Focal nodular hyperplasia

Focal nodular hyperplasia (FNH) is a benign, non-neoplastic regenerative lesion of the liver characterized by a proliferation of normal-appearing hepatocytes organized around a central stellate scar containing malformed blood vessels and bile ductules.^[1] It is the second most common benign hepatic tumor after hemangioma, accounting for approximately 8% of all non-hemangiomatous liver lesions.^[2] Unlike malignant tumors, FNH has no potential for malignant transformation and is considered a reactive response to local vascular abnormalities rather than a true neoplasm.^[3] FNH most commonly affects women in their 20s to 50s, with a female-to-male ratio of 8:1 to 9:1, and has a prevalence estimated at 0.4% to 3% in the general population based on autopsy and imaging studies.^[2] Lesions are typically solitary (in about 80% of cases) and measure 4 to 8 cm in diameter, though they can be multiple or larger, up to 20 cm; they are often discovered incidentally during imaging for unrelated issues.^[2] Clinically, FNH is usually asymptomatic, but larger lesions (>10 cm) may cause right upper quadrant pain or a palpable mass, with approximately 20% of all patients experiencing such symptoms; complications such as rupture or hemorrhage are exceedingly rare (<1%).^[3] Laboratory tests, including liver function, are generally normal, though mild elevations in transaminases can occur.^[1] Diagnosis relies on characteristic imaging findings, with multiphase contrast-enhanced MRI being the modality of choice, offering up to 99% sensitivity and 100% specificity when using hepatobiliary contrast agents like gadobenate dimeglumine, which highlight the lesion's iso- or hyperintensity due to preserved Kupffer cells.^[2] Ultrasound, CT, or scintigraphy (e.g., with Tc-99m sulfur colloid) can support diagnosis but are less specific; biopsy is rarely needed except in atypical cases to differentiate from hepatic adenoma or malignancy.^[3] Management is conservative, involving serial imaging every 3 to 6 months for monitoring, as surgical resection is reserved for symptomatic patients or diagnostic uncertainty; oral contraceptives do not promote growth and can often be continued safely.^[1] FNH has been associated with conditions like hereditary hemorrhagic telangiectasia,^[2] and in children, it may relate to prior chemotherapy.^[1]

Clinical Presentation

Signs and Symptoms

Focal nodular hyperplasia (FNH) is typically asymptomatic, with the majority of cases discovered incidentally during imaging studies performed for unrelated abdominal complaints or routine evaluations.^[1] Approximately 80% to 90% of patients experience no symptoms attributable to the lesion, allowing it to remain undetected until advanced imaging reveals the benign hepatic mass.^[4]^[5] In rare instances, symptomatic presentations occur, primarily due to mass effect from larger lesions exceeding 10 cm in diameter, manifesting as right upper quadrant abdominal pain, discomfort, or a sensation of fullness.^[1] These symptoms are nonspecific and often chronic or intermittent, such as epigastric pain lasting months, and may prompt further investigation.^[4] FNH does not typically cause jaundice, weight loss, or other constitutional symptoms, which are more indicative of malignant processes if present.^[1] Extremely rare complications include spontaneous rupture or hemorrhage, which can lead to acute abdominal pain, tenderness, and hemodynamic instability requiring urgent intervention.^[6] Such events are documented in fewer than 1% of cases and may present with sudden upper abdominal pain and peritoneal signs.^[4]^[7] Physical examination findings are usually normal in patients with FNH, reflecting the lesion's asymptomatic nature and subdiaphragmatic location.^[1] However, very large lesions may result in a palpable abdominal mass, potentially tender to palpation.^[1]

Epidemiology

Focal nodular hyperplasia (FNH) is the second most common benign liver tumor after hemangioma, with a reported prevalence ranging from 0.4% to 3% in the general adult population based on autopsy series.^[2] This prevalence is thought to increase with age, though exact incidence rates remain uncertain due to frequent incidental discovery.^[2] Advanced imaging techniques, such as MRI, have led to higher detection rates compared to historical autopsy data, contributing to an apparent rise in diagnosed cases.^[1] Demographically, FNH predominantly affects women, with a female-to-male ratio of approximately 8:1 to 9:1.^[1]^[2] It is most commonly diagnosed in individuals of reproductive age, between 20 and 50 years, though cases can occur across all age groups.^[1]^[2] The lesion is rare in children and the elderly, with pediatric occurrences often associated with prior chemotherapy or underlying malignancies.^[1] No significant geographic or ethnic variations in FNH prevalence have been reported in the literature.^[8] The observed increase in incidence over recent decades is largely attributed to the widespread adoption of abdominal imaging for unrelated conditions, rather than true changes in disease occurrence.^[2] FNH occasionally coexists with other benign liver lesions, such as hemangiomas, in up to 25% of cases, but it is not typically associated with syndromic conditions except in rare instances like hereditary hemorrhagic telangiectasia.^[9]^[1]

Pathobiology

Etiology and Risk Factors

The exact etiology of focal nodular hyperplasia (FNH) remains unknown, though it is widely hypothesized to represent a hyperplastic response of hepatocytes to abnormal blood flow resulting from vascular anomalies in the liver, such as aberrant arterial development or arteriovenous shunts.^[1]^[10] These anomalies may lead to localized hypoperfusion or hyperperfusion, prompting regenerative nodule formation without neoplastic transformation.^[1] FNH is explicitly not associated with infectious agents, toxic exposures, or malignant processes, distinguishing it from other hepatic lesions.^[10] A strong association exists between FNH and oral contraceptive use, particularly long-term exposure to estrogen-progestin combinations, which correlates with increased lesion prevalence and size in women.^[1]^[10] While oral contraceptives do not definitively cause FNH, discontinuation has been observed to lead to regression in some cases, supporting a hormonal influence on lesion growth.^[10] Other risk factors include rare reports of FNH development in men using anabolic steroids, potentially mimicking hormonal effects seen in women.^[11] Weaker evidence links FNH to pregnancy or hormone replacement therapy, where transient size increases may occur due to elevated estrogen levels, though these associations are less consistent.^[10] No established genetic mutations or familial patterns predispose to FNH, despite occasional reports in monozygotic twins suggesting a possible heritable component; however, congenital vascular malformations, such as those in hereditary hemorrhagic telangiectasia, represent a rare predisposing factor.^[1]^[10]

Pathophysiology

Focal nodular hyperplasia (FNH) represents a benign hyperplastic nodule of the liver, resulting from localized circulatory disturbances that induce aberrant proliferation of hepatocytes in response to altered blood flow. These lesions develop as a compensatory reaction to vascular anomalies, leading to regions of hypoperfusion or hyperperfusion within the hepatic lobule, which trigger hepatocyte hypertrophy and the formation of a distinctive architectural pattern. Unlike neoplastic processes, FNH exhibits polyclonal hepatocyte origins, maintaining a non-atypical cellular composition without evidence of dysplasia.^[1]^[12] Histologically, FNH is defined by a central stellate scar present in approximately 70% of lesions larger than 3 cm, featuring mature collagen deposition, stellate cells, and a prominent central artery, from which radiating fibrous septa extend to delineate nodules of hepatocytes. These nodules are interspersed with Kupffer cells that retain phagocytic function and malformed, dystrophic vessels, but lack true fibrosis or cellular atypia, distinguishing FNH from fibrotic or malignant liver conditions. The overall structure mimics regenerative hepatic tissue, with preserved bile ductules and sinusoidal architecture.^[10]^[1]^[13] The prevailing vascular theory posits that FNH arises from congenital or acquired arterial malformations, including abnormal arterial branches and portal vein hypoplasia or absence, which disrupt normal portal venous inflow and create localized ischemia or hyperperfusion. This imbalance upregulates angiogenic factors such as vascular endothelial growth factor (VEGF) and increases the angiopoietin-1 (ANGPT1)/angiopoietin-2 (ANGPT2) ratio, promoting the development of compensatory hyperplastic nodules and dystrophic vessels to restore hemodynamic equilibrium. Such vascular aberrations are often subclinical but can be associated with systemic conditions like hereditary hemorrhagic telangiectasia.^[10]^[1]^[14] Hormonal influences, particularly estrogen, appear to modulate FNH growth, as evidenced by the expression of estrogen receptors in the majority of lesion cells (observed in up to 92% of cases), which may enhance proliferative responses in a hormone-sensitive microenvironment and contribute to the marked female predominance (8:1 ratio). Lesions in women using oral contraceptives tend to be larger, suggesting a promotional rather than causative role for estrogen, though direct growth induction remains unproven and inconsistent across studies.^[15]^[1]^[16] FNH is generally considered to carry no malignant potential, manifesting as a stable, non-progressive lesion. However, rare cases of clonal relationship between FNH and hepatocellular carcinoma (HCC) have been documented through genomic analysis, suggesting an extremely rare potential for malignant transformation, such as via TERT promoter mutations, as reported in studies from 2022 and 2025.^[17]^[12]^[18]^[19]^[20]

Diagnostic Approach

Diagnostic Methods

Focal nodular hyperplasia (FNH) is typically diagnosed through non-invasive imaging techniques, with ultrasound serving as the first-line modality due to its accessibility and lack of radiation. On ultrasound, FNH appears as a well-circumscribed, homogeneous isoechoic or mildly hypoechoic mass relative to the surrounding liver parenchyma, with a central hyperechoic scar visible in approximately 20-50% of cases.^[1] Multiphase computed tomography (CT) further characterizes the lesion, demonstrating hypervascularity with intense enhancement in the arterial phase, followed by isoattenuation to the liver in the portal venous and delayed phases; the central scar, when present, remains hypodense and may enhance late.^[21] Magnetic resonance imaging (MRI) is the preferred non-invasive method for confirming FNH, offering high sensitivity and specificity, particularly with hepatocyte-specific contrast agents, with multiphase contrast-enhanced MRI using hepatobiliary agents like gadoxetate disodium providing >90% accuracy and nearly 100% specificity. On MRI, FNH is typically isointense on T1-weighted images and isointense to slightly hyperintense on T2-weighted images, with a characteristic T2-hyperintense central scar visible in 50-70% of cases. Administration of hepatocyte-specific contrasts, such as gadoxetate disodium, results in uptake by the lesion in the hepatobiliary phase, appearing iso- or hyperintense to the liver, which helps confirm its benign nature.^[22]^[21]^[23] Nuclear medicine imaging, such as sulfur colloid scintigraphy, can aid in diagnosis by demonstrating normal or increased uptake in the lesion due to preserved Kupffer cell function, a feature that distinguishes FNH from adenomas, which typically show no uptake.^[1]^[21] Biopsy is rarely required for diagnosis, reserved for cases where imaging is inconclusive, and is performed via percutaneous core needle under ultrasound or CT guidance. Histologically, it reveals bland hepatocytes arranged in nodules, a central fibrous scar with ductal proliferation, and absence of atypia or mitoses.^[1] Laboratory evaluation supports the diagnosis by showing normal liver function tests and negative alpha-fetoprotein levels, helping to exclude malignant lesions.^[21]

Differential Diagnosis

Focal nodular hyperplasia (FNH) must be differentiated from other hepatic lesions due to overlapping imaging appearances, as misdiagnosis can lead to unnecessary interventions or missed malignancies.^[1] The primary mimics include both benign and malignant tumors, with distinctions often relying on imaging characteristics, clinical context, and occasionally histopathology.^[10] Hepatic adenoma is a key benign differential, particularly in women with oral contraceptive use, as it shares hypervascularity with FNH but carries risks of rupture, hemorrhage, and malignant transformation.^[1] Unlike FNH, adenomas typically lack a central scar, exhibit heterogeneous enhancement with possible fat, calcification, necrosis, or hemorrhage on CT/MRI, and show no hepatobiliary retention on gadoxetate-enhanced MRI.^[10] They also demonstrate decreased uptake on Tc-99m sulfur colloid scintigraphy due to absent Kupffer cells.^[2] Hemangioma, the most common benign liver lesion, presents as a cavernous vascular malformation with peripheral nodular enhancement progressing centripetally on contrast imaging, contrasting FNH's homogeneous arterial enhancement and central scar.^[1] On MRI, hemangiomas are markedly hyperintense on T2-weighted images without a scar, while FNH appears iso- to slightly hyperintense.^[2] Angiomyolipoma, another rare benign entity, is distinguished by its fat content visible on CT or MRI, which is absent in FNH.^[1] Among malignant exclusions, hepatocellular carcinoma (HCC) is differentiated by its malignant potential, often elevated alpha-fetoprotein levels, and heterogeneous enhancement with arterial phase hyperenhancement followed by washout on portal venous or delayed phases.^[10] FNH lacks these features, showing iso- to hypointensity in delayed phases and preserved hepatobiliary function.^[2] Fibrolamellar HCC, more common in young patients without cirrhosis, may mimic FNH with a central scar but typically includes calcifications, larger size, heterogeneous T2 hyperintensity, and vascular invasion.^[1] Its scar is hypointense on T2-weighted MRI, unlike the hyperintense scar in FNH.^[10] Metastases are suggested by multiple lesions and a history of primary malignancy, with hypervascular patterns differing from FNH's solitary, benign profile.^[2] Diagnostic clues favoring FNH include its homogeneous enhancement, visibility of the central scar (present in about 50% of cases) on MRI, and map-like glutamine synthetase immunostaining pattern on biopsy if needed.^[1] Atypical imaging findings, such as absent scar or unusual enhancement, warrant further evaluation with biopsy or serial imaging to exclude alternatives.^[10]

Management and Outcomes

Treatment Options

Focal nodular hyperplasia (FNH) is a benign liver lesion that typically requires no intervention in asymptomatic patients, with conservative observation serving as the standard approach. Once confidently diagnosed via imaging, no routine follow-up imaging is necessary, as FNH demonstrates stability and lacks malignant potential. This watchful waiting strategy minimizes unnecessary procedures and patient anxiety, given the lesion's indolent course.^[24] Regarding hormonal influences, recent guidelines do not recommend routinely discontinuing oral contraceptives in patients with FNH, as evidence linking estrogen exposure to lesion growth or complications remains weak and inconsistent. Similarly, the European Association for the Study of the Liver (EASL) advises against cessation, noting no established role of hormones in FNH progression.^[24] The American College of Gastroenterology (ACG) 2024 guidelines also support continuing oral contraceptives without routine discontinuation.^[25] Management remains unchanged during pregnancy or in men, emphasizing that FNH poses no specific risks related to hormonal therapies. For symptomatic cases, which are uncommon and often unrelated to the lesion itself, surgical resection is considered on a case-by-case basis, particularly if pain, mass effect, or diagnostic uncertainty persists despite imaging. Laparoscopic hepatectomy is preferred when feasible due to its minimally invasive nature and favorable outcomes for accessible lesions.^[1] Transarterial embolization (TAE), sometimes combined with bleomycin, represents a rare alternative for inoperable symptomatic FNH or complications like bleeding, though its use is limited by the lesion's benign behavior. Chemotherapy and ablative therapies, such as radiofrequency ablation, have no established role in FNH management, as the condition is non-progressive and non-malignant, rendering such interventions unwarranted and potentially harmful.^[1] A multidisciplinary team, including hepatologists, radiologists, and surgeons, is advisable for complex or atypical presentations to guide decisions on intervention.^[24]

Prognosis

Focal nodular hyperplasia (FNH) is a benign liver lesion with an excellent prognosis, characterized by its non-cancerous nature and absence of malignant transformation risk, even with long-term follow-up.^[24] No documented cases of progression to hepatocellular carcinoma have been reported in large series.^[26] The natural history of FNH is marked by stability in the majority of cases, with approximately 77% of lesions remaining unchanged in size over a mean follow-up of 19 months.^[27] Spontaneous regression occurs in 8-27% of cases, particularly following cessation of oral contraceptives, with some lesions decreasing by up to 60% or even disappearing completely.^[27]^[26] Growth is uncommon, affecting about 15% of lesions, but even when observed, it is typically slow and does not warrant intervention in the absence of symptoms.^[27] Complications from FNH are rare, occurring in less than 1% of cases, and primarily include compression of adjacent structures leading to pain or obstructive symptoms, such as hepatic vein compression in select patients.^[10] Intralesional hemorrhage or rupture is exceptional, mostly associated with lesions larger than 5 cm, and does not typically result in significant morbidity.^[10] Follow-up recommendations emphasize conservative management for confirmed, asymptomatic FNH, with no routine imaging required according to European Association for the Study of the Liver (EASL) and American College of Gastroenterology (ACG) guidelines.^[24]^[25] Monitoring may be considered if symptoms persist or in cases of diagnostic uncertainty. Surgical intervention may be considered for complications, as detailed in treatment guidelines. The impact on quality of life is minimal for most patients with FNH, as the lesion does not cause liver dysfunction or systemic effects, though rare symptomatic cases may necessitate intervention.^[24]