Focal Nodular Hyperplasia

Article Author:
Sammy Hamad
Article Editor:
Sandeep Mukherjee
Updated:
3/2/2019 8:56:40 AM
PubMed Link:
Focal Nodular Hyperplasia

Introduction

The liver is the only self-regenerative internal organ within the human body. This regenerative capability places the liver at an inherent risk for developing atypical masses. While the majority of liver masses present as predominantly solid or cystic masses, 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 which is the hemangioma, focal nodular hyperplasia is thought to be the result of increased hepatocyte number caused by hypoperfusion or hyperperfusion from anomalous arteries within the hepatic lobule.[1] Focal nodular hyperplasia often is confounded by comorbid conditions making establishing a diagnosis and management difficult.

Previously, focal nodular hyperplasia was referred to by a variety of 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

The exact etiology of focal nodular hyperplasia has not been definitively established. However, it is thought to be caused by arterial malformations within the liver. These malformations, coupled with 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 developing focal nodular hyperplasia. Hereditary hemorrhagic telangiectasia also known as Osler-Weber-Rendu syndrome can cause an increased incidence of focal nodular hyperplasia. The incidence of focal nodular hyperplasia also increases in the presence of hemangiomas.[3]

Further complicating the delineation of any exact cause is the fact that focal nodular hyperplasia may develop without any 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 researchers in gastroenterology believe intermittent disruptions of blood flow within the hepatic lobule lead to the characteristic cellular response.

Arguably, the cornerstone distinction that differentiates focal nodular hyperplasia from other hepatic masses is its origin. A series of studies showed that the majority of hepatocytes within a focal nodular hyperplasia 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 focal nodular hyperplasia among monozygotic twins indicating a possible genetic component.[5] However, a genetic mutation responsible for predisposing individuals to focal nodular hyperplasia has not yet been identified.

Epidemiology

In adults, the most common benign hepatic lesion in adults is the hemangioma. However, focal nodular hyperplasia is the second most common accounting for approximately eight percent of all non-hemangiomatous liver lesions. Focal nodular hyperplasia 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 focal nodular hyperplasia is increased in females age 20 to 50, further suggesting that the condition may be linked to increased estrogen. In recent literature, oral contraceptives as a cause of developing of focal nodular hyperplasia are not proven. However, women who are on a daily oral contraceptive regimen display larger nodules that 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]

Focal nodular hyperplasia 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 focal nodular hyperplasia 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 focal nodular hyperplasia.[9]

Histopathology

A majority of patients with focal nodular hyperplastic lesions present with solitary lesions between 4 and 8 centimeters. Only 3% of cases reach a diameter greater than ten centimeters. The hallmark feature of focal nodular hyperplasia that is 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 pseudocapsule which distinguishes it from hepatocellular carcinoma, hepatocellular adenomas, and fibrolamellar hepatocellular carcinoma. Because of this, 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 that are commonly seen in hepatic adenomas. Cytologically, these hepatocytes from focal nodular hyperplastic lesions are unremarkable reaffirming benign origin.[10]

If a biopsy sample lacks a “central scar,” bile duct canals, or calcifications that would aid in the differentiation between hepatic adenomas and focal nodular hyperplasia, immunohistochemical stainings may aid in establishing a diagnosis. Focal nodular hyperplasia displays an increased expression of glutamine synthetase located in the periphery of the nodules, which may be stained and identified.[11]

History and Physical

Focal nodular hyperplasia is most often discovered incidentally after imaging is performed 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 focal nodular hyperplasia consists of biopsy or imaging consistent with the characteristics of FNH and exclusion of other similar lesions. Lab work is largely unremarkable in the setting of focal nodular hyperplasia.[14] Alpha-fetoprotein levels (AFP) are generally within reference ranges, further supporting the benign clinical course associated with focal nodular hyperplasia. Additionally, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT) levels may display minor elevations, but these may be confounded by comorbid conditions as they are rarely elevated in the sole presence of focal nodular hyperplasia.[15]

Ultrasonography is most often the first imaging modality used in the evaluation of liver lesions including focal nodular hyperplasia, but lacks an appropriate sensitivity (twenty percent) 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 focal nodular hyperplasia and hepatocellular adenoma can be distinguished with the advent of early arterial phase imaging which reveals arterial morphology and filling direction.[17][18]

Triphasic helical computed tomography with and without contrast, although not the gold standard imaging modality, is a cheap and reliable imaging modality. Pre-contrast, focal nodular hyperplasia 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. Similar to CT imaging, the lesion enhances on arterial phase images and is relatively obfuscated on venous and delayed phase images. Sensitivity and specificity of 99% and 100%, respectively, may be achieved with hepatobiliary contrast media consisting of administration of gadobenate dimeglumine. Thus, MRI with hepatobiliary scintigraphy is the best test to diagnose focal nodular hyperplasia.[20][21]

Treatment / Management

Given the inherent procedural risks associated with percutaneous biopsy and surgical resection and the indolent nature of focal nodular hyperplasia, close observation is recommended with serial imaging every three to six 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]

Focal nodular hyperplasia was first described in the 1960s prior to the widespread use of oral contraceptive pills. Since then, there has been no proven increase in the incidence of focal nodular hyperplasia 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. In the pediatric population, a thorough examination of the patient’s risk factors for underlying malignancy or liver disease is warranted.[23]

Differential Diagnosis

  • 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 to do no 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 nodule if the benefits do not outweigh the risks.[24] To avoid unnecessary risk, a comprehensive evaluation of a patient by physicians, nurses, pharmacists, and other healthcare professionals is necessary. 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

[1] Lizardi-Cervera J,Cu�llar-Gamboa L,Motola-Kuba D, Focal nodular hyperplasia and hepatic adenoma: a review. Annals of hepatology. 2006 Jul-Sep     [PubMed PMID: 17060885]
[2] Nat L,Poantă LI, Focal nodular hyperplasia (FNH). Romanian journal of internal medicine = Revue roumaine de medecine interne. 2014 Jan-Mar     [PubMed PMID: 25000678]
[3] Herman 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     [PubMed PMID: 10658075]
[4] 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]
[5] Mindikoglu AL,Regev A,Levi JU,Casillas J,Schiff ER, Focal nodular hyperplasia in identical twins. The American journal of gastroenterology. 2005 Jul     [PubMed PMID: 15984990]
[6] Naganuma 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     [PubMed PMID: 27550510]
[7] Kubota 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     [PubMed PMID: 11813612]
[8] Turaihi 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]
[9] Koolwal J,Birkemeier KL,Zreik RT,Mattix KD, Pedunculated focal nodular hyperplasia in a healthy toddler. Proceedings (Baylor University. Medical Center). 2018 Jan     [PubMed PMID: 29686569]
[10] 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     [PubMed PMID: 23829376]
[11] Joseph 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     [PubMed PMID: 23807780]
[12] 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]
[13] 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     [PubMed PMID: 29492364]
[14] Roncalli M,Sciarra A,Tommaso LD, Benign hepatocellular nodules of healthy liver: focal nodular hyperplasia and hepatocellular adenoma. Clinical and molecular hepatology. 2016 Jun     [PubMed PMID: 27189732]
[15] 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     [PubMed PMID: 21790865]
[16] D'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     [PubMed PMID: 26102419]
[17] 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     [PubMed PMID: 25701530]
[18] 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     [PubMed PMID: 23392189]
[19] Scialpi 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     [PubMed PMID: 25495861]
[20] Masand PM, Magnetic resonance imaging features of common focal liver lesions in children. Pediatric radiology. 2018 Aug     [PubMed PMID: 30078045]
[21] 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]
[22] Fodor 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     [PubMed PMID: 29875801]
[23] 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     [PubMed PMID: 21455626]
[24] 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     [PubMed PMID: 26494164]