ABSTRACT

Non-neoplastic tumor-like conditions of the liver can appear similar to hepatic neoplasms. In many cases, a biopsy is required to confirm the pathology. However, several tumor-like conditions can be correctly diagnosed or suggested prospectively, thus saving patients from unnecessary anxiety and expense. In this image-focused review, we present the ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography scan features of eight such entities. Clues that indicate the correct pathology are discussed, and the usual clinical setting is described. Many of these lesions are treated differently from true neoplasms, and the current treatment plan is discussed in many of the cases presented. After reviewing this article, the reader will have a better understanding of these lesions and the situations in which they should be included in the differential diagnosis.

Main points

• Non-neoplastic lesions of the liver can appear similar to hepatic tumors. Although pathologic evidence is often necessary for a definitive diagnosis, including these entities in the differential diagnosis can aid the clinician with the diagnostic workup.

• Multiple clinical clues might suggest that a liver lesion is benign. Although these may not be definitive, key factors include normal tumor markers, a history of infection, and a history of a systemic disease known to involve the liver.

Differentiating hepatic tumors from tumor-like conditions can be challenging because the imaging features may overlap. An understanding of several of the more common tumor-like lesions that can be misdiagnosed as tumors is vital so that the correct pathology can be included in the differential diagnosis. In this article, we describe the clinical and imaging features of some of the more common tumor-like conditions to assist radiologists in determining the correct diagnosis.

Mesenchymal hamartoma

Mesenchymal hamartomas of the liver (MHL) represent only 5% of pediatric tumors. However, after infantile hemangiomas, they are the second most common benign liver tumors in children younger than 5 years. The lesions normally present as painless abdominal distention in a patient with a normal or slightly elevated alpha fetoprotein level.¹ In some cases, the alpha fetoprotein level is substantially elevated, leading to diagnostic confusion. The tumors can be very large (up to 20–30 cm).¹ Mesenchymal hamartomas are associated with Beckwith–Wiedemann syndrome and multiple congenital fetal anomalies.² Most cases (75%) arise from the right hepatic lobe, and up to 20% of tumors are pedunculated.¹

On imaging, an MHL appears as a large, well-demarcated, multilocular cystic mass with septal and/or stromal enhancement (Figure 1). On magnetic resonance imaging (MRI), the cystic components demonstrate high signal intensity on T2-weighted images and variable signal intensity on T1-weighted images as a result of hemorrhagic or proteinaceous debris (Figure 2). The solid and stromal components are mildly enhanced by the administration of intravenous gadolinium.³

Histologically, MHLs are composed of hepatocytes, haphazardly arranged bland spindle cells, and benign bile ducts in a collagenous stroma.^{1, 4} They have no malignant features and are usually cured through surgical resection. On rare occasions, MHLs have been theorized to progress to embryonal sarcoma, as the two entities have similar molecular alterations in chromosome 19.¹ Additionally, there have been case reports of benign bile duct-like structures in the periphery of embryonal sarcomas with a similar histologic configuration to MHL, raising the possibility that the MHL was the precursor lesion.¹ Therefore, complete surgical excision is crucial.² Rarely, symptomatic unresectable disease has necessitated liver transplantation.²

Myofibroblastoma

Myofibroblastomas (inflammatory pseudotumors), which represent less than 1% of liver tumors, are a heterogenous group of masses that form benign tumors composed of inflammatory cells and fibrous stroma. These tumors may be very slightly more prevalent in men. Patients are diagnosed at an average age of 50 years, and there is no association with cirrhosis. The etiology of myofibroblastomas is unknown; however, it has been hypothesized that they result from hepatic infection, cholangitis, or a vascular injury.^{4, 5} In most cases, the infectious agent is not identified. Some of these tumors occur in patients with immunoglobulin G4 sclerosing disease, and these patients may have a history of autoimmune pancreatitis or sclerosing cholangitis.^{2, 5} Patients may present with fever, abdominal pain, and weight loss. Most tumors are 2–5 cm in diameter when detected, but some patients have presented with tumors greater than 20 cm.⁵ Patients may have elevated erythrocyte sedimentation rates, neutrophil counts, and C-reactive protein levels.⁵The pathologic features can overlap with other disease entities, and a subset requires next generation sequencing to aid in diagnosis.²

On ultrasound, myofibroblastomas present as well-circumscribed heterogeneous masses with solid and cystic components. On computed tomography (CT), they are commonly hypoattenuating compared with the liver on unenhanced images, and they usually demonstrate peripheral or septal enhancement on delayed images. At least part of the lesion may demonstrate delayed enhancement, presumed to be related to abundant fibrous tissue (Figure 3). On MRI, they are hypointense in T1-weighted images and isointense or hyperintense on T2-weighted images, with a similar postcontrast enhancement pattern to that seen on CT (Figure 4). Typically, no associated desmoplastic reaction occurs. The differential diagnosis includes cholangiocarcinoma, which can also demonstrate delayed enhancement, abscess, metastasis, and hepatocellular carcinoma.⁶

Myofibroblastomas are often treated conservatively because they may resolve spontaneously or respond to antibiotic therapy or steroid therapy. Although surgical resection is curative, it is generally reserved for cases in which no biopsy was performed or in which the diagnosis remained unclear after biopsy. Surgery may also be performed in cases in which the lesion does not respond to conventional therapy.

Extramedullary hematopoiesis

Extramedullary hematopoiesis (EMH) refers to the production of blood cells outside the bone marrow, a phenomenon observed in patients with defective marrow synthesis (e.g., chronic myelofibrosis) or with conditions associated with peripheral red blood cell destruction (such as hemoglobinopathies and hemolytic anemias).⁷ The liver and spleen are the most common sites for EMH. Organ enlargement, particularly hepatomegaly, is more frequently observed than discrete lesions. When discrete lesions do occur, they may present as single or multiple focal masses or as infiltrative periportal or peribiliary soft tissue lesions.^{8, 9}

On ultrasound, lesions associated with EMH can appear hypoechoic or hyperechoic and typically present as heterogeneously attenuated nodules.^{10, 11} CT generally reveals hypodense lesions with variable attenuation and may show no, mild, or heterogeneous enhancement (Figure 5).^{10, 12, 13} In rare cases, lesions may exhibit fat density without enhancement.¹⁴

On MRI, EMH lesions have variable signal characteristics, depending on whether the lesion is functional (actively hematopoietic) or inactive. Active lesions typically exhibit intermediate T1 and high T2 signal intensities with mild to moderate enhancement (Figure 6). By contrast, inactive lesions, which are predominantly composed of fibrous tissue, indicate low T1 and T2 signal intensity with minimal or no enhancement.^{12, 15} Macroscopic fat, which can occur in inactive lesions, produces a signal intensity that detects fat in all sequences. In patients with transfusion-related hemochromatosis, decreased background hepatic signal intensity is seen on sequences most sensitive to magnetic susceptibility.¹⁵ Despite these imaging findings, a definitive diagnosis usually requires pathologic evaluation, which often reveals erythroid or myeloid precursors along with fatty or fibrous tissue.¹⁶

Epstein–Barr virus-associated smooth muscle tumor

Epstein–Barr virus (EBV)-associated smooth muscle tumors are rare slow-growing mesenchymal tumors that primarily affect immunocompromised patients. The incidence is highest among individuals who are HIV positive, followed by patients with drug-induced immunosuppression after organ transplantation, and, less commonly, patients with congenital immunodeficiency disorders.^17-20

These tumors impact both adult and pediatric patients and are slightly more prevalent among women.²¹ Abdominal pain is frequently reported as the main presenting symptom.^{17, 21}

In patients with AIDS, multicentric involvement is common, either occurring simultaneously or sequentially.²² Molecular analyses of such multicentric presentations have revealed distinct clonal origins for the lesions at each site, suggesting that these lesions represent multiple primary tumors rather than metastases.^{20, 23-25} The tumors can affect various organs, including the central nervous system, spleen, lungs, gastrointestinal tract, larynx, pharynx, skin, adrenal glands, and eyes. The liver is the most commonly involved organ in immunosuppressed organ transplant recipients, the second most common site in patients with AIDS, and the least common site in patients with congenital immunodeficiencies.^{21, 25-31}

The imaging characteristics of EBV-associated smooth muscle tumors are generally non-specific. On CT, the tumors present as hypodense lesions, often with rim enhancement^{22, 32}and sometimes with central necrosis.^{21, 27} Findings on MRI typically include isointensity on T1-weighted images and isointensity to mild hyperintensity on T2-weighted images, with substantial contrast enhancement (Figure 7).³³ Diagnosis is confirmed through immunohistochemistry, which shows positivity for smooth muscle actin and EBV-encoded RNA.²²

Differentiating EBV-associated smooth muscle tumors from non-EBV-related primary or metastatic smooth muscle tumors of the liver, such as leiomyosarcomas, is crucial because of the latter’s less favorable prognosis. Even without intervention, EBV-associated tumors tend to progress slowly.^{17, 22}

Hepatobiliary tuberculosis and tuberculomas

Hepatobiliary tuberculosis and tuberculomas of the liver most commonly occur in patients with disseminated disease. In an autopsy series, a hepatosplenic prevalence of 80% to 100% was seen in the setting of pulmonary miliary disease.^{34, 35} There are three types of hepatobiliary tuberculosis: parenchymal (including the miliary, nodular, and mixed subtypes), biliary, and serohepatic.³⁶ Imaging plays a key role in the diagnosis and management of these patients because the symptoms of patients with these lesions are often vague and non-specific, potentially delaying appropriate treatment. Most cases ultimately require tissue sampling to confirm the diagnosis.

In parenchymal hepatobiliary tuberculosis, imaging findings typically identify multiple (<2 cm) well-defined nodules throughout the liver that may contain calcifications (Figure 8). Larger lesions (>2 cm) in the less commonly seen macronodular type of hepatobiliary tuberculosis tend to demonstrate peripheral rim enhancement and central necrosis on CT, and they may contain chunky peripheral or central calcifications (Figure 9).³⁷ However, their appearance is dependent on the degree of caseous necrosis and liquefaction. On CT imaging, non-caseating granulomas appear hypoattenuating with no or mild peripheral rim enhancement.³⁸ However, lesions with caseous necrosis and liquefaction can resemble pyogenic abscesses with a honeycomb appearance, multiple enhancing septations, and regions of scattered necrosis.³⁸ On MRI , macronodular lesions typically appear as T1 hypointense. On T2-weighted images, they have varied intensity (hypointense to hyperintense) with peripheral T2-hypointense rims, and on postcontrast sequences, they have heterogenous enhancement.^{36, 39} Larger macronodular nodules may represent the fusion of miliary and/or micronodular nodules. Mixed parenchymal lesions have imaging findings of both the miliary and nodular types. Sonographically, these lesions usually appear uniformly hypoechoic or heterogeneous, with intermixed echogenic and hypoechoic regions.⁴⁰ However, lesions with other patterns have been observed, including -rarely- hypoechoic to echogenic lesions with echogenic centers.⁴⁰ The lesion borders tend to be poorly defined, but this too varies. The imaging characteristics of these lesions can be non-specific and can vary depending on the stage of the hepatic granuloma. Therefore, tissue sampling is often required to confirm the diagnosis.

Tuberculous cholangitis is a rare presentation of hepatobiliary tuberculosis and primarily occurs in children.³⁸ Imaging findings consist of dilated irregular intrahepatic ducts or diffuse miliary calcifications along the affected bile ducts.⁴¹ Involvement of the biliary tree may be caused by biliary tract contamination from enteric mycobacterium infection, hematogenous spread, or direct extension from adjacent infected structures (e.g., caseating granuloma or hilar lymphadenopathy).⁴⁰

The serohepatic type of hepatobiliary tuberculosis is the rarest form. Imaging findings consist of multiple hypoattenuating nodules in a subcapsular distribution with a thickened hepatic capsule.³⁶ These findings give the liver a characteristic appearance of subcapsular nodularity, which has been characterized as having “sugar coating” or a “frosted liver” appearance.⁴¹

The diagnosis of serohepatic hepatobiliary tuberculosis should be considered among high-risk patients or in those who have suspected tuberculous involvement of the lungs, spleen, or lymph nodes. A definitive diagnosis is made with acid-fast staining and with histology revealing caseating granulomas.⁴²

Peliosis hepatis

Peliosis hepatitis is an uncommon lesion characterized by abnormal sinusoidal dilatation and multiple blood-filled lacunar spaces.⁴³ It is thought to be caused by hepatic flow obstruction at the sinusoidal level and is potentially caused by steroids, oral contraceptives, cytotoxic drugs, chronic lung disease, infections (e.g., HIV and tuberculosis), and various malignancies (especially hepatomas).⁴⁴ In HIV-related peliosis hepatis, Bartonella henselae has been identified as a causative agent, with regression after appropriate antibiotic therapy.⁴⁵ Peliosis hepatitis can also develop in patients with a renal or cardiac transplant. Hematologic disorders, diabetes, and necrotizing vasculitis also seem to be associated with peliosis hepatis. However, up to 50% of peliosis hepatis cases are idiopathic.⁴⁴ These lesions are normally asymptomatic, but they may cause symptoms if they rupture and hemorrhage. Additional complications include portal hypertension, cholestasis, liver enlargement, ascites, and even liver failure.

Two different pathologic forms of peliosis hepatitis have been described: the phlebectatic and parenchymal types. The phlebectatic type is characterized by blood-filled cavities lined with endothelial cells and an aneurysmal dilatation of the central vein. By contrast, in the parenchymal type, the blood-filled cavities are not lined by endothelial cells, and it occurs in the setting of hemorrhagic parenchymal necrosis.^{46, 47}

Lesions typically measure up to a few centimeters and usually demonstrate no mass effect on transiting vessels. Imaging features vary according to the age of the blood components and the presence or absence of hepatic steatosis. On ultrasound, these lesions tend to be hypoechoic in the setting of background steatosis and hyperechoic in the setting of normal liver tissue with increased perinodular or intranodular vascular flow on Doppler imaging.

On multiphasic CT and MRI, peliosis hepatitis lesions exhibit intralesional hemorrhage and predominantly progressive centrifugal enhancement, although centripetal enhancement is also possible (Figure 10). The appearance of these lesions can vary based on the age of the hemorrhagic components.⁴⁸ Cavities within these lesions that communicate with sinusoids demonstrate enhancement in line with that of blood vessels, whereas thrombosed portions are not enhanced. These lesions usually demonstrate early discontinuous (globular) arterial enhancement. In atypical cases where the enhancement is centripetal rather than classic centrifugal, the lesions may be mistaken for hemangiomas.⁴⁸

Sarcoidosis

Sarcoidosis is a multisystemic inflammatory disease that is histologically defined by the formation of non-necrotic granulomas. The cause of sarcoidosis remains unclear, but currently accepted theories suggest that a genetic predisposition and exposure to environmental or occupational antigens lead to a dysfunctional immune response.⁴⁹ The disease mainly affects young and middle-aged adults, and there is a slight predominance in women compared with men.⁴⁹ Although all populations worldwide are affected, some studies report increased rates among African Americans and people from the Nordic countries.⁵⁰

The lungs are the most common site of involvement; however, every organ system can be affected. Hepatic disease is reported in up to 80% of cases.^{50, 51} The formation of hepatic granulomas can incite an inflammatory response leading to fibrosis and, eventually, cirrhosis.⁵⁰ Most patients with hepatic sarcoidosis (50%–80%) are asymptomatic. Symptoms include fatigue, fever, weight loss, pruritus, jaundice, and abdominal pain.⁵⁰ 

Imaging findings in sarcoid-related liver disease are often non-specific and vary substantially. In most patients with sarcoidosis, the liver appears normal on imaging. The most common finding, reported in up to 29% of cases, is hepatomegaly.^{51, 52} Other abnormalities include portal hypertension, portal vein or hepatic vein thrombosis, and cirrhosis.^{51, 53}

Focal hepatic lesions are also a feature in a small percentage of patients with sarcoidosis. They often appear as multiple small lesions, which can coalesce and form larger lesions.^{51, 52} On non-contrast CT, these lesions are usually hypodense (Figure 11), whereas on MRI , the lesions are typically T1 isointense or slightly hypointense and T2 hypointense. However, increases in lesion size, the coalescence of larger granulomas, or active inflammation can result in hyperintense T2-weighted signal intensity.⁵⁴ On both imaging modalities, lesions are hypoenhancing relative to the surrounding parenchyma (Figure 12). Concomitant lesions can also be seen within the spleen, and portal lymphadenopathy may also be present. Both of these findings can aid in diagnosis.⁵⁵ 

Cholestasis is another feature of hepatic sarcoidosis, and it can result in intrahepatic or extrahepatic biliary ductal dilatation.^{52, 53} The latter could also be secondary to disease involving the common hepatic duct or extrinsic compression from enlarged lymph nodes. The appearance may mimic that of a primary biliary tumor, necessitating caution during imaging interpretation.⁵² 

Amyloidosis   

Amyloidosis is a general term referring to a group of disorders characterized by the deposition of misfolded serum proteins -amyloid fibrils- in extracellular spaces.⁵⁶ Amyloid fibrils result when precursor proteins that are usually soluble aggregate, forming insoluble fibers that are resistant to degradation.^56-58 In localized amyloidosis, the formation and deposition of amyloid fibrils occurs in the same organ. In systemic amyloidosis, the formation of the amyloid fibrils occurs in one organ, and the deposition of the fibrils occurs in a distant location.⁵⁸ Systemic amyloidosis can be classified into multiple types, depending on the precursor protein; over 15 types of precursor proteins have been described.⁵⁸ Common conditions associated with the systemic form of the disease include plasma cell disorders, malignancy, and chronic infection or inflammation.^56-58

Amyloidosis can affect all organ systems. In the abdomen, amyloid deposition occurs in the genitourinary and gastrointestinal tracts as well as in the liver, spleen, peritoneum, and retroperitoneum.⁵⁶

Within the liver, amyloid fibril deposition occurs in the perisinusoidal spaces and along the blood vessel walls.^{59, 60} As with sarcoidosis, imaging findings in the liver can be non-specific, and amyloidosis most commonly manifests as hepatomegaly.⁶¹ Some reported patterns that can mimic other infiltrative liver diseases, such as steatosis and hepatic venous congestion, include diffusely decreased attenuation on CT, heterogeneity of liver parenchyma, and heterogeneous contrast enhancement.^{59, 61} More well-defined masses, along with focal and diffuse calcifications, can also occur (Figure 13).⁶¹

On MRI, diffusely decreased signal intensity on T2-weighted images has been observed, possibly from amyloid deposition and/or increased iron deposition in the liver occurring secondary to amyloid-associated chronic renal disease.^{60, 61} Increased liver stiffness has also been observed and can be evaluated using magnetic resonance elastography.^{59, 62} 

In conclusion, a large variety of pathologies can present within the liver, and this can make diagnosing liver lesions challenging. Although most lesions are common tumors, on rare occasions, radiologists may encounter one of the aforementioned rare lesions. By being familiar with these lesions and including them in the differential diagnosis, radiologists and clinicians can ensure that patients receive the correct diagnosis and treatment.

Conflict of interest disclosure

The authors declared no conflicts of interest.