Brief description on the benign tumors of liver that includes hemangioma, focal nodular hyperplasia, regenerative nodular hyperplasia, dysplastic foci, dysplastic nodules and focal fatty change.

1. Pratap Sagar Tiwari, MD(IM), DM Resident, Hepatology
NAMS, Bir Hospital, Nepal

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.
• A study indicated that from 1996 to 2010 the use of CT examinations tripled (52/
1,000 pts in 1996 to 149/1,000 in 2010, 7.8 % annual growth), MRIs
quadrupled (17 /1,000 to 65/1,000, 10 % annual growth).[1]
• A descriptive nomenclature was set out by an international panel of experts
sponsored by the World Congress of Gastroenterology 1994.[1 ]
• Benign liver tumors are a heterogeneous group of nodular lesions originating from
different cell lines.
1. Smith-Bindman R , Miglioretti DL , Johnson E et al. Use of diagnostic imaging studies and associated radiation exposure for patients enrolled in large integrated health care systems, 1996-2010 . JAMA
2012 ; 307 : 2400 – 9 .

3. Terminology of Nodular Hepatocellular Lesions
INTERNATIONAL WORKING PARTY 1995[1]
1. International Working Party. Terminology of nodular hepatocellular lesions. Hepatology. 1995 Sep;22(3):983-93.
Regenerative Nodule
A RN is a well-defined region of parenchyma that has enlarged in
response to necrosis, altered circulation, or other stimuli.
Monoacinar regenerative nodule is a RN containing no more than
one portal tract.
Monoacinar nodules are usually multiple and involve most of the
liver as diffuse nodular hyperplasia (DNH).
When DNH occurs in the absence of fibrous septa, it is also known
as nodular regenerative hyperplasia (NRH)
DNH may also be superimposed on a previously cirrhotic liver.
Multiacinar Regenerative Nodule
A RN containing >1 portal tract, in a liver that is otherwise
abnormal, either with cirrhosis or with Severe disease of PV, HV, or
sinusoids.
These nodules are usually multiple surrounded by fibrous septa, the
nodules are synonymous with cirrhotic nodules.
When multiacinar RN are distinctly larger than most cirrhotic
nodules of the same liver, generally at least 5 mm in diameter, they
may be called large RN or macroregenerative nodules

4. Classification of Benign Nodular Lesions of the Liver
Hepatocellular Mesenchymal
Regenerative lesions
• Monoacinar regenerative nodule
 Diffuse nodular hyperplasia without fibrous septa (NRH)
 Diffuse nodular hyperplasia with fibrous septa or in cirrhosis
• Multiacinar regenerative nodule
• Lobar or segmental hyperplasia
• Focal nodular hyperplasia
Dysplastic or neoplastic lesions
• Hepatocellular adenoma
• Dysplastic focus
• Dysplastic nodule
Leiomyoma
Lipoma
Myeloid lymphoma
Angiomyolipoma
Pseudolymphoma
Fibrous mesothelioma
Hamartoma
Benign teratoma
Biliary Vascular
Bile duct adenoma
Biliary hamartoma
Biliary cystoadenoma
Biliary papillomatosis
Hemangioma
Infantile hemangioendothelioma
Hereditary hemorrhage telangiectasia
Lymphangiomatosis
ZAKIM

5. NOTE: This PPT contains the topic HEMANGIOMA, FOCAL NODULAR HYPERPLASIA, NODULAR REGENERATIVE
HYPERPLASIA , Macronodules developing on cirrhosis including DYSPLASTIC FOCI, DYSPLASTIC NODULES and
briefly about FOCAL FATTY CHANGE .
IT DOES NOT INCLUDE HEPATOCELLULAR ADENOMA AND OTHERS. PLEASE LOOK FOR ANOTHER PPT.
THANKYOU.
This PPT Slides is a compilation from various sources with references includes. You may download for academic
interest but please do not download and edit my name. Thankx.

6. Introduction / Epidemiology
• Hepatic hemangiomas are MC benign, vascular tumors of the liver, the second MC liver mass
after metastatic cancer.
• Hemangiomas affect 0.7% to 1.5% of the general population, being typically discovered
incidentally during evaluation of nonspecific abdominal complaints.[1,2,3,4]
• The prevalence of hemangiomas in autopsy series is 0.4%-20%).[5,6,7]
• 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%).
• There is some controversy about the term cavernous hemangioma. Whereas some authors
use it as a general name for hemangiomas, others use it to describe a stage of development
of the lesion.
1. Lu SN, et al: Abdominal sonographic screening in a single community. Gaoxiong Yi Xue Ke Xue Za Zhi 6:643–646, 1990.
2. Gandolfi L, et al: Natural history of hepatic haemangiomas: clinical and ultrasound study. Gut 32:677–680, 1991.
3. Gibney RG, et al: Sonographically detected hepatic hemangiomas: absence of change over time. AJR Am J Roentgenol 149:953–957,1987.
4. Rungsinaporn K, Phaisakamas T: Frequency of abnormalities detected by upper abdominal ultrasound. J Med Assoc Thai 91:1072–1075, 2008.
5. Karhunen PJ: Benign hepatic tumours and tumour like conditions in men. J Clin Pathol 39:183–188, 1986.
6. Reddy KR, Schiff ER: Approach to a liver mass. Semin Liver Dis 13:423–435, 1993.
7. Rubin RA, Mitchell DG: Evaluation of the solid hepatic mass. Med Clin North Am 80:907–928, 1996.
8. Adam YG, Huvos AG, Fortner JG. Giant hemangiomas of the liver. Ann Surg 1970; 172:239.
9. Grieco MB, Miscall BG. Giant hemangiomas of the liver. Surg Gynecol Obstet 1978; 147:783.
Some consider >4 cm as large and >10 as Giant Hemangioma ,however some consider >5 cm as Giant hemangiomas. [8,9]

7. Epidemiology of Liver Nodules in Normal
or Near-Normal Liver
ZAKIM

8. 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.

9. Pathology
• Macroscopically, 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]
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.
3. 613 – 648 .
Peliosis hepatis may also form large, blood - filled cavities but the walls do not have the well - developed structure
seen in haemangioma [2] . A history of anabolic steroid therapy would favour a diagnosis of peliosis.

10. Hemangioma
(A, B) Laparoscopic appearance of a
giant hemangioma showing a well-
circumscribed soft lesion with dark
colored areas.
(C) Histologic examination exhibits
numerous dilated vascular channels
containing blood.
(A&B:Courtesy of Dr P. A. Bejarano, Department of Pathology,
University of Miami School of Medicine.)
Src of C:Available at http://ilovepathology.com/cavernous-hemangioma/

11. Clinical manifestations
• The long-term clinical course of most HHs is benign [1]. The vast majority
of pts will never experience any symptoms and HH are typically discovered
when the liver is imaged for another reason [1].
• 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.
1. Schiff ER, Sorrell MF,Maddrey WC. Schiff’s Diseases of the Liver, 10th edn. Philadelphia: LippincottWilliams &Wilkins, 2007.

12. Other manifestations
• Large HHs (>5 cm) or HMs 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].
• Large or multiple lesions may be a/with High output heart failure
especially in children [2,3] .
1. Hall GW. Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol 2001;112:851–62.
2. Wananukul S , Voramethkul W , Nuchprayoon I et al . Diffuse neonatal hemangiomatosis: report of 5 cases . J. Med. Assoc. Thai. 2006 ; 89 : 1297 – 1303 .
3. Kim JD , Chang UI , Yang JM . Clinical challenges and images in GI. Diffuse hepatic hemangiomatosis involving the entire liver . Gastroenterology 2008 ; 134 : 1830 , 2197 .
4. Farges O, et al: Cavernous hemangiomas of the liver: are there any indications for resection? World J Surg 19:19–24, 1995.
5. 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[4] but not in another study.[5] In addition,
there seems to be no correlation between symptoms and the number of tumors.

13. Clinical Features
• Diagnosis was incidentally made in 23% to 62% of cases, whereas clues
to diagnosis were abdominal pain in 23% to 53% of cases, suspected
metastases in 3% to 16% of cases, palpable mass in 0% to 2% of cases,
and nonspecific complaints in 5% to 9% of cases.[1,2,3]
1. Reddy KR, Schiff ER: Approach to a liver mass. Semin Liver Dis 13:423–435, 1993.
2. Terkivatan T, et al: Indications and long-term outcome of treatment for benign hepatic tumors: a critical appraisal. Arch Surg 136:1033–1038, 2001.
3. Weimann A, et al: Benign liver tumors: differential diagnosis and indication for surgery. World J Surg 21:983–990, 1997.
Physical examination
• Physical examination is usually unremarkable. Occasionally, there is
abdominal tenderness over the right upper quadrant and a palpable
mass may be encountered.
• Rarely, a bruit may be heard over a large hemangioma.

14. 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 hemi-megalencephaly.
• In Kasabach-Merritt syndrome, giant HH are a/with thrombocytopenia
and intravascular coagulation. In this condition, pts are typically male and
younger than 1 year. [1] The goal of RX is eradication of the HH, with
subsequent control over the pt's coagulopathy. [2]
• 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.
1. Reischle S, Schuller-Petrovic S. Treatment of capillary hemangiomas of early childhood with a new method of cryosurgery. J Am Acad Dermatol. 2000 May. 42(5 Pt 1):809-13.
2. Aslan A, Meyer Zu Vilsendorf A, Kleine M, Bredt M, Bektas H. Adult Kasabach-Merritt Syndrome due to hepatic giant hemangioma. Case Rep Gastroenterol. 2009 Nov 20. 3(3):306-12.

15. Hepatic Hemangiomas & Associations
• 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.

16. 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 a-fetoprotein and carcinoembryogenic antigen (CEA) are
invariably normal.
• Use of needle aspiration or biopsy in the evaluation of a possible
hemangioma is not recommended.
Thrombocytopenia can result from sequestration and destruction of platelets in large lesions.
Hypofibrinogenemia has been attributed to intratumoral fibrinolysis.

17. Imaging :Ultrasonography and CEUS
• The MC 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]
• Posterior acoustic enhancement is a common feature.
• Doppler does not usually detect flow because of the slow blood flow.
(Larger HH r more heterogenous & occasionally contain central fibrosis due to a previous
hemorrhage. )
• During the early phase of the contrast-enhanced study: most HH(78%-93%) show
peripheral nodular enhancement, with progressive centripetal fill-in.[2,3] during the
portal venous phase. With delayed imaging, the lesion may completely "fill in.“[4]
(However, complete enhancement might not occur in large lesions where central thrombosis or scarring
may be present.)
• 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%.[5]
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 hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence. Radiology 232:420–
430, 2004.
3. Shaked O, et al: Biologic and clinical features of benign solid and cystic lesions of the liver. Clin Gastroenterol Hepatol 9:547–562, 2011.
4. Dietrich CF, Mertens JC, Braden B, et al. Contrast-enhanced ultrasound of histologically proven liver hemangiomas. Hepatology. 2007 May. 45(5):1139-45.
5. von Herbay A, Vogt C, Willers R, et al. Real-time imaging with the sonographic contrast agent SonoVue: differentiation between benign and malignant hepatic lesions. J Ultrasound Med. 2004 Dec.
23(12):1557-68.

18. Source: Danilo Sirigu, MD Hepatic Cavernous Hemangioma https://sonoworld.com
Abdominal sonography revealed a large mass
approximately 8cm x 6 cm in diameter with
heterogeneous echo pattern. Color Doppler
shows no flow inside the mass.

19. Hemangioma: CEUS
Description: After contrast agent
intravenous administration, the lesion
demonstrates peripheral enhancement
in arterial phase with slow and complete
filling in venous phase.
Source: Danilo Sirigu, MD Hepatic Cavernous Hemangioma Available @https://sonoworld.com

20. Computed Tomography
• 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[1]
• This pattern has a SN of 67%-86% and a SP of 99%-100% for the DX of
hemangioma. [2,3]
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.
2. Nino-Murcia M, et al: Focal liver lesions: pattern-based classification scheme for enhancement at arterial phase CT. Radiology 215:746–751, 2000.
3. Kim T, et al: Discrimination of small hepatic hemangiomas from hypervascular malignant tumors smaller than 3 cm with threephase helical CT. Radiology 219:699–706, 2001.

21. Extra notes
• Atypical CT features are observed in HH with either high flow or very
slow flow. High-flow hemangiomas show rapid filling after contrast
agent administration, resulting in homogeneous enhancement during
the hepatic arterial or portal venous phase.[1] This feature is relatively
common in small hemangiomas.
• Very slow flow hemangiomas appear either as nonenhanced lesions or
as lesions with weak peripheral enhancement without centripetal
progression. These features may be related to thrombosis or abundant
fibrosis, and mimic a hypovascular malignant tumor.
1. Kim T, et al: Discrimination of small hepatic hemangiomas from hypervascular malignant tumors smaller than 3 cm with threephase helical CT. Radiology 219:699–706, 2001.

22. Hepatic hemangioma: CECT
Dynamic, contrast-enhanced
computed tomography (CT)
scan demonstrates globular
peripheral enhancement with
gradual diffusion of the contrast
from the periphery to the center
of the lesion:
(A) 40 seconds,
(B) 60 seconds,
(C)90 seconds, and
(D)120 seconds after
intravenous contrast injection.

23. Magnetic Resonance Imaging
• The MRI protocol for characterizing suspected HH includes T1-weighted sequences, T2-weighted sequences and gadolinium enhanced T1-
weighted sequences.
• 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 relative to spleen.
• 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.

24. Hemangioma, magnetic resonance imaging (MRI)
A, On the baseline T2-weighted MRI : the lesion shows very high signal intensity(Light bulb pattern).
B, On the baseline T1-weighted MRI: the HH is hypointense compared with surrounding liver parenchyma.
C, During the arterial phase of the CE dynamic study, the lesion shows peripheral globular enhancement.
D, In the delayed phase, complete homogeneous enhancement is observed within the lesion.
ZAKIM

25. Hemangioma, magnetic resonance imaging (MRI)
A, On the baseline T2-weighted MRI, a tiny lesion is detected as a
hyperintense nodule (arrow).
B, On the baseline T1-weighted MRI, the HH is hypointense
compared with surrounding liver (arrow).
C, In the arterial phase of the CE dynamic MR study, the small lesion
shows uniform enhancement (arrow).
D, In the delayed phase the lesion remains hyperintense because of
persistent enhancement (arrow).
ZAKIM

26. MRI of a hemangioma
The lesion appears as a hypointense mass on T1-weighted
MRIs and as a hyperintense mass on T2-weighted MRIs .
Gadolinium-enhanced MRI
These images demonstrate the progressive,
centripetal contrast enhancement in a HH.

27. Management
• Because most hemangiomas are asymptomatic, rarely enlarge in size or
rupture, and have no malignant potential, observation is sufficient and
surgical intervention is rarely indicated.
• Surgical therapy is indicated only in pts with severe symptoms,
complications, or inconclusive diagnoses that cannot be resolved with
imaging studies. Overall, surgical resection is indicated in about 2% of dx
hemangiomas.
No randomized trials are available showing a superior effect of resection as compared to conservative treatment [1]
1. Miura JT, Amini A, Schmocker R, Nichols S, Sukato D, Winslow ER, et al. Surgical management of hepatic hemangiomas: a multi-institutional experience. HPB (Oxford) 2014;16:924–928.

28. Management: Surgery
• When symptoms are clearly related to the hemangioma, resolution may
be observed in as many as 96% of the pts after surgical treatment.
• Another major reason for surgery is to exclude the presence of
malignancy.
• The surgical mortality in experienced centers is zero or nearly zero .
Nevertheless, even in specialized centers the frequency of postoperative
complications may be as high as 25%.
• Enucleation is the preferred approach by many groups because it allows
the resection of large hemangiomas with less blood loss and preservation
of more hepatic parenchyma compared with resection.
• Laparoscopy is currently used as the procedure of choice in many centers
when the DX is well established.

29. Management: Transarterial embolization & others
• Although surgical resection remains the main definitive RX for symptomatic HH, other
less effective options are occasionally used.
• Transarterial embolization has been used for symptomatic lesions, acute bleeding ,
and consumption coagulopathy.
• However, there are few data on its long-term efficacy, and the procedure may have to
be repeated or may lead to liver abscesses.
• Hepatic resection and transcatheter hepatic embolization are effective treatment
modalities for Kasabach-Merritt syndrome, although in a few instances unresectable
cavernous hemangiomas with this complication may be an indication for LT.[1] Medical
treatment with corticosteroids or vincristine have also been achieved [3,4].
• Hepatic artery ligation, radiation therapy ( AE: radiation hepatitis), radiofrequency
ablation, and LT have been used on rare occasions for unresectable giant
hemangiomas.
• Recurrence has been described after surgical, intra-arterial, and radiation therapy.
1. Longeville JH, et al: Treatment of a giant haemangioma of the liver with Kasabach-Merritt syndrome by orthotopic liver transplant: a case report. HPB Surg 10:159–162, 1997.
2. European Association for the Study of the Liver. EASLClinical Practice Guidelines on the management of benign liver tumours. J Hepatol 2016;65:386–98.
3. Belghiti J, Cauchy F, Paradis V, Vilgrain V. Diagnosis and management of solid benign liver lesions. Nat Rev Gastroenterol Hepatol 2014;11:737–49.

30. • When local ethanol injection therapy was delivered to 37 pts with
symptomatic hemangiomas (41% with multiple nodes, 60% with
cavernous tumors), the tumors shrank in 27 of the pts (73%) and pain
disappeared in 10 of the 29 pts (35%) with symptoms.[1]
• LT may be indicated for large, unresectable tumors, for extensive multiple
tumors, or when surgical resection is not feasible.
1. Tanaka A, et al: Atypical liver hemangioma with shunt: long-term follow-up. J Hepatobiliary Pancreat Surg 9:750–754, 2002.
2. 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.
Pregnancy and the use of OCPs are not contraindicated in the presence of stable asymptomatic
haemangioma.
Incidental reports described the development of KMS during pregnancy in females with liver
haemangiomas larger than 5cm [2]. EASL

31. Possible utility of growth factor and kinase inhibitors
• 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. The pt had received bevacizumab, a monoclonal
antibody capable of inhibiting the activity of VEGF.[1]
• Sorafenib, a multikinase inhibitor, was used in the MX of a 76-year-old man
with a giant cavernous hemangioma measuring >20 cm in diameter. Tumor
volume decreased 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.

32. Radiologic study follow-up
• Once the DX of HH is confirmed by radiologic studies, it remains uncertain
whether follow-up radiologic studies are warranted to reassess the size of the
tumor. In the authors' practices, pts typically undergo USG at 6 months and at
12 mnths after the initial DX. Providing that no change in HH size has occurred,
long-term follow-up radiologic studies are probably not necessary.
• However, there are a number of important exceptions to this practice.
Certainly, pts with a new onset of abdominal pain deserve a follow-up imaging
study.
• The same is true for 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.
MEDSCAPE
Due to its benign course, imaging follow-up is not required for typical haemangioma. EASL

33. Prognosis and Natural History
• The risk that a pt with an asymptomatic HH will develop abdominal pain is
negligible.[1,3] In a series of pts presenting with abdominal pain, pain
disappeared in most pts either after RX of comorbidities or without specific
treatment.
• Pain persisted in two thirds of pts who underwent RX of HH with hepatic
resection, embolization, or artery ligation.[2] The mechanisms for development
of symptoms or pain are unclear but may include expansion of tumor size with
pressure effects on adjacent hepatic parenchyma or Glisson’s capsule.
• In a few cases, symptoms relate to intralesional hemorrhage, localized
thrombosis, or torsion of a pedunculated hemangioma.
• During a follow-up of 3 mnths to 180 mnths, a tiny minority of pts (10%) with a
HH showed a decrease of tumor size, whereas in a similar percentage of pts the
tumor grew in size.[2]
1. Weimann A, et al: Benign liver tumors: differential diagnosis and indication for surgery. World J Surg 21:983–990, 1997.
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.

34. Longitudinal Studies Assessing Changes of
Volume of Hemangiomas During Follow-Up
ZAKIM

35. Hemangioma: Summary
US CT MRI
• Well defined
• Hyperechoic mass (70%)
• Homogenous (60-75%)
• Posterior Enhancement (77%)
• No Doppler flow
Unenhanced
• Hypodense
• Central scar (fibrosis, necrosis)
• Calcifications( phleboliths)
Dynamic
• Peripheal globular enhancement
• Progressive peripheral
enhancement with Centripetal
enhancement
• Further irregular fill-in Late iso or
hyperattenuation
• Homogenous
• Hyperintense on T2
• Hypointense on T1
• Dynamic(=CT)

36. Focal nodular hyperplasia

37. 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.[5,6]
• It is characterized by a strong female predominance (f:m ratio 8 : 1) and
usually occurs between the third and fifth decades [2]. (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.
5. Buetow PC, et al: Focal nodular hyperplasia of the liver: radiologicpathologic correlation. Radiographics 16(2):369–388, 1996.
6. Hussain SM, et al: Focal nodular hyperplasia: findings at state-ofthe-art MR imaging, US, CT, and pathologic analysis. Radiographics 24(1):3–17, discussion 18-19, 2004.

38. Pathogenesis
• FNH appears to be the result of a hyperplastic response of the hepatic
parenchyma, mainly composed of reactive polyclonal proliferating
hepatocytes,[1] to an arterial lesion and/or portal venous malformation.
• The consequent formation and enlargement of arterial to venous
shunts[2] 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.[3,4 ]
• FNH can be a/with other vascular abnormalities, such as hepatic
hemangioma and hereditary hemorrhagic telangiectasia (Rendu-Osler-
Weber disease)[5,6,7] or the congenital absence of the portal vein.
1. Fukukura Y, et al: Angioarchitecture and blood circulation in focal nodular hyperplasia of the liver. J Hepatol 29:470–475, 1998.
2. Wanless IR, et al: The pathogenesis of focal nodular hyperplasia: an hypothesis based on histologic review of 20 lesions including 3 occurring in early biliary cirrhosis. Hepatology 44:491a, 2006.
3. Shaked O, et al: Biologic and clinical features of benign solid and cystic lesions of the liver. Clin Gastroenterol Hepatol 9:547–562,2011.
4. Sato Y, et al: Hepatic stellate cells are activated around central scars of focal nodular hyperplasia of the liver—a potential mechanism of central scar formation. Hum Pathol 40:181–188, 2009.
5. Haber M, et al: Multiple focal nodular hyperplasia of the liver associated with hemihypertrophy and vascular malformations. Gastroenterology 108:1256–1262, 1995.
6. Mathieu D, et al: Association of focal nodular hyperplasia and hepatic hemangioma. Gastroenterology 97:154–157, 1989.
7. Buscarini E, et al: High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia. Ultrasound Med Biol 30:1089–1097, 2004.

39. 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 [1,2].
• 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 [2].
• FNH also demonstrates activation of the TGF-β pathway related to the
fibrous features of the lesions and activation of the WNT/β-catenin
pathway [3].
• 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 [3].
1. Paradis V, Laurent A, Flejou JF, Vidaud M, Bedossa P. Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation. Hepatology 1997;26:891–5.
2. Paradis V, Bieche I, Dargere D, et al. Aquantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia. Gastroenterology 2003;124:651–9.
3. Rebouissou S, Couchy G, Libbrecht L, et al. The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J Hepatol 2008;49:61–71.

40. 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.
• Histologically, FNH is a multinodular mass composed of normal-appearing
hepatocytes [1,2].
• Ductular reaction, dystrophic vessels, and inflammatory infiltrates are usually
identified within the fibrous septa and/or the central scar.
• An important feature for DX is the "map-like" expression of glutamine synthetase
immunostaining[3,4].
• FNH does not contain portal venous supply[5]
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. Bosman FT, World Health Organization, International Agency for Research on Cancer. WHO Classification of Tumours of the Digestive System, 4th edn. Lyon: International Agency for Research on Cancer, 2010:417 pp.
3. Rebouissou S, Bioulac-Sage P, Zucman-Rossi J. Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol 2008;48:163–70.
4. Rebouissou S, Couchy G, Libbrecht L, et al. The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J Hepatol 2008;49:61–71.
5. Baert AL. Focal Liver Lesions, Detection, Characterization, Ablation. Springer. (2010) ISBN:3642084141.

41. Histopathology examination
(A)Gross appearance : the lesion has a
multinodular architecture with a central
fibrous scar (arrow).
(B) At low magnification, the lesion (T) is well
demarcated from the surrounding
parenchyma (NT) (hematein–eosin–saffron, ×20).
(C) Multiple fibrous septa arise from the central
fibrous scar (F) (hematein–eosin–saffron, ×100).
(D)Immunohistochemical staining with an anti-
glutamine synthetase antibody reveals the
typical “map-like” expression pattern in the
tumor (T).
Schiff

42. FNH: Types & Variants
• FNH is divided into two types [1]:
1. Typical/classic: 80%
2. 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.[4]
Variants of Atypical: Some authors also describe division of atypical FNH into several variants
which include [2]:
1. telangiectatic variant: most common
2. mixed hyperplastic and adenomatous variant
3. lesions with large cell hepatocellular atypia
Note: The previously classified atypical/ telangiectatic FNH is now recognized as a subtype of
HCA with the new molecular classification.[3]
1. Lencioni R, Cioni D, Bartolozzi C. Focal liver lesions, detection, characterization, ablation. Springer Verlag. (2005) ISBN:3540644644.
2. Ferlicot S, Kobeiter H, Tran van nhieu J et-al. MRI of atypical focal nodular hyperplasia of the liver: radiology-pathology correlation. AJR Am J Roentgenol. 2004;182 (5): 1227-31.
3. Zucman-Rossi J, et al: Genotype-phenotype correlation in hepatocellular adenoma. New classification and relationship with HCC. Hepatology 43:515–524, 2006.
4. Nguyen BN, Fléjou JF, Terris B, Belghiti J, Degott C. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol.
1999 Dec. 23(12):1441-54.

43. 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 [1].
• Intratumor bleeding may also occur in rare cases.
1. Cherqui D, Rahmouni A, Charlotte F, et al. Management of focal nodular hyperplasia and hepatocellular adenoma in youngwomen: a series of 41 patients with clinical, radiological, and
pathological correlations. Hepatology 1995;22:1674–81.
2. Weimann A, et al: Benign liver tumors: differential diagnosis and indication for surgery. World J Surg 21:983–990, 1997.
3. Nguyen BN, et al: Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol 23:1441–1454, 1999.
2 3

44. Diagnostic Workup
• Diagnostic confirmation can rely solely on imaging findings.
• Serum AFP levels are normal. The mass lesion seen on US and CT is not
specific for FNH [1,2] 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.[3]
• 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.[4]
• The immunohistochemical staining of glutamine synthase may add SN
and SP to the histologic DX whenever a liver biopsy is deemed necessary.
1. Rettenbacher T. Focal liver lesions: Role of contrastenhanced ultrasound. Eur J Radiol 2007; 64:173-82.
2. Heiken J. Distinguishing benign from malignant liver tumours. Cancer Imaging 2007; 7:S1-14.
3. Choi CS, Freeny PC: Triphasic helical CT of hepatic focal nodular hyperplasia: incidence of atypical findings. AJR Am J Roentgenol 170:391–395, 1998.
4. Lencioni R, et al: Magnetic resonance imaging of liver tumors. J Hepatol 40:162–171, 2004.

45. 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 %. [1,2,3]
• Lesion shows a characteristic Doppler vascular pattern, including
hypervascularity, centrifugal arterial flow radiating peripherally from a
central vessel. [4]
1. Uggowitzer MM, Kugler C, Mischinger HJ, et al. Echo-enhanced Doppler sonography of focal nodular hyperplasia of the liver. J Ultrasound Med. 1999 Jul. 18(7):445-51; quiz 453-4.
2. De Gaetano A, De Franco A, Maresca G, et al. [The integrated diagnosis of hepatic focal nodular hyperplasia: echography, color Doppler, computed tomography and magnetic resonance compared]. Radiol Med (Torino). 1996 Mar. 91(3):258-69.
3. Uggowitzer M, Kugler C, Machan L, et al. Power Doppler imaging and evaluation of the resistive index in focal nodular hyperplasia of the liver. Abdom Imaging. 1997 May-Jun. 22(3):268-73.
4. Parulekar G, Bree LR. Liver In: Goldberg BB, McGahan GP eds. Diagnostic Ultrasound: Logical Approach. 2nded. New York: Lippincott Williams & Wilkins 2008:367-368.
5. Kim MJ et al. Evaluation of hepatic focal nodular hyperplasia with contrast-enhanced gray scale harmonic Sonography: initial experience. J Ultasound Med. 2004;23:297-305.
6. Malhi H, Grant EG, Duddalwar V. Contrast-Enhanced Ultrasound of the Liver and Kidney. Radiol. Clin. North Am. 2014;52 (6): 1177-1190. doi:10.1016/j.rcl.2014.07.005
7. X-Q Pei,et al.Quantitative analysis of contrast-enhanced ultrasonography: differentiating focal nodular hyperplasia from hepatocellular carcinoma. Br J Radiol. 2013 Mar; 86(1023): 20120536. doi: 10.1259/bjr.20120536
In general, this typical pattern has
been observed in 74% to 100% of
cases.[5]
In the portal phase the lesion
remains hyperechoic relative to
normal liver tissue, & becomes
isoechoic in the late
phase.[zakim]
The SN and SP of CEUS for diagnosis of FNH were 67.6% and 93.9%, respectively.[7]

46. USG of FNH
Source: http://appliedradiology.com/articles/imaging-focal-nodular-hyperplasia

47. A 35 -year-old woman with a history of oral contraception
presents with right upper quadrant pain.
Caption: B-mode gray scale imaging
Description: Transabdominal ultrasound
shows a mass in the right lobe of the liver.
The mass is isoechoic to the surrounding
liver parenchyma and is causing contour
deformity.
Hepatic Focal Nodular Hyperplasia Author: Danilo Sirigu, MD
Available: https://sonoworld.com/CaseDetails/Hepatic_Focal_Nodular_Hyperplasia.aspx?ModuleCategoryId=1110

48. Caption: Color Doppler
Description: Transverse Color Doppler
ultrasound shows a "central spider" pattern
with multiple vessels radiating peripherally
from the centre of the lesion.
Hepatic Focal Nodular Hyperplasia Author: Danilo Sirigu, MD
Available: https://sonoworld.com/CaseDetails/Hepatic_Focal_Nodular_Hyperplasia.aspx?ModuleCategoryId=1110

49. Caption: Contrast Enhanced Ultrasound
(CEUS)
Description: Transverse arterial phase
image after injection of microbubble
contrast agent (SonoVue) shows small
central enhancement of the lesion with a “
spoke wheel “ appearance. CEUS image in
portal venous phase and late phase shows
persistent positive homogeneous
enhancement with iso-enhancing
appearance.
Hepatic Focal Nodular Hyperplasia Author: Danilo Sirigu, MD
Available: https://sonoworld.com/CaseDetails/Hepatic_Focal_Nodular_Hyperplasia.aspx?ModuleCategoryId=1110

50. Enhancement patterns of FNH and HCC on CEUS
1. X-Q Pei,et al.Quantitative analysis of contrast-enhanced ultrasonography: differentiating focal nodular hyperplasia from hepatocellular carcinoma. Br J Radiol. 2013 Mar; 86(1023): 20120536. doi:
10.1259/bjr.20120536
• In the arterial phase, 21 FNHs (61.8%) showed early complete hyperenhancement,
• 13 FNHs (38.2%) showed centrifugal enhancement with a spoke-wheel artery.
• Hypoenhancing central scars were present in four FNHs (11.8%) in the portal venous phase and/or in the late
phase.
• Centrifugal enhancement or hypoenhancing central scar was not present in any HCC.

51. Imaging: CT features in FNH
• Non Contrast : FNH is usually isoattenuating or slightly hypoattenuating (hyperattenuated in fatty liver)
compared with surrounding liver
• 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.[1]
• In Arterial Phase: FNH shows strong homogeneous enhancement.[2]
• The central scar is typically hypoattenuating.
• In the portal venous and delayed phases, FNH becomes isoattenuating compared with the hepatic
parenchyma.[2]
• On delayed images, the central scar may become hyperattenuating(80%) because of contrast agent distribution
within its fibrous stroma.
• CT features may allow correct characterization of FNH in 78% of cases.
1. Brancatelli G, et al: Focal nodular hyperplasia: CT findings with emphasis on multiphasic helical CT in 78 patients. Radiology 219:61–68, 2001.
2. Shanbhogue AK, et al: Recent advances in cytogenetics and molecular biology of adult hepatocellular tumors: implications for imaging and management. Radiology 258:673–693, 2011.

52. Focal nodular hyperplasia: CT
A, Coronal postcontrast CT image in the arterial phase demonstrating a solid hypervascular hepatic
mass (arrow) with a hypodense central scar.
B, Subsequent delayed postcontrast image showing that the mass (arrow) is now isodense to adjacent
liver apart from delayed enhancement of the central scar (arrowhead).
ZAKIM

53. CT of Focal Nodular Hyperplasia[1]
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
as A shows small early
homogeneously enhancing mass
(arrow) consistent with FNH.
Such stealth lesions are often
invisible on unenhanced CT and
may be detectable only during
arterial-dominant phase of
contrast enhancement.
1. Carlson SK, Johnson CD, Bender CE, Welch TJ. CT of focal nodular hyperplasia of the liver. AJR Am J Roentgenol. 2000 Mar;174(3):705-12.

54. CT of Focal Nodular Hyperplasia[1]
1. Carlson SK, Johnson CD, Bender CE, Welch TJ. CT of focal nodular hyperplasia of the liver. AJR Am J Roentgenol. 2000
Mar;174(3):705-12.

55. 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.[1]
• 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.[1]
• On baseline MRI, however, the mentioned typical features are observed in
only 22% of cases.[2]
1. Bartolozzi C, et al: Focal liver lesions: MR imaging-pathologic correlation. Eur Radiol 11:1374–1388, 2001.
2. Ba-Ssalamah A, et al: Atypical focal nodular hyperplasia of the liver: imaging features of nonspecific and liver-specific MR contrast agents. AJR Am J Roentgenol 179:1447–1456, 2002.

56. MRI features of focal nodular hyperplasia
A.FNH is usually slightly hypointense with respect to normal liver parenchyma on T1-weighted images
B. isointense on T2-weighted images
The hallmark of the lesion, the central stellate scar, is hyperintensity on T2-weighted images,
Source
A. Courtesy of Alain Luciani, CHU Henri Mondor.
B. B. ZAKIM
BA
Lesion Central scar
T1 Slight hypointense/Isointense Hypointense
T2 Isointense/ Slight Hyperintense Hyperintense (75%)

57. 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.[1]
• 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.[1]
1. Grazioli L, et al: Focal nodular hyperplasia: morphologic and functional information from MR imaging with gadobenate dimeglumine. Radiology 221:731–739, 2001.
Phase Lesion
Arterial Hyperintense
Portal Venous Isointense
Delayed Isointense

58. MRI:T1 C+ (Eovist/Primovist) 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.
• In contrast, HCAs and HCCs typically do not show contrast agent retention; FNH
appear hyperintense compared with normal parenchyma on T1-weighted
images.[1]
• Also, the central scar, which does not take up the hepatocyte-targeted agent,
becomes well delineated in up to 90% of cases.[2]
• This approach may allow DX of 90% of the FNHs with atypical features on the
baseline and conventional contrast-enhanced dynamic study.[3]
1. Zech CJ, et al: Diagnostic performance and description of morphological features of focal nodular hyperplasia in Gd-EOBDTPA-enhanced liver magnetic resonance imaging: results of a multicenter trial. Invest Radiol 43:504–511, 2008.
2. Savellano DH, et al: Assessment of sequential enhancement patterns of focal nodular hyperplasia and hepatocellular carcinoma on mangafodipir trisodium enhanced MR imaging. Invest Radiol 39:305–312, 2004.
3. Grazioli L, et al: Focal nodular hyperplasia: morphologic and functional information from MR imaging with gadobenate dimeglumine. Radiology 221:731–739, 2001.
4. Mortelé KJ, Praet M, Van Vlierberghe H, et al. CT and MR imaging findings in focal nodular hyperplasia of the liver: radiologic-pathologic correlation. AJR Am J Roentgenol. 2000; 175(3):687-692.
Compared to CT and US, MRI has higher SN (70%) and SP (98%) for detecting FNH.[4] MRI is also more accurate in detecting the
central scar than CT, with a SN of 78% and 60%, respectively.

59. 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. (cf. adenomas, which are classically hypointense relative to liver on hepatobiliary phase)
ZAKIM
Precontrast Phase Delayed PhaseArterial Phase Delayed hepatobiliary Phase

60. FNH VS HEPATIC ADENOMA
• Purysko et al studied the performance of gadoxetate disodium-enhanced MRI to
evaluate its performance and potential advantages in the characterization of FNH
and HCA of hepatocyte phase imaging in identifying features that distinguish
FNH from HCA.[1]
• The authors concluded that gadoxetate disodium-enhanced MRI has accuracy in
distinguishing FNH and HCA, and the hepatocyte phase improved their
distinction. The authors found that FNH enhances significantly more than HCA
and suggested that an enhancement ratio, in the hepatocyte phase, can be
potentially used to improve diagnostic accuracy.
• Portilha et al also concluded in their study that MRI hepatocyte contrast agents
are a valuable tool for differentiating FNH from hepatic adenoma, based on the
different patterns of uptake and retention of gadoxetic acid.[2]
1. Purysko AS, Remer EM, Coppa CP, Obuchowski NA, Schneider E, Veniero JC. Characteristics and distinguishing features of hepatocellular adenoma and focal nodular hyperplasia on gadoxetate disodium-
enhanced MRI. AJR Am J Roentgenol. 2012 Jan. 198(1):115-23.
2. Portilha MA, Pedro MT, Ruivo C, Semedo LC, Marques C, Alves FC. [Gd-EOB-DTPA-enhanced magnetic resonance imaging: differentiation between focal nodular hyperplasia and hepatocellular adenoma]. Acta
Med Port. 2011 Dec. 24 Suppl 2:531-8.

61. Nuclear imaging:Technectium-99m Sulfur Colloid Scintigraphy
• Technectium-99m sulfur colloid scintigraphy has long been used to characterize
FNH. Up to 80% of these lesions show uptake owing to their Kupffer cell
population.[1]
• Unfortunately, the uptake of sulfur colloid is not highly specific.
• In a series of 20 lesions, sulfur colloid studies were diagnostic in only 16% of
FNHs larger than 3.5 cm and in 14% of lesions smaller than 3.5 cm.[2]
• Tc-99m sulfur colloid uptake in pts with FNH depends on the concentration of
Kupffer cells in the FNH lesion. Unfortunately, other hepatocellular neoplasms,
such as a HCA and HCC, may also have Kupffer cells and demonstrate99m Tc sulfur
colloid uptake.
• Hepatic adenoma, hemangioma, hepatoblastoma, and HCC may be similar in
appearance on99m Tc sulfur colloid scans.
1. Welch TJ, et al: Focal nodular hyperplasia and hepatic adenoma:comparison of angiography, CT, US and scintigraphy. Radiology 156:593–595, 1985.
2. Broglia L, et al: Computerized tomography, magnetic resonance, and nuclear medicine in the non-invasive diagnosis of focal nodular hyperplasia of the liver. Radiol Med 96:218–225, 1998.

62. 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]
1. Buetow PC, et al: Focal nodular hyperplasia of the liver: radiologicpathologic correlation. Radiographics 16(2):369–388, 1996.
2. Grazioli L, et al: Hepatic adenomas: imaging and pathologic findings. Radiographics 21(4):877–892, discussion 892-894, 2001.

63. 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.
1. Blachar A, et al: Radiologists’ performance in the diagnosis of liver tumors with central scars by using specific CT criteria. Radiology 223(2):532–539, 2002.
2. 30. McLarney JK, et al: Fibrolamellar carcinoma of the liver: radiologicpathologic correlation. Radiographics 19(2):453–471, 1999.

64. Summary of MRI Features
ZAKIM

65. Associated Conditions
• The syndrome of multiple FNH is the presence of FNH, hepatic hemangiomas, and
disorders of the CNS such as meningioma, astrocytoma, and arterial malformations.
• This syndrome has been described in a/with Klippel-Trénaunay-Weber syndrome, a
nonhereditary congenital condition characterized by capillary malformations,
hemihypertrophy, and venous stasis.[1]
1. Haber M, et al: Multiple focal nodular hyperplasia of the liver associated with hemihypertrophy and vascular malformations. Gastroenterology 108:1256–1262, 1995.
2. Mathieu D, et al: Association of focal nodular hyperplasia and hepatic hemangioma. Gastroenterology 97:154–157, 1989.
3. Buscarini E, et al: High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia. Ultrasound Med Biol 30:1089–1097, 2004.
Src: https://www.omicsonline.org
• FNH can be a/with other vascular
abnormalities, such as hepatic hemangioma
and hereditary hemorrhagic telangiectasia
(Rendu-Osler-Weber disease)[1,2,3] or the
congenital absence of the portal vein.
• The association between FNH and
fibrolamellar carcinoma is disputed.
Src: http://www.dermis.net/dermisroot/en/50133/image.htm

66. Associations and Complications of FNH
SLEISENGER

67. FNH & Other associations
• 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]
• The role of oral contraceptives in FNH is disputed.
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.

68. FNH and Pregnancy
• 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.
• An MRI should be obtained to confirm a DX of FNH.
• A liver biopsy is not routinely indicated to confirm the diagnosis.
• Asymptomatic FNH does not require intervention.
ZAKIM

69. 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.[6]
• 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.
• In recent reports the size of the lesions did not increase during oral contraceptive use
and pregnancy[3] nor did it increase in pts receiving immunosuppressive therapy.[4]
• The risk of bleeding of FNH seems remote,[5] and neoplastic transformation has never
been reported.
• In a few pts, FNH has been reported to progress to develop clinically important
symptoms.[5] 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%)[2].
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. Mathieu D, et al: Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 118:560–564, 2000.
4. Tan M, et al: Successful outcome after transplantation of a donor liver with focal nodular hyperplasia. Liver Transpl 7:652–655,2001.
5. Sadowski DC, et al: Progressive type of focal nodular hyperplasia characterized by multiple tumors and recurrence. Hepatology 61:210–214, 1995.
6. Kuo Y-H, Wang J-H, Lu S-N, et al. Natural course of hepatic focal nodular hyperplasia: A long-term follow-up study with sonography. J Clin Ultrasound 2009;37:132-7.

70. 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. (Sleisenger)
• 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.[2,3,4]
1. Terkivatan T, et al: Indications and long-term outcome of treatment for benign hepatic tumors: a critical appraisal. Arch Surg 136:1033–1038, 2001.
2. Charny CK, et al: Management of 155 patients with benign liver tumours. Br J Surg 88:808–813, 2001.
3. Amesur N, et al: Management of unresectable symptomatic focal nodular hyperplasia with arterial embolization. J Vasc Interv Radiol 20:543–547, 2009.
4. Hedayati P, et al: Treatment of symptomatic focal nodular hyperplasia with percutaneous radiofrequency ablation. J Vasc Interv Radiol 21:582–585, 2010.
5. European Association for the Study of the Liver. EASLClinical Practice Guidelines on the management of benign liver tumours. J Hepatol 2016;65:386–98.

71. FNH: Imaging Summary
US CT MRI
• Homogenous
• Mostly isoechoic
• Echogenic central scar (20 %)
• Doppler: centrifugal arterial flow
radiating peripherally from a
central vessel
CEUS
AP: Enhance relative to background
liver
• Prominent feeding vessel with
spoke wheel pattern
PV: Centrifugal fill (opposite to
hemangioma)
• Sustained enhancement (opposite
to adenoma)
• Unenhanced scar may be present
Unenhanced
• Isoattenuating or slightly
hypoattenuating
(hyperattenuated in fatty liver)
Dynamic
AP: Homogenous enhancement
• Centralscar : Hypoattenating
PV & DP: Isoattenuating
• Capsule like peripheral
vascularity
• Central scar may be
hyperattenuating
• T1:SLight Hypointense or hypointense
with hyperintense central scar
• T2: Isointense or slight hyperintense
with hypointense central scar
Gadolinium enhanced MRI
• AP: homogeneous enhancement
,sparing the central scar
• PV & DP: Isointense
Gadoxetate MRI
• AP: uniform hyperenhancement, apart
from central scar.
• Enhancement persists into DP due to
the presence of normal hepatocytes
and abnormal bile ductules
• HBP :typical retention of contrast with a
hypointense central scar. (cf. adenomas,
which are classically hypointense
relative to liver on hepatobiliary phase)

72. Nodular regenerative
hyperplasia

73. Nodular regenerative hyperplasia
• NRH was first described as “miliary hepatocellular adenomatatosis” by Ranstrom in
1953[3] in a pt with RA, neutropenia, and splenomegaly (Felty’s syndrome). This
lesion was subsequently termed nodular regenerative hyperplasia by Steiner.[4]
• NRH,, is an uncommon condition of the liver defined by the diffuse transformation of
the parenchyma into regenerative nodules without significant fibrosis.
• It is not a true tumor but may result in a nodular appearance of the liver commonly
seen at the hepatic hilum . The disease affects pts predominantly >60 yrs and pts with
PHTN or portal vein thrombosis.[1]
• In a large study of more than 2000 consecutive autopsies, Wanless observed that
NRH was present in 2.6% of cases without sex disparity.[2]
• Considered to be a consequence of abnormal hepatic blood flow, NRH may be a/with treatment for a wide variety of
diseases, such as rheumatological (RA, SLE, antiphospholid syndrome, etc.) or hematological (PV, SCA, HL, etc.)
disorders, or congenital vascular abnormalities. It has also been reported after treatment with various drugs, such as
immunosuppressive or anticancer agents.
SCHIFF
1. Nakanuma Y: Nodular regenerative hyperplasia of the liver: retrospective survey in autopsy series. J Clin Gastroenterol 12:46–50, 1990.
2. Wanless IR: Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules.
Hepatology 11:787–797, 1990.
3. Ranstrom S. Miliary hepatocellular adenomatosis. Acta Pathol Microbiol Scand 1953;33:225-229.
4. Steiner PE. Nodular regenerative hyperplasia of the liver. Am J Pathol 1959;35:943-953.

74. NRH: CLINICAL PRESENTATION
• The clinical presentation of NRH is heterogeneous and may range from asymptomatic
to end-stage liver disease.
• NRH is usually an underdiagnosed cause of non-cirrhotic portal hypertension.
• The disease is usually asymptomatic, slowly or non-progressive unless complications
of PHTN develop.
• Pt can present with f/of PHTN, such as ascites, splenomegaly, hepatomegaly, and
EV.[2,3] Portal hypertension with VH and ascites may develop in 5% to 13% of pts.[2]
• Hepatomegaly and splenomegaly occur in <half of pts with NRH.[1]
NRH has been defined as a secondary and nonspecific tissue adaptation to heterogeneous distribution of blood flow,
occurring as part of a spectrum of architectural changes known as nodular transformation.[2]
1. Nakanuma Y: Nodular regenerative hyperplasia of the liver: retrospective survey in autopsy series. J Clin Gastroenterol 12:46–50, 1990.
2. Wanless IR: Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology
11:787–797, 1990.
3. Nakanuma Y: Nodular regenerative hyperplasia of the liver: retrospective survey in autopsy series. J Clin Gastroenterol 12:460–465, 1990.

75. NRH: DIAGNOSIS
• The lesions are routinely too small to be identified radiographically and, when
visualized, too difficult to distinguish from the regenerating nodules of
cirrhosis.
• A liver biopsy may allow diagnosis of NRH. However, because NRH, incomplete
cirrhosis, and complete cirrhosis may occur in different regions of the same
liver, large quantities of liver tissue have to be examined for complete DX.[1]
• Three histologic criteria help to distinguish NRH from cirrhosis:
1. Nodules of regenerative hepatocytes separated by atrophic parenchyma
2. Absence of fibrous septa between nodules
3. Curvilinear compression of the central lobule.[2,3,4]
1. Wanless IR: Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology
11:787–797, 1990.
2. Biecker E, et al: Portal hypertension and nodular regenerative hyperplasia in a patient with celiac disease. Z Gastroenterol 44:395–398, 2006.
3. Ferlitsch A, et al: 6-Thioguanine associated nodular regenerative hyperplasia in patients with inflammatory bowel disease may induce portal hypertension. Am J Gastroenterol 102:2495–2503, 2007.
4. Trotter JF, Everson GT: Benign focal lesions of the liver. Clin Liver Dis 5:17–42, 2001.

76. Nodular regenerative hyperplasia
• While the initial RX is to address the underlying disease, ultimately the
therapy is directed to the management of PHTN.
• It is not known whether NRH is a reversible process once the presumed
cause is removed, such as might occur with stopping a drug.
• The natural course is unclear and the prognosis of NRH depends on both
the severity of the underlying illness and the prevention of secondary
complications of portal hypertension.
• Three pts presenting with progressive liver failure from NRH underwent
LT, and in at least one of these patients NRH recurred after transplant.[1]
1. Loinaz C, et al: Orthotopic liver transplantation in 4 patients with portal hypertension and non-cirrhotic nodular liver. Hepatogastroenterology 45:1787–1794, 1998.

77. NRH FNH HCA
Location/distribution
of nodules
Numerous;diffuse Usually single Usually single
Typical size of nodules 1-3 mm <5 cm 3-15 cm
Histology Presence of nodules <3 mm in
diameter Without surrounding
fibrosis
Normal-appearing
hepatocytes; dense central
stellate scar with radiating
septa; proliferating bile
ductules
Large plates of
normal-appearing
hepatocytes; dilated
sinusoids; no true capsule;
no bile ductules
Fibrosis Absent to minimal
Perisinusoidal fibrosis
Present in septae
of central scar; remainder
of liver normal
Absent to minimal
Portal hypertension May be present None None
Imaging
characteristics
CT: may be normal or have
diffuse nodularity in
Heterogeneous hepatic
parenchyma; may see evidence
of PHTN
CT/MRI: central feeding
artery with enhancement
in arterial phase; rapid
washout and isointensity to
liver in delayed imaging
CT: heterogeneous nodule
due to necrosis, fat,
hemorrhage; early arterial
enhancement

78. Macronodules developing on cirrhosis
• Cirrhosis is the ultimate stage of CLD, and is defined as the diffuse
destruction of the liver’s normal architecture, with the development of
regenerative nodules completely surrounded by fibrous septa [1].
• Cirrhosis is a major RF for HCC, and malignant transformation is
considered to be a multistep process that involves preneoplastic lesions
i.e macronodules (MN) [2,,3,4].
• MN are cirrhotic nodules that they can be single or multiple and are
usually >10mm in diameter.
SCHIFF
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. Bosman FT, World Health Organization, International Agency for Research on Cancer. WHO Classification of Tumours of the Digestive System, 4th edn. Lyon: International Agency for Research on Cancer, 2010:417 pp.
3. International Consensus Group for Hepatocellular NeoplasiaThe International Consensus Group for Hepatocellular N. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.
Hepatology 2009;49:658–64.
4. Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis. Liver Int 2005;25:16–27.

79. • The preneoplastic nature of MN is supported by pathological, and
molecular evidence [1-5].
• Kobayashi and collaborators followed a cohort of pts with histologically
proven regenerative MN, LGDN, and HGDN and observed that the risk of
malignant transformation increased progressively from regenerative MN
to HGDN [4].
• It has been shown that the frequency of TERT promoter
mutations, the most frequent molecular alteration in HCC,
rapidly ↑ during the different steps of the transformation of
MN into HCC [1].
• The main function of the TERT enzyme is to maintain
telomere length and its expression allows preneoplastic or
neoplastic cells to overcome replicative senescence [6].
1. Nault JC, Calderaro J, Di Tommaso L, et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 2014;60:1983–92.
2. Oh BK, Jo Chae K, Park C, et al. Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis. J Hepatol 2003;39:786–92.
3. Oh BK, Kim YJ, Park YN, et al. Quantitative assessment of hTERT mRNA expression in dysplastic nodules of HBV-related hepatocarcinogenesis. Am J Gastroenterol 2006;101:831–8.
4. Kobayashi M, Ikeda K, Hosaka T, et al. Dysplastic nodules frequently develop into hepatocellular carcinoma in patients with chronic viral hepatitis and cirrhosis. Cancer 2006;106:636–47.
5. Tornillo L, Carafa V, Sauter G, et al. Chromosomal alterations in hepatocellular nodules by comparative genomic hybridization: highgrade dysplastic nodules represent early stages of hepatocellular carcinoma. Lab Invest 2002;82:547–53.
6. Harley CB, Kim NW, Prowse KR, et al. Telomerase, cell immortality,and cancer. Cold Spring Harb Symp Quant Biol 1994;59:307–15.

80. Dysplastic foci
• Dysplastic foci are uniform foci <1 mm that exhibit cellular atypia but do not
fulfill the criteria for malignancy.
There are two types of dysplastic foci:
1. Small cell dysplastic foci
2. Large cell dysplastic foci
• Although both are considered to be premalignant lesions, large cell dysplastic
foci are more likely to progress to HCC.
Small cell dysplastic foci Large cell dysplastic foci
SCDF contain hepatocytes with ↑ nuclear/cytoplasmic
ratio and have low rates of apoptosis.
LCDF have enlargement of both the nucleus and the
cytoplasm, with a preserved nuclear/cytoplasmic ratio.
They have more abnormal DNA than SCDF but have
higher rates of apoptotic activity.

81. LGDN HGDN EARLY HCC (WD)
Minimal atypia
Slight ↑ in cellular density upto 2 cells
thick.
Very rare unpaired arteries.
No Stromal invasion & pseudo-
glandular formations.
No mitotic figures
Not expressed: GPC3, GS, and HSP70
↑ nuclear to cytoplasmic ratio
Trabeculae more than two cells thick,
Unpaired arteries occurring outside
the portal tracts,
No Stromal invasion
Occasional Mitotic figures
Expression of one of the
immunohistochemical markers .
↑↑ nuclear to cytoplasmic ratio,
Increased cellular density and
Unpaired arteries are commonly
observed.
With or without stromal invasion
Expression of at least two
immunohistochemical markers is
observed in about 2/3RD of the cases .
• Dysplastic nodules are lesions >1 mm that are typically found in cirrhotic livers.
• Patients with high-grade dysplastic nodules have a 4X higher risk of HCC than those without them.186
• Staining with CK7/19 can highlight a ductular reaction that is present only in dysplastic nodules.
• CD34 is another stain that can help differentiate high-grade dysplastic nodules from HCC. In dysplastic nodules, CD34
is seen in the periphery, whereas in HCC staining it is seen diffusely throughout the specimen.187
• All three markers are present in HCC, and a study showed that with a cutoff of two of three markers, achieve a
sensitivity of 72% and specificity of 100% for detection of malignancy.188

82. Imaging
• Detection and accurate staging of MN by imaging is challenging due to nonspecific and overlapping
features .
• On CEUS, MN are typically hypo- or isovascular compared to the
surrounding parenchyma during the arterial phase and isoechoic during
the following phases.
• DD between dysplastic nodules (LGDN and HGDN) and early HCC is most often challenging, as these
lesions very often display the same US features.
• A nodule in nodule pattern (focal enhancement in the arterial phase
within a hypovascular nodule) is rarely observed but favors a diagnosis
of early HCC.
• Sensitivity of CT scan for detection of MN is reported as low.

83. MRI
• Dysplastic nodules are both detected and characterized better with MRI
than CT scan.
• LGDN and HGDN are usually hyperintense on T1-weighted sequences
and hypo- or isointense on T2-weighted sequences [1].
• Accumulating evidence supports that detection of MN may be enhanced
by the use of gadoxetic acid: a finding of a hypointense nodule >1 cm on
hepatobiliary phase MRI in a cirrhotic liver is suggestive of a dysplastic
nodule or an early HCC.
• This may be related to a decrease in the expression of organic anionic transporting polypeptide 8, the transporter responsible
for gadoxetic acid uptake, during the early steps of hepatocarcinogenesis [2].
1. Choi BI, Lee JM, Kim TK, Burgio MD, Vilgrain V. Diagnosing borderline hepatic nodules in hepatocarcinogenesis: imaging performance. AJR Am J Roentgenol 2015;205:10–21.
2. Kitao A, Matsui O, Yoneda N, et al. The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging. Eur Radiol
2011;21:2056–66.

84. Focal fatty change
• Steatosis is a diffuse process that involves the whole liver; however, a
localized, tumor-like form designated as focal fatty change is now well
recognized [1].
• It has been a/with obesity, DM, alcohol intake, malnutrition, parenteral nutrition,
chemotherapy, corticosteroid treatment, and acquired immunodeficiency syndrome
[2-6].
• The imaging criterion for focal fatty infiltration of the liver on CT was a
geometric or ovoid low-attenuation area adjacent to the falciform ligament,
gallbladder fossa, or porta hepatis.
• A retrospective review of 305 consecutive CECT scans found the overall prevalence of
9.2%, 80% described as geometric and 20% as ovoid.[7] The prevalence increased
dramatically with age in this series, with 0% up to 4 years of age, 7.3% from 5–9 years
of age, 10.2% from 10–14 years of age, and 25.6% from 15–19 years of age.
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. BakerME, Silverman PM. Nodular focal fatty infiltration of the liver: CT appearance. AJR Am J Roentgenol 1985;145:79–80.
3. Dioguardi Burgio M, Bruno O, Agnello F, et al. The cheating liver: imaging of focal steatosis and fatty sparing. Expert Rev Gastroenterol Hepatol 2016;10:671–8.
4. Dohan A, Eveno C, Soyer P, PocardM. Focal fatty infiltration in Segment IV of the liver mimicking peritoneal carcinomatosis on CT and MR imaging. J Visc Surg 2014;151:319–21.
5. Fukukura Y, Fujiyoshi F, Inoue H, et al. Focal fatty infiltration in the posterior aspect of hepatic segment IV: relationship to pancreaticoduodenal venous drainage. Am J Gastroenterol 2000;95:3590–5.
6. Hamer OW, Aguirre DA, Casola G, et al. Fatty liver: imaging patterns and pitfalls. Radiographics 2006;26:1637–53.
7. Kammen BF, Pacharn P, Thoeni RF, et al. Focal fatty infiltration of the liver: analysis of prevalence and CT findings in children and young adults. AJR Am J Roentgenol. 2001;177:1035–1039.

85. Etiology of FHC
• Its pathogenesis is unknown but it is thought to be related to variations in
vascular supply.
• Vascular supply to the liver other than the PV or HA is one of the
mechanisms that has been proposed to account for this finding (as well as for
the finding of focal areas of fatty sparing among a diffusely steatotic liver).[1,2]
• This vascular supply may consist of either aberrant or normal veins that enter
the liver directly, independent of the portal venous system. These veins may
communicate with intrahepatic portal branches to various degrees, producing
focal variation in portal venous perfusion, and may contribute to focal
metabolic changes that manifest as hepatic steatosis.
• Three venous systems that have been recognized to produce FFC are the
cholecystic veins, the epigastric-periumbilical venous system, and the
parabiliary venous system.[2]
1. Battaglia DM, Wanless IR, Brady AP, et al. Intrahepatic sequestered segment of liver presenting as focal fatty change. Am J Gastroenterol. 1995;90:2238–2239.
2. Yoshimitsu K, Honda H, Kuroiwa T, et al. Unusual hemodynamics and pseudolesions of the noncirrhotic liver at CT. Radiographics. 2001;21(spec no):S81–S96.

86. FFC: Imaging
• On US, FFC usually appears as an illdefined, hyper echogenic area.
• CT scan shows a hypodense area without mass effect.
• When diagnosis is less than certain, MRI is the imaging modality of
choice and shows an increased T1 signal and signal dropout on out of
phase imaging.
A, CECT scan during PV phase of enhancement shows small ovoid low-density lesion
(arrow) in medial segment of left lobe of liver adjacent to falciform ligament.
B, Delayed CT image at same level shows persistence of lesion (arrow) described in A.
Bamidele F. Kammen. Focal Fatty Infiltration of the Liver Analysis of Prevalence and CT Findings in Children and Young Adults. American Journal of
Roentgenology. 2001;177: 1035-1039. 10.2214/ajr.177.5.1771035
• Biopsy may be performed but is not
always required. It shows
hepatocytes with macrovacuolar
steatosis and no cellular atypia.

87. END OF SLIDES
References:
• Schiff’s Diseases of the Liver 12th ed 2018
• Zakim and Boyer’s Hepatology:A Textbook of Liver Disease 7th ed 2018
• Sherlock's Diseases of the Liver and Biliary System, 12th Edition
• Sleisenger 10 thed
• Uptodate 21.6
• Medscape