment Treatment is rarely indicated. Treatment of FNH should be reserved also for pts with a lesion that demonstrates growth on sequential imaging, those are symptomatic and complicated usually by segmental resection or enucleation. Recurrence after resection is rare. In a series of 150 pts with FNH in Hannover, five pts (3%) underwent hepatic resection because of the onset of symptoms. The rate of recurrence or persistence of presenting symptoms following resection may exceed 20%.[1] Although partial hepatic resection is the most common intervention, embolization and radiofrequency ablation have more recently been used as they are a/with fewer complications and lower morbidity. 1. Perrakis A, Muller V, Oeckl K, Adamietz B, Demir R, Hohenberger W, et al. Indications and longterm outcome after elective surgery for hepatocellular adenoma. Am Surg. 2012;78:80–85

74. Flow chart for the management of FNH (EASL 2018) MRI

75. Hepatocellular adenoma

76. Introduction HCA is a rare, frequently capsulated nodular lesion of the liver characterized by benign monoclonal proliferation of liver cells. Hepatocellular adenoma, also termed liver cell adenoma, hepatic adenoma, or telangiectatic adenoma is a benign tumor of epithelial origin occurring primarily in women of childbearing age. Adenomas may be solitary or multiple and may reach more than 20 cm in size. HCA has a very strong a/with the OCP and other estrogens ( possible trophic effect of estrogen on this tumor) , though it may rarely occur in the absence of exogenous estrogens and in men. The annual incidence in long-term users of OCPs is to 3–4 per 100,000 compared to 1–1.3 per million in nonusers.

77. E pidemiology HCA is by far a less frequent disease than FNH, with a prevalence of 0.001% to 0.004 %. The recent increase in the HCA prevalence is noticeably associated with the rising prevalence of obesity and the metabolic syndrome. Rarer associations with implications for management include: familial HCA associated with maturity onset diabetes type 3 (MODY3), iron overload related to b-thalassemia or hemochromatosis, McCune Albright syndrome, T ype I , III and IV glycogen storage disease (lifelong risk of HCA is particularly high)

78. GSD and HCA HCA (typically multiple lesions) are commonly encountered in a/with type I and III glycogen storage diseases; the incidence is 22–75% in type I and 25% in type III . In sharp contrast to HCA in general, which show a strong female preponderance, those a/with GSD show a male predominance. Furthermore, adenomas a/with GSD develop before the age of 20 years. A condition in which more than ten lesions are present has been termed liver adenomatosis . This condition has been reported in men and women in the absence of OCP use or GSD.

79. Although the female : male ratio is 4 : 1 the incidence of HCA appears to have increased in males because the use of anabolic drugs has become widespread in sports. In a series of patients collected between 1989 and 1992 the adenoma/FNH ratio was 1:10 , occurring more commonly in reproductive age women who use oral contraceptives. (subsequently strengthened by the demonstration of a dose-response risk ratio and tumor regression on drug withdrawal) In one study the relative risk of HCA was 25 for women who used oral contraceptives for more than 109 months compared with those who used contraceptives for less than 12 months. E pidemiology Socas L, Zumbado M, Pérez- Luzardo O, et al. Hepatocellular adenomas associated with anabolic androgenic steroid abuse in bodybuilders: a report of two cases and a review of the literature. Br J Sports Med 2005; 39:e27.

80. Genotype/phenotype classification More recently, a genotypic and phenotypic classification for HCA has been proposed by the Bordeaux group that subdivides HCA into four groups. Hepatocyte nuclear factor 1 inactivated group Beta-catenin mutations Inflammatory hepatocellular adenoma Hepatocellular adenomas without genetic or phenotype markers (unclassified)

81. Hepatic Adenoma Subtypes Hepatocellular adenomas without genetic or phenotype markers (unclassified): The tumors in this group represent 5% of HCA and have no evidence of mutations in HFNF1A or B -catenin and have no inflammatory infiltrates.

82. HCA with hepatocyte nuclear factor (HNF)-1 alpha mutation HCAs with HNF-1 alpha mutation occur almost exclusively in women, comprise 35 to 50 % of HCAs, and are characterized by diffuse steatosis and a lack of cytologic abnormalities or inflammatory infiltrates. Characterized by mutations of the HNF1A gene which encodes hepatocyte nuclear factor 1 α ( HNF1 α), and it was identified as a human tumor suppressor gene involved in hepatic carcinogenesis. HCAs harboring HNF1 α mutations show inhibition of gluconeogenesis coordinated with an activation of glycolysis citrate shuttle and fatty acid synthesis, which may lead to high rates of lipogenesis . ( contribute to the fatty phenotype of HCA ) This subtype is associated with a low risk of complications for lesions <5 cm.

83. HCA with beta-catenin activation More frequently found in males and are associated with use of androgens . Morphologically, the beta-catenin subtype is characterized by cellular atypia, cholestasis, and pseudoglandular formation. Highest risk of malignant transformation. A few HCCs representing 10% of all HCAs harbor a mutation of the Wnt /β-catenin pathway, thus pathogenetically linking these adenomas with a subgroup of HCCs, characterized by mutations of β-catenin.

84. Inflammatory HCA Inflammatory HCA are predominantly seen in women and comprise 40 to 55 percent of HCAs. C haracterized by the increased expression of members of the acute-phase inflammatory response such as serum amyloid A (SAA) protein, C-reactive protein (CRP ), and the interleukin 6 (IL-6) signaling pathway. The histologic appearance is characterized by inflammatory infiltrates, sinusoidal dilation, tortuous blood vessels, and hemorrhage.

85. Natural history In a systematic review of 157 studies published from 1970 to 2009, the natural history of 1617 patients with an HCA was revisited: It should be remembered that HCA may increase in size during pregnancy, yet pregnancy is not contraindicated in patients with an HCA smaller than 5 cm . Jan H.M.B.StootRobert J.S.CoelenMechteld C.De JongCornelis H.C.Dejong . Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases. HPB. Volume 12, Issue 8, October 2010

86. P athology HCAs are soft, yellow lesions often with a highly vascularized surface and a capsule, and focal areas of hemorrhage in the parenchyma. HCAs are typically solitary lesions with a clear margin, and size ranges from a few millimeters to several centimeters. Lesions are often located in the right lobe of the liver, with a tan appearance. Complications such as hemorrhage and necrosis occur because the hepatic sinusoids are supplied by a prominent arterial system, and the lack of a fibrous capsule contributes to lesion rupture and free intraperitoneal bleeding.

87. Photograph of the resected specimen shows a well-circumscribed mass with extensive hemorrhage (open arrow), a partial capsule (curved arrow), and foci of yellow-tan tissue (straight solid arrow). These tissue foci demonstrated markedly increased cytoplasmic lipid content at histologic analysis. Pathology

88. M icroscopically The histologic features are sheets of hepatocytes two or more cells thick without cellular atypia (to differentiate them from adenocarcinoma ), portal tracts (to differentiate them from liver cell regeneration), and biliary ductules and fibrosis (to differentiate them from FNH). Hepatocellular adenoma with diffuse steatosis, absence of cell atypias , and scattered small arteries not accompanied by veins: A, hematoxylin-eosin, ×5; B, hematoxylin-eosin, ×100.

89. According to the typical histologic features, HCAs are classified as S teatotic HCAs (overlapping with the HNF1α mutation subgroup of the molecular classification) - characterized by prominent steatosis (> 60%) without other specific features. T elangiectatic HCAs (overlapping with the inflammatory subgroup of the molecular classification) - characterized by the presence of portal tract remnants associated with vascular changes and/or inflammatory infiltrates. ( Telangiectatic HCA is a clinical variant of inflammatory HCA, frequently associated with use of oral contraceptives , hormonal therapy, and obesity, and the presence of other benign focal lesions of the liver. These HCAs are considered at high risk of bleeding and neoplastic transformation can occur.) U nclassified HCAs - no specific histologic features M icroscopically

90. Clinical features HCAs are usually solitary. Typical, the pt is a woman between 20-50 years who has a history of more than 5 years of OCP use . Approximately 30% of the patients have multiple nodules, and the presence of 10 or more adenomas defines liver adenomatosis , where the somatic HNF1α mutations are frequently found. Approximately half of the cases of adenomas have been discovered incidentally, whereas in the remaining cases there have been symptoms such as pain or abdominal mass. Clinical Findings Leading to Diagnosis of Hepatocellular Adenoma

91. Imaging studies: USG Ultrasonography is nonspecific, often showing a well demarcated mass with smooth borders and variable echogenicity. On color or power Doppler ultrasonography, the arterial hypervascularity is well demonstrated by arterial vessels running along the border of the lesion in a basket pattern.

92. On contrast-enhanced ultrasonography, adenoma shows intense enhancement during the arterial phase (centripetal filling). During the portal venous and equilibrium phases, adenomas may appear as an isoechoic or slightly hyperechoic mass. None of these features, unfortunately, is specific enough for the diagnosis. Imaging studies: USG

93. When necrotic or hemorrhagic changes occur, adenoma appears as a complex mass with large cystic components. Imaging studies: USG

94. CT SCAN On precontrast images, the adenoma appears as a hypo- or isodense mass, which may show high-density areas, consistent with intratumoral hemorrhage. In the arterial phase, the mass may show irregular enhancement with areas of normal, increased, and decreased density, which is characteristic for HCA. In the portal-venous phase, enhancement fades, becomes more uniform . There can be peripheral enhancement due to feeding vessels. On delayed imaging there can be “washout” similar to that seen with HCC. In the setting of an acute hemorrhage, the center may be hyperdense in the arterial phase. In the presence of an old hemorrhage, the center usually remains hypodense after contrast injection, making the differential diagnosis from a central scar difficult.

95. CEUS and dynamic CT images of HCA demonstrate a hypoechoic (a) and hypointense (e) lesion to the surrounding liver. On contrast-enhanced imaging, both modalities showed hyper-enhancement in the arterial phase (b, f). During the portal and late phases on CEUS, the lesion showed hypo-enhancement (c, d). However, the lesion is iso -enhanced (g, h)

96. A. The baseline CT scan shows a large , heterogeneous mass in left liver lobe. B , In the arterial phase of the contrast-enhanced CT study, rapid , inhomogeneous enhancement of the lesion is detected. C , In the portal venous phase, the lesion shows heterogeneous features, with hypoattenuating and hyperattenuating areas

97. MRI MRI is considered the most comprehensive and noninvasive imaging technique for evaluating HCA. MRI findings include fatty, necrotic, and hemorrhagic components, but a homogeneous hypervascular appearance may also be observed. MRI shows a well demarcated lesion that on T1-weighted images may show a mildly hypointense to mildly hyperintense signal. T2-weighted images show an isointense to slightly hyperintense signal that may be heterogenous because of areas of bleeding. Central necrosis typically appears as low signal intensity on T2-weighted images, whereas a recent hemorrhage may show increased signal on T1 images.

98. T he axial T1 in-phase image shows an isointense lesion in liver segment V; B : With signal dropout in the T1 out-of-phase image; C : Slightly hyperintense in the T2-weighted; D : In diffusion-weighted; E : In the arterial phase images; F : Washout of the contrast media in the portal-venous phase ; G : In the delayed phase images; H : Hypointense in the hepatobiliary phase image.

99. MRI (different subtypes) HCAs with HNF-1 alpha mutation demonstrate moderate arterial enhancement that does not extend into the portal venous phase B catetin - no specific characteristic features on contrast-enhanced, multiphasic MRI Inflamattory - demonstrates intense arterial enhancement persisting into the portal venous and delayed phases.

100. Hepatocyte-selective contrast agents Hepatocyte-selective contrast agents such as Gd -BOPTA ( gadobenate dimeglumine ) have been shown to improve the differentiation between FNH and adenoma. This contrast agent is selectively taken up by functioning hepatocytes and excreted into the bile. It results in prolonged enhancement of the liver parenchyma. More than 1 hour after contrast injection, almost all FNH lesions appear hyper- or isointense, whereas almost all HCA are hypointense .

101. 99mTc-sulfur colloid scintigraphy May be helpful in the diagnosis of HCA because it typically shows no uptake of the colloid due to decreased activity of Kupffer cells within the adenoma. This is in contrast to FNH, which shows normal to increased uptake.

102. Diagnosis There are no completely reliable radiologic features for the DX of HCA though some enhancement patterns are suggestive. A tentative diagnosis of HCA is usually made in the setting of women aged 20–50 years, with a history of OCP use, and a typical-appearing focal hepatic lesion or lesions. Although there is considerable overlap in the radiologic features of HCA and HCC, the latter is usually a/with a background of CLD, usually with evidence of cirrhosis. In patients with chronic hepatitis B or cirrhosis, any suspicious focal lesion with radiologic features consistent with both HCC and adenoma should be regarded as HCC until proved otherwise. High or increasing serum levels of a-fetoprotein, significant increase in nodule size, abnormal hepatic biochemical test results, and involvement of the portal vein are highly suggestive of HCC. Despite the advances in imaging modalities, the diagnosis often remains uncertain and histologic examination may be necessary.

103. Differential diagnosis Focal nodular hyperplasia – Although contrast-enhanced multiphasic imaging ( ie , magnetic resonance imaging [MRI]) can often distinguish between focal nodular hyperplasia and HCA, further evaluation and/or intervention ( eg , surgical resection) may be required for definitive diagnosis . Hepatocellular carcinoma – HCA with beta-catenin activation are not characterized by any specific features on contrast-enhanced MRI and may mimic hepatocellular carcinoma with arterial enhancement and portal venous washout; however, patients with hepatocellular carcinoma often have history of cirrhosis. Metastatic disease – Metastases to the liver are a likely cause of a solid liver lesion in patients with a history of extrahepatic malignancy. In such patients, the evaluation should start with imaging to search for metastatic disease in other organs .

104. Flowchart for management of HCA EASL 2018

105. M anagement Management of HCA depends upon the presence of symptoms, patient sex, lesion size, and pattern of lesion progression. General measures for all patients: Discontinue and avoid estrogen-containing medications ( eg , oral contraceptives [OCs]). Regression of HCA ≤5 cm has been observed after discontinuing OCs. Maintain an ideal body weight, including diet modification and exercise for patients with body mass index (BMI) >25 kg/m2.

106. Asymptomatic women with lesions ≤5 cm If the lesion's size does not increase on surveillance imaging at six months, contrast-enhanced MRI is obtained in one year and then annually thereafter. However , if the lesion appears to be growing ( ie , ≥20 percent increase in diameter) or if the lesion becomes >5 cm, intervention ( eg , surgical resection) is typically performed because of the risk of hemorrhage with larger lesions. M anagement

107. Women with symptoms or lesions >5 cm — For most women who have symptoms attributable to the lesion ( eg , persistent abdominal pain) or who have a lesion >5 cm in size, surgical resection with minimal margins is typically performed because larger lesions are associated with higher bleeding risk. For asymptomatic women with lesions >5 cm in the setting of OC use, discontinuing OC and obtaining follow-up contrast-enhanced MRI in 6 to 12 months is a reasonable option. If the lesion remains >5 cm or if symptoms develop, surgical resection is typically performed. M anagement

108. Management Surgical approaches for HCA have includes enucleation, resection, and LT. Enucleation is a/with less blood loss and preservation of normal liver tissue . Almost all solitary lesions can be completely resected, but there is often residual HCA if there were multiple lesions . The mortality of an elective surgery is about 1%, but it increases to 5–8% for emergency resection. In rare pts with multiple adenomas, OLT may be the only way to remove all the lesions, though transplantation is generally reserved for pts with glycogen storage disease .

109. Other modalities Transarterial embolization (TAE) – TAE has been used primarily for HCA complicated by bleeding, but TAE can also be used as an elective intervention for patients with symptomatic or large (>5 cm) lesions. TAE is associated with lesion regression. In a systematic review of 40 studies, including 851 patients with HCA, TAE was performed in 151 patients (17 percent), and surgical resection was avoided in 68 of these patients (45 percent). Lesion regression was seen in 75 percent of cases, and complete resolution was seen in 10 percent of cases. Radiofrequency ablation – Radiofrequency ablation is a nonoperative intervention for symptomatic HCAs that are <3 cm; however, many patients require multiple treatment sessions to achieve complete ablation. van Rosmalen BV, Coelen RJS, Bieze M, et al. Systematic review of transarterial embolization for hepatocellular adenomas. Br J Surg 2017; 104:823.

110. Observation and surveillance – While most patients with symptomatic lesions or lesions >5 cm (in the absence of estrogen-containing medications) undergo procedural intervention, some patients prefer an initial period of observation and surveillance. For these patients , repeated contrast-enhanced MRI of the liver is obtained in 6 to 12 months, and if the lesion has not regressed to ≤5 cm, either surgical resection or TAE is performed. In an observational study of 86 patients with HCA >5 cm who were observed without intervention, surveillance imaging demonstrated that 15 percent of the lesions regressed to <5 cm after six months, 25 percent of the lesions regressed after one year, and approximately 60 percent of the lesions regressed after two years. Other modalities Klompenhouwer AJ, Bröker MEE, Thomeer MGJ, et al. Retrospective study on timing of resection of hepatocellular adenoma. Br J Surg 2017; 104:1695

111. Regarding Pregnancy Generally, pregnancy should be avoided to prevent the risk of rapid tumor growth, rupture, and bleeding . Women who have had HCA, whether resected or not, should avoid the use of OCPs permanently. In pts with glycogen storage disease, pregnancy is probably safe. In the few reports of pts with GSD and HCA who became pregnant, there was no change in the size or number of the adenomas. This observation supports the notion that the pathogenesis of HCA in pts with GSD may be different from that of adenomas occurring in healthy individuals. Noels JE, van Aalten SM, van der Windt DJ, et al. Management of hepatocellular adenoma during pregnancy. J Hepatol 2011; 54:553.

112. For pregnant women with HCA, imaging surveillance and intervene is performed if the lesion becomes symptomatic or large. Specifically, liver ultrasound is obtained every 6 to 12 weeks to monitor the size of the lesion. For lesions that are growing ( ie , ≥20 percent increase in diameter), large (>5 cm), or symptomatic , intervention is done ( eg , surgical resection) because of the increased risk of lesion bleeding and rupture. Resection should ideally be performed during the second trimester, during which the risks to the mother and the fetus are minimized. Regarding Pregnancy

113. Complications Bleeding Incidence and risk factors — The risk of bleeding is difficult to establish since incidence estimates have been derived mostly from studies of predominantly symptomatic patients in whom the risk of bleeding ranges from 25 to 64 percent. Risk factors for bleeding include larger lesion size (>5 cm), recent hormone use, pregnancy, exophytic morphology, and inflammatory subtype. Clinical presentation — Patients with HCA complicated by bleeding may present with severe abdominal pain with or without hemodynamic instability . Bleeding related to HCA is often confined to the lesion, but in some cases, bleeding may lead to lesion rupture resulting in hypotension and acute hemoperitoneum . Computed tomography (CT) is typically performed if bleeding is suspected because CT images can be obtained quickly to confirm lesion hemorrhage and to facilitate management.

114. C omplications Management — Therapeutic interventions for HCA complicated by hemorrhage include emergent surgical resection, transarterial embolization (TAE) with or without subsequent surgery, or supportive care alone with subsequent surgery. Selection of initial therapy depends on severity of bleeding, the hemodynamic status of the patient, local expertise, and clinician preference. Subsequent therapy depends on lesion residual or recurrence following initial treatment ( eg , TAE). For patients with bleeding HCA, TAE is preferred for initial intervention because emergency surgery is associated with greater blood loss and complication risk compared with delayed resection.