Tools
Focal Nodular Hyperplasia
Introduction
The liver is the only self-regenerative internal organ in the human body. This regenerative capability places the liver at risk of developing atypical masses. While most liver masses present as predominantly solid or cystic, the etiologies are broad. In 1958, pathologist Hugh Edmondson, MD, first described focal nodular hyperplasia (FNH) as a solid, benign hepatic mass of non-vascular origin. Unlike the most common liver mass, the hemangioma, FNH is thought to result from increased hepatocyte number caused by hypoperfusion or hyperperfusion from anomalous arteries within the hepatic lobule.[1] FNH is often confounded by comorbid conditions, making establishing a diagnosis and management difficult.
Previously, FNH was referred to by various synonyms, including pedunculated adenoma, solitary hyperplastic nodule, focal cirrhosis, and hepatic hamartoma. Because of the indeterminate classification, a standard diagnosis needed to be established. In 1994, the International Working Party of the World Congresses of Gastroenterology standardized the diagnosis term as follicular nodular hyperplasia and categorized it as a regenerative liver nodule. After that, follicular nodular hyperplasia was distinguished from neoplastic hepatic conditions.[2]
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
The etiology of FNH has not been definitively established. However, it is thought to be caused by arterial malformations within the liver. These malformations and changes in perfusion cause a regenerative, hyperplastic response of the normal hepatocyte. Interestingly, hepatocytes may respond with hyperplasia after both hypoperfusion and hyperperfusion.[3] Therefore, any comorbid condition that causes a predisposition to the development of arterial malformations may increase the risk of FNH. Hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu syndrome, can cause an increased incidence of FNH. The incidence of FNH also increases in the presence of hemangiomas.[3]
Further complicating the delineation of any exact cause is that FNH may develop without comorbid vascular malformation. The research does not reveal a clear reason why this is the case. This may be due to an inadequate biopsy or structural malformations, confounding histological examination and imaging. Other leading gastroenterology researchers believe intermittent blood flow disruptions within the hepatic lobule lead to the characteristic cellular response. Arguably, the cornerstone distinction that differentiates FNH from other hepatic masses is its origin. A series of studies showed that most hepatocytes within an FNH nodule stem from a polyclonal origin.[4] Because of this, it has been classified as a benign condition. One study demonstrated an increased incidence of FNH among monozygotic twins, which indicates a possible genetic component.[5] However, a genetic mutation responsible for predisposing individuals to FNH has not yet been identified.
Epidemiology
In adults, the most common benign hepatic lesion is hemangioma. However, FNH is the second most common, accounting for approximately 8% of all non-hemangiomatous liver lesions. FNH can present as early as childhood; however, it disproportionately affects women more than men at a ratio of approximately 8 to 1.[6] The incidence of FNH is increased in females aged 20 to 50, further suggesting that the condition may be linked to increased estrogen. In recent literature, oral contraceptives as a cause of the development of FNH have not been proven. However, women who are on a daily oral contraceptive regimen display larger nodules than women who are not taking oral estrogen-based contraception.[7] Additionally, females, regardless of oral contraceptive use, have been shown to have larger nodules than men.[8]
FNH has rarely presented in children. Most pediatric cases have been reported in patients with a history of chemotherapy, malignancy, or hematopoietic stem cell therapy. However, Baylor University Medical Center reported a case of FNH in a healthy 3-year-old female with no pertinent past medical history. In this instance, the patient underwent surgical resection of a palpable abdominal mass for what oncologists believed to be a hepatic malignancy. After histological evaluation, it was determined that this patient had FNH.[9]
Histopathology
Most patients with focal nodular hyperplastic lesions present with solitary lesions between 4 and 8 centimeters. Only 3% of cases reach a diameter greater than 10 cm. The hallmark feature of FNH, evident grossly, is known as a "central scar." Histologically, the central scar consists of mature collagen surrounded by aberrant arteries, draining veins, and fibrous septae forming a pseudo capsule distinguishing it from hepatocellular carcinoma, hepatocellular adenomas, and fibrolamellar hepatocellular carcinoma. Because of this, a biopsy of the central scar is essential in determining diagnosis and ruling out malignant causes. Focal nodular hyperplastic lesions may also contain bile ducts and reticuloendothelial hepatic macrophages, also known as Kuppfer cells. Additionally, these lesions lack the calcifications commonly seen in hepatic adenomas. Cytologically, these hepatocytes from focal nodular hyperplastic lesions are unremarkable, reaffirming benign origin.[10] Suppose a biopsy sample lacks a “central scar,” bile duct canals, or calcifications that would aid in the differentiation between hepatic adenomas and FNH. In that case, immunohistochemical stainings may aid in establishing a diagnosis. FNH displays an increased expression of glutamine synthetase located in the periphery of the nodules, which may be stained and identified.[11]
History and Physical
FNH is most often discovered incidentally after imaging for an unrelated abdominal complaint.[12] Even though it is usually asymptomatic, it may present as a palpable abdominal mass that is more likely to be tender when the lesion’s diameter exceeds 10 centimeters. As focal hyperplastic nodules are solitary lesions, hepatomegaly is uncommon. Spontaneous rupture has occurred but is extremely rare.[13]
Evaluation
Diagnosis of FNH consists of biopsy or imaging consistent with the characteristics of FNH and exclusion of other similar lesions. Lab work is largely unremarkable in the FNH setting.[14] Alpha-fetoprotein levels are generally within reference ranges, further supporting the benign clinical course associated with FNH. Additionally, serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase (GGT) levels may display minor elevations. Still, these may be confounded by comorbid conditions as they are rarely elevated in the sole presence of FNH.[15] Ultrasonography is often the first imaging modality to evaluate liver lesions, including FNH. Still, it lacks an appropriate sensitivity (20%) to be utilized as the gold standard imaging modality. FNH often appears as an isoechoic or hypoechoic mass with a hyperechoic central scar relative to the liver parenchyma.[16] Contrast-enhanced ultrasonography has been utilized outside the United States, with some reports indicating that FNH and hepatocellular adenoma can be distinguished with the advent of early arterial phase imaging, which reveals arterial morphology and filling direction.[17][18]
Although not the gold standard imaging modality, triphasic helical computed tomography with and without contrast is a cheap and reliable imaging modality. Pre-contrast, FNH appears hypodense or isodense, with a central scar evident in approximately one-third of cases. FNH appears hyperdense during the hepatic arterial phase and isodense during the portal venous phase, rendering the lesion indistinguishable from the rest of the liver parenchyma.[19] With magnetic resonance imaging, focal nodular hyperplastic lesions appear isointense to hypointense lesions on T1-weighted images and isointense to hyperintense on T2-weighted images. Like CT imaging, the lesion is enhanced in arterial phase images and relatively obfuscated in venous and delayed phase images. Sensitivity and specificity of 99% and 100% may be achieved with hepatobiliary contrast media by administering gadobenate dimeglumine. Thus, MRI with hepatobiliary scintigraphy is the best test to diagnose FNH.[20][21]
Treatment / Management
Given the inherent procedural risks associated with percutaneous biopsy and surgical resection and the indolent nature of FNH, close observation is recommended with serial imaging every 3 to 6 months. However, biopsy or resection is often pursued if a patient is symptomatic, if there is a concern for underlying malignancy after an inconclusive biopsy, or if a lesion displays continued growth. The definitive therapy remains surgical resection.[22] FNH was first described in the 1960s before the widespread use of oral contraceptive pills. Since then, there has been no proven increase in the incidence of FNH with the use of estrogens. However, almost all documented cases of hemorrhage or rupture have occurred in patients taking oral contraceptives. While discontinuation of oral contraceptives is not necessarily indicated, follow-up imaging is advised for any patient on estrogen therapy to monitor for growth. A thorough examination of the patient’s risk factors for underlying malignancy or liver disease is warranted in the pediatric population.[23]
Differential Diagnosis
The differential diagnosis for focal nodular hyperplasia include the following:
- Hepatic adenoma
- Hepatocellular carcinoma
- Fibrolamellar hepatocellular carcinoma
- Hemangioma
- Idiopathic noncirrhotic portal hypertension
- Regenerative nodules
- Metastatic disease
Enhancing Healthcare Team Outcomes
One of the hallmark mantras of medicine is not to harm. Given the inherent risk of surgical instrumentation of the liver, it is ethically questionable to perform a risky procedure such as resection of liver nodules if the benefits do not outweigh the risks.[24] A comprehensive patient evaluation by physicians, nurses, pharmacists, and other healthcare professionals is necessary to avoid unnecessary risk. Oral contraceptive pills and obesity contribute to a patient's estrogen load, and thus, a patient may benefit from a modification of their lifestyle in addition to cessation of offending medications. A patient-centered approach by a team of healthcare professionals may slow the progression of a liver nodule and decrease the risk of necessitating surgical intervention.
References
Lizardi-Cervera J, Cuéllar-Gamboa L, Motola-Kuba D. Focal nodular hyperplasia and hepatic adenoma: a review. Annals of hepatology. 2006 Jul-Sep:5(3):206-11 [PubMed PMID: 17060885]
Nat L, Poantă LI. Focal nodular hyperplasia (FNH). Romanian journal of internal medicine = Revue roumaine de medecine interne. 2014 Jan-Mar:52(1):45-9 [PubMed PMID: 25000678]
Level 3 (low-level) evidenceHerman P, Pugliese V, Machado MA, Montagnini AL, Salem MZ, Bacchella T, D'Albuquerque LA, Saad WA, Machado MC, Pinotti HW. Hepatic adenoma and focal nodular hyperplasia: differential diagnosis and treatment. World journal of surgery. 2000 Mar:24(3):372-6 [PubMed PMID: 10658075]
Koehne de Gonzalez AK,Salomao MA,Lagana SM, Current concepts in the immunohistochemical evaluation of liver tumors. World journal of hepatology. 2015 Jun 8 [PubMed PMID: 26052385]
Mindikoglu AL, Regev A, Levi JU, Casillas J, Schiff ER. Focal nodular hyperplasia in identical twins. The American journal of gastroenterology. 2005 Jul:100(7):1616-9 [PubMed PMID: 15984990]
Level 3 (low-level) evidenceNaganuma H, Ishida H, Ogawa M, Watanabe Y, Watanabe D, Ohyama Y, Watanabe T. Focal nodular hyperplasia: our experience of 53 Japanese cases. Journal of medical ultrasonics (2001). 2017 Jan:44(1):79-88. doi: 10.1007/s10396-016-0734-9. Epub 2016 Aug 22 [PubMed PMID: 27550510]
Level 3 (low-level) evidenceKubota T, Shimizu K, Sonoyama T, Ikeda E, Kurioka H, Ouchi T, Suyama Y, Hosokawa Y, Yamagishi H. Enlarged focal nodular hyperplasia of the liver under the influence of oral contraceptives. Hepato-gastroenterology. 2001 Nov-Dec:48(42):1736-9 [PubMed PMID: 11813612]
Level 3 (low-level) evidenceTuraihi HH,Thambi-Pillai TC,Binneboese A, Hepatic Adenoma - A Case Report. South Dakota medicine : the journal of the South Dakota State Medical Association. 2017 Mar [PubMed PMID: 28813771]
Level 3 (low-level) evidenceKoolwal J, Birkemeier KL, Zreik RT, Mattix KD. Pedunculated focal nodular hyperplasia in a healthy toddler. Proceedings (Baylor University. Medical Center). 2018 Jan:31(1):97-99. doi: 10.1080/08998280.2017.1401845. Epub 2018 Jan 11 [PubMed PMID: 29686569]
Valentino PL, Ling SC, Ng VL, John P, Bonasoni P, Castro DA, Taylor G, Chavhan GB, Kamath BM. The role of diagnostic imaging and liver biopsy in the diagnosis of focal nodular hyperplasia in children. Liver international : official journal of the International Association for the Study of the Liver. 2014 Feb:34(2):227-34. doi: 10.1111/liv.12241. Epub 2013 Jul 7 [PubMed PMID: 23829376]
Level 2 (mid-level) evidenceJoseph NM, Ferrell LD, Jain D, Torbenson MS, Wu TT, Yeh MM, Kakar S. Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2014 Jan:27(1):62-72. doi: 10.1038/modpathol.2013.114. Epub 2013 Jun 28 [PubMed PMID: 23807780]
Cristiano A,Dietrich A,Spina JC,Ardiles V,de Santibañes E, Focal nodular hyperplasia and hepatic adenoma: current diagnosis and management. Updates in surgery. 2014 Mar [PubMed PMID: 23807711]
Ashby PF, Alfafara C, Amini A, Amini R. Spontaneous Rupture of a Hepatic Adenoma: Diagnostic Nuances and the Necessity of Followup. Cureus. 2017 Dec 20:9(12):e1975. doi: 10.7759/cureus.1975. Epub 2017 Dec 20 [PubMed PMID: 29492364]
Roncalli M, Sciarra A, Tommaso LD. Benign hepatocellular nodules of healthy liver: focal nodular hyperplasia and hepatocellular adenoma. Clinical and molecular hepatology. 2016 Jun:22(2):199-211. doi: 10.3350/cmh.2016.0101. Epub 2016 May 18 [PubMed PMID: 27189732]
Mneimneh W, Farges O, Bedossa P, Belghiti J, Paradis V. High serum level of alpha-fetoprotein in focal nodular hyperplasia of the liver. Pathology international. 2011 Aug:61(8):491-4. doi: 10.1111/j.1440-1827.2011.02691.x. Epub 2011 Jul 21 [PubMed PMID: 21790865]
Level 3 (low-level) evidenceD'Onofrio M, Crosara S, De Robertis R, Canestrini S, Mucelli RP. Contrast-Enhanced Ultrasound of Focal Liver Lesions. AJR. American journal of roentgenology. 2015 Jul:205(1):W56-66. doi: 10.2214/AJR.14.14203. Epub [PubMed PMID: 26102419]
Kong WT, Wang WP, Huang BJ, Ding H, Mao F, Si Q. Contrast-enhanced ultrasound in combination with color Doppler ultrasound can improve the diagnostic performance of focal nodular hyperplasia and hepatocellular adenoma. Ultrasound in medicine & biology. 2015 Apr:41(4):944-51. doi: 10.1016/j.ultrasmedbio.2014.11.012. Epub 2015 Feb 17 [PubMed PMID: 25701530]
Pei XQ, Liu LZ, Xiong YH, Zou RH, Chen MS, Li AH, Cai MY. Quantitative analysis of contrast-enhanced ultrasonography: differentiating focal nodular hyperplasia from hepatocellular carcinoma. The British journal of radiology. 2013 Mar:86(1023):20120536. doi: 10.1259/bjr.20120536. Epub 2013 Feb 7 [PubMed PMID: 23392189]
Level 2 (mid-level) evidenceScialpi M, Pierotti L, Gravante S, Piscioli I, Pusiol T, Schiavone R, D'Andrea A. Split-bolus versus triphasic multidetector-row computed tomography technique in the diagnosis of hepatic focal nodular hyperplasia: a case report. Journal of medical case reports. 2014 Dec 14:8():425. doi: 10.1186/1752-1947-8-425. Epub 2014 Dec 14 [PubMed PMID: 25495861]
Level 3 (low-level) evidenceMasand PM. Magnetic resonance imaging features of common focal liver lesions in children. Pediatric radiology. 2018 Aug:48(9):1234-1244. doi: 10.1007/s00247-018-4218-5. Epub 2018 Aug 4 [PubMed PMID: 30078045]
Scardapane A,Ficco M,Sabbà C,Lorusso F,Moschetta M,Maggialetti N,Suppressa P,Angelelli G,Stabile Ianora AA, Hepatic nodular regenerative lesions in patients with hereditary haemorrhagic telangiectasia: computed tomography and magnetic resonance findings. La Radiologia medica. 2013 Feb [PubMed PMID: 22327916]
Level 2 (mid-level) evidenceFodor M, Primavesi F, Braunwarth E, Cardini B, Resch T, Bale R, Putzer D, Henninger B, Oberhuber R, Maglione M, Margreiter C, Schneeberger S, Öfner D, Stättner S. Indications for liver surgery in benign tumours. European surgery : ACA : Acta chirurgica Austriaca. 2018:50(3):125-131. doi: 10.1007/s10353-018-0536-y. Epub 2018 May 22 [PubMed PMID: 29875801]
Sugito K, Uekusa S, Kawashima H, Furuya T, Ohashi K, Inoue M, Ikeda T, Koshinaga T, Tomita R, Mugishima H, Maebayashi T. The clinical course in pediatric solid tumor patients with focal nodular hyperplasia of the liver. International journal of clinical oncology. 2011 Oct:16(5):482-7. doi: 10.1007/s10147-011-0210-x. Epub 2011 Apr 1 [PubMed PMID: 21455626]
Hau HM, Atanasov G, Tautenhahn HM, Ascherl R, Wiltberger G, Schoenberg MB, Morgül MH, Uhlmann D, Moche M, Fuchs J, Schmelzle M, Bartels M. The value of liver resection for focal nodular hyperplasia: resection yes or no? European journal of medical research. 2015 Oct 22:20():86. doi: 10.1186/s40001-015-0181-x. Epub 2015 Oct 22 [PubMed PMID: 26494164]