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Gastrointestinal Imaging |
1 From the Department of Radiology, University of Pittsburgh Medical Center, Presbyterian Hospital, 200 Lothrop St, Rm 4660 CHP MT, Pittsburgh, PA 15213-2582 (G.B., M.P.F., A.B., M.S.P., L.T.), and the Department of Radiology, University of Brescia, Italy (L.G.). Received May 26, 2000; revision requested July 17; revision received August 7; accepted August 30. G.B. supported by the Nicholas Green Fulbright Grant. Address correspondence to M.P.F. (e-mail: federle+@pitt.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Clinical, pathologic, and preoperative imaging findings were retrospectively reviewed in 78 patients. Conventional liver CT was performed in nine patients; helical multiphasic CT, in 69. Diagnosis was based on complete resection (n = 20), biopsy (n = 42), or clinical and imaging follow-up for a minimum of 6 months (n = 16). Number, size, location, margins, surface, homogeneity of enhancement, and presence of a central scar, mass effect, exophytic growth, calcification, pseudocapsule, or vessels feeding or draining the lesion were evaluated.
RESULTS: CT depicted 124 tumors (mean diameter, 4.1 cm; range, 1–11 cm); 62 were small (
3 cm). FNHs were hypervascular and hyperattenuating to liver on 106 of 106 arterial phase scans and were isoattenuating to liver on 82 of 89 delayed scans. Of the 124 tumors, 111 enhanced homogeneously, 109 had a smooth surface, 101 were subcapsular, 89 had ill-defined margins, and 62 had a central scar that was observed more often in large lesions (40 of 62 lesions) than in small lesions (22 of 62 lesions). FNHs less frequently exerted a mass effect (43 lesions), had vessels around or within the lesion (42 lesions), demonstrated exophytic growth (40 lesions), or showed a pseudocapsule (10 lesions). Only one FNH had calcification.
CONCLUSION: Helical CT demonstrates characteristic features that may allow confident diagnosis of FNH. In typical cases, neither biopsy nor further imaging is necessary.
Index terms: Liver, focal nodular hyperplasia, 761.3198 • Liver neoplasms, 761.3198 • Liver neoplasms, CT, 761.12115, 761.12119 • Liver neoplasms, diagnosis, 761.12119
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Study Population
There were 69 women and eight men aged 16–70 years (mean, 37 years) and one boy aged 5 years. Nineteen of the women had a history of oral contraceptive use. None of the men had a history of anabolic steroid use. For 48 patients, FNH was an unexpected finding on images obtained for unrelated reasons, while the other 30 patients had abdominal symptoms or signs, including pain (n = 29) and abnormal liver function (n = 1). Four patients had a history of breast carcinoma; two, of renal carcinoma; and one, of seminoma. One patient had clinical evidence of viral hepatitis.
Twenty-two FNHs were removed in 20 patients (18 patients with one lesion and two each with two lesions) by means of resection (n = 21) or orthotopic liver transplantation (n = 1). In three patients with two (n = 2) or three (n = 1) lesions each, only one FNH was resected because of the small dimensions of the others. In 42 patients, specimens were obtained from at least one hepatic lesion by means of percutaneous (n = 41) or laparoscopic (n = 1) needle biopsy. In patients with more than three lesions, biopsy was performed in at least two masses. Percutaneous biopsy included histologic core-needle and aspiration cytologic analysis in all patients. Histopathologic confirmation of FNH was based on demonstration of a central scar or of normal-appearing hepatocytes, Kupffer cells, and blood vessels arranged in nodules and surrounded by fibrous septa that contained a variable amount of primitive bile ductules. Sixteen patients underwent additional CT and clinical follow-up for a minimum of 6 months (range, 6–60 months; mean, 25 months) (Table 1).
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We also recorded any imaging and histopathologic evidence of hepatic vascular abnormalities or non-FNH tumors among the patients with proved FNH.
CT Protocols
CT examinations through the liver included nonenhanced imaging in 73 patients and contrast material–enhanced imaging in 78 patients. Helical CT was performed in 69 patients, including both hepatic arterial phase (HAP) (n = 64) and portal venous phase (PVP) (n = 69) imaging through the liver, with delays of 25–35 seconds and 60–70 seconds, respectively, after initiation of the intravenous bolus injection of contrast material. All nine patients who underwent conventional (nonhelical) CT had postcontrast scans, with a delay of 60 seconds. On average, patients received 150 mL of 60% iodinated contrast medium (iothalamate meglumine [Conray 60] or ioversol [Optiray 320]; Mallinckrodt Medical, St Louis, Mo). For conventional CT, contrast agent was intravenously administered at a rate of 2.5 or 3.0 mL/sec. For helical multiphasic examinations, the rate was 4 or 5 mL/sec, with use of a power injector (model OP 100; Medrad, Pittsburgh, Pa). Fifty-four patients also underwent delayed phase imaging through the liver, 5 minutes (n = 39) or 10–20 minutes (n = 15) after initiation of contrast medium administration. Section thickness was 5–7 mm for conventional and helical imaging. All CT examinations were performed with a model 9800, Advantage, HiLight Advantage, HiSpeed Advantage, or LightSpeed scanner (GE Medical Systems, Milwaukee, Wis) or a Somatom Plus 4 CT scanner (Siemens Medical Systems, Erlangen, Germany).
Image Analysis
The CT scans were reviewed retrospectively and independently by two abdominal radiologists (G.B., L.G.) at one university (University of Brescia, Italy) or by three abdominal radiologists (A.B., M.S.P., L.T.) at a second university (University of Pittsburgh Medical Center, Pa) with knowledge of the diagnosis of FNH but without knowledge of the specific number of tumors or clinicopathologic findings in any patient. The radiologists’ experience varied from 5 to 21 years (mean, 12.4 years). Because our purpose was to evaluate the CT imaging features of FNH in these patients and not to evaluate the accuracy of the diagnostic modality or readers, we did not test for interobserver disagreement but used consensus opinion. All observers agreed on the number of masses in all cases.
The number, size, and location (peripheral or central) of the FNH lesions were evaluated. A lesion was considered small if it was 3 cm or less in maximum diameter. The nature of the tumor margins (sharply or ill defined) and surface (smooth or grossly lobulated) was noted. A lesion was defined as peripheral or central if its margins were respectively adjacent or not adjacent to the liver surface. A mass was considered homogeneous if it enhanced to the same degree in all its parts, with the exception of the scar or septa. Vessels adjacent to the FNH were judged as displaced if the tumor clearly exerted a mass effect on them. The lesion was considered to have an exophytic growth if it produced a focal convex bulge of the liver contour.
The presence of enlarged vessels feeding or draining the mass, as well as peripheral, central, or septal arteries, was assessed. A pseudocapsule was judged to be present if a thin, curvilinear border surrounded the tumor and had a distinct attenuation difference compared to the surrounding liver parenchyma on nonenhanced or enhanced scans. The liver was considered fatty if its attenuation was equal to or less than that of the spleen on nonenhanced or delayed scans. The presence of intralesional calcifications or upper abdominal lymphadenopathy was also evaluated.
The attenuation of the lesion was judged relative to that of the surrounding liver on nonenhanced scans, as well as on scans obtained in each phase (HAP, PVP, and delayed phase) of contrast enhancement. A central scar was defined as an area of distinctly different attenuation in or near the center of the lesion on nonenhanced scans or at different phases of enhancement. The scar was considered large if it had a diameter of more than 1 cm. Septa were defined as linear structures radiating peripherally from the central scar. When a patient had serial images, the size stability of a lesion was assessed.
The exact number and nature of the hepatic tumors could not be determined because only one patient underwent liver transplantation, and none underwent autopsy. The total number of lesions detected with consensus interpretation of scans obtained in each phase of the multiphasic CT examination was used to judge the detection and characterization of the hepatic masses at each phase of imaging. Specific and detailed imaging criteria were sought and recorded for each lesion, each patient, and each study.
The protocol for this investigation was approved by our institutional review board at the University of Pittsburgh.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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CT Findings
Each radiologist identified 124 lesions in the 78 patients. Sixty patients (77%) had a single lesion, while 18 patients had multiple FNH lesions: One patient had 11 lesions believed to be FNH, one patient had eight, one patient had seven, three patients had four, two patients had three lesions, and the other 10 patients had two lesions. In all patients with multiple FNH lesions, the lesions were identified on multiphasic helical CT scans. Of the nine patients with conventional (nonhelical) CT scans, in none were multiple lesions detected. The lesions had a mean maximum diameter of 4.1 cm (range, 1–11 cm).
Interval Change
Of the 16 patients who underwent serial CT evaluation (mean follow-up, 25 months), seven patients had a temporal change in the size of the FNH. In two patients, the tumor decreased from 11.0 to 6.5 cm and from 10 to 4 cm after the interruption of oral contraceptive use during 12 months. The larger of these lesions became slightly heterogeneous and developed a focal calcification within the FNH. In one patient, a nodule of 3 cm newly appeared during 14 months. In one patient, a lesion increased in size from 4.0 to 5.5 cm in 18 months. In one patient, a lesion increased in size from 5.5 to 7.0 cm, and a nodule newly appeared during 12 months. In one patient, an FNH was detected with helical CT during HAP enhancement; this lesion was not detected with the conventional CT scan (nonenhanced and PVP phases) obtained 2 years previously. In one patient, the size (all 3 cm) and overall number of FNH apparently increased, while other FNH lesions were not visible on subsequent CT scans. All these lesions were well documented at repeated helical multiphasic CT, magnetic resonance (MR) imaging, ultrasonography, and radionuclide studies, along with biopsy of multiple lesions during 4 years. The patients remained healthy, with normal liver function. No patients in whom the size or number of FNH lesions increased or decreased had other evidence of hepatic malignancy, and none was receiving chemotherapy.
Four patients with breast carcinoma underwent biopsy of the FNH lesions (n = 3) or were followed up for 19 months, with no change in the size of the lesion (n = 1). Two patients with renal carcinoma underwent biopsy of the FNH lesion. One patient with seminoma was followed up for 48 months, with no change in size of a hypervascular subcapsular lesion and with imaging findings considered diagnostic of FNH. There has been no other evidence of metastatic disease among these patients.
CT Morphologic Features
A summary of characteristic CT findings is presented in Table 2. The surface of the FNH was smooth in 109 (88%) of 124 lesions (lobulated in 15 [12%] lesions), and the margins were ill-defined in 89 (72%) (sharply defined in 35 [28%]) (Fig 2). The lesions were predominantly in a subcapsular location in 101 (81%, deeper within the liver in 23 [19%]). Forty-three FNH lesions (35%) exerted a mass effect and displaced adjacent blood vessels. Exophytic growth, or distortion of the hepatic contour, was present in 40 (32%) lesions.
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CT demonstrated a central scar in 62 (50%) of the 124 tumors. The size of the central scar was described as small in 44 lesions (71%) and large in 18 lesions (29%) (Figs 2, 5). The central scar showed radiating septal bands that extended toward the periphery of the tumor in five lesions (8%) (Fig 2). In a comparison of the central scar with the surrounding mass, on nonenhanced scans the scar was hypoattenuating in 30 (54%) of 56 lesions and isoattenuating in 26 (46%). On HAP scans, the scar was hypoattenuating in 43 (90%) of 48 lesions, isoattenuating in three (6%), and hyperattenuating in two (4%). On PVP scans, the scar was hypoattenuating in 42 (68%) of 62 lesions, isoattenuating in 14 (22%), and hyperattenuating in six (10%). On delayed phase scans at 5 minutes, one (4%) of 27 scars was hypoattenuating, four (15%) were isoattenuating, and 22 (81%) were hyperattenuating. On 10–20-minute delayed scans, the scar was judged to be hypoattenuating in four (27%) of 15 lesions, isoattenuating in eight (53%), and hyperattenuating in three (20%) (Fig 2).
Size
In our series, 62 lesions were 3 cm or smaller in diameter. All but one of these lesions (61 [98%] lesions) were identified on helical CT scans. A central scar was identified less frequently in these smaller FNH lesions (22 [35%] lesions) than in the larger lesions (40 [65%] lesions). Small FNH lesions almost never had abnormal vessels identified within or around the lesion (n = 2) and rarely showed exophytic growth (n = 1) or displacement of adjacent vessels (n = 2). Small FNH lesions were isoattenuating to liver and nondetectable on nonenhanced (44 [71%] of 62 lesions), PVP (57 [92%] of 62 lesions), and delayed (45 [98%] of 46 lesions) CT scans and were invariably homogeneous. All 62 small FNH lesions showed homogeneous hyperattenuation to liver on HAP scans.
Only two lesions had CT characteristics that were substantially different, consisting of large (9- and 11-cm–diameter) lesions with a grossly lobulated contour, heterogeneous enhancement, large scar, and broad septa that demonstrated delayed persistent enhancement. One of these also had calcification within the central scar (Fig 5).
Associated Lesions
Of the 78 patients with FNH, 18 (23%) had at least one other benign hepatic tumor. Five (6%) had a hepatic adenoma, single in four and multiple in one. The solitary adenomas were 4.0, 7.0, 7.5, and 8.0 cm in diameter and were hypoattenuating to liver on nonenhanced and PVP scans; these were homogeneous (n = 3) or heterogeneous (n = 1) on both enhanced and nonenhanced scans. In the patient with multiple adenomas, the largest adenoma was 7.5 cm, and all adenomas were distinctly hypoattenuating to the nonenhanced liver due to the fat content in the lesions. The diagnosis of both adenoma and FNH was confirmed at histopathologic examination after resection (n = 3) or percutaneous biopsy (n = 2) of multiple masses.
Thirteen patients (17%) had an associated cavernous hemangioma. The hemangiomas were single in eight and multiple in five, ranging from 0.7 to 6.0 cm; these were isoattenuating to the blood pool on nonenhanced and enhanced CT scans and showed nodular peripheral enhancement. Only one patient had a congenital or acquired hepatic vascular anomaly, which was due to Budd-Chiari syndrome. In this patient, an angiogram showed occlusion of the vena cava in the intrahepatic portion, and the hepatic veins were not visualized.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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In our series of 78 patients with FNH, 18 (23%) had an associated benign vascular neoplasm. Hepatocellular adenoma was present in five, including one patient with adenomatosis (>10 adenomas). Other investigators have also noted this association: Nguyen et al (5) reported a surgical pathologic series of 305 FNH lesions in 168 patients and found hepatic adenomas in 3.6% and one case of adenomatosis. The same investigators found cavernous hemangiomas in 6.5% of the patients with FNH, lower than the 17% incidence in our series, and somewhat higher than the 2.3% incidence in another article (6). We also report a case of FNH in a patient with Budd-Chiari syndrome. All these associations serve to support the theory that hepatic vascular derangement predisposes the development of FNH.
Before helical multiphasic hepatic CT became prevalent, FNH was rarely diagnosed with confidence. Even with multiphasic CT, some authors (3) have reported atypical features of FNH that may hinder diagnosis. Our experience suggests that most FNHs are easily recognized on CT scans when proper CT techniques are used and when the size of the FNH and the status of the surrounding liver are taken into account.
A CT protocol designed to optimize detection and characterization of a focal hepatic mass would include the acquisition of nonenhanced sections and of images during the HAP, PVP, and ideally 5–10-minute delayed phase. On nonenhanced CT scans, FNH is usually isoattenuating (57% of our lesions) or slightly hypoattenuating (40%). FNH is only hyperattenuating to nonenhanced liver when there is hepatic steatosis or when the liver is otherwise abnormally decreased in attenuation. In some patients with hepatic steatosis, the FNH is still isoattenuating or hypoattenuating on nonenhanced CT; in rare cases, this may be due to fatty infiltration of the FNH itself (7).
FNH is usually isoattenuating to liver on PVP and delayed phase scans, which accounts for the rarity of this diagnosis in the pre–helical CT era. Depending on factors including the rate of contrast medium injection, scanning delay, and circulation time, the upper half of the liver may be scanned during the late HAP–early PVP of imaging, accounting for the tendency to observe hyperattenuating FNH in the dome of the liver on PVP scans, on both helical and nonhelical scans.
The most reliable CT signs of FNH are homogeneous bright enhancement and a central scar. These are optimally depicted with thin (5–7-cm) CT sections and helical scanning during the HAP (30–35-second delay) while an adequate volume of contrast medium (approximately 2 mL per kilogram of body weight) is injected at a rapid rate (4 or 5 mL/sec). With use of these factors, all of our FNH lesions were hyperattenuating on HAP scans. Additional common features of FNH in our series were smooth (nonlobulated) contour (88%), ill-defined margins (72%), and a subcapsular location (81%).
A central scar was identified on CT scans in 62 (50%) of the 124 FNH lesions and was small (<1 cm in width) in 71% of these (44 lesions). Radiating fibrous bands or septa were a characteristic but infrequent (8%) finding. The scar was almost always visualized as being hypoattenuating to the remainder of the FNH on nonenhanced and enhanced scans, except for delayed scans in which the retention of contrast material within the fibrous scar made it isoattenuating (15%) or even hyperattenuating (81%). Detection of a central scar was clearly related to the size of the FNH. A scar was identified in only 35% of FNH 3 cm or less in diameter but in 65% of larger FNH.
Other features of FNH also appear to be related to its size. Smaller lesions invariably enhance homogeneously, rarely distort liver architecture, and rarely have displaced or enlarged peritumoral blood vessels.
We do not consider many of the CT findings of FNH reported by other authors (3) to be atypical, even if they are encountered in a minority of lesions. As noted before, FNH is usually and predictably hyperattenuating to fatty liver on nonenhanced and enhanced CT scans. Larger lesions reliably demonstrate a central scar, may be slightly heterogeneous (mostly attributable to the fibrous septa), and demonstrate dilated feeding arteries or draining veins in 34% of lesions. Enlarged vessels on the surface of an FNH lesion and penetrating to the central scar are a well-recognized pathologic feature of FNH (5), and demonstration of such vessels on CT scans should not be regarded as suggestive of malignancy.
A pseudocapsule or capsulelike rim has also been reported (3,8) as an atypical feature of FNH. We detected such a pseudocapsule in 8% of our lesions. We recognized at least two potential causes for the FNH pseudocapsule. In patients with fatty liver, a pseudocapsule may be evident because compressed liver and mild fibrosis along the periphery of the lesion may be more dense than the liver or FNH (8). Another well-documented source of a capsulelike rim are the dilated vessels and sinusoids around the FNH (9). Again, we believe that good-quality CT scans should be expected to demonstrate such features in some FNHs and that a pseudocapsule should not be regarded as a sign of malignancy.
Relatively little is known about the natural course of FNH, but interval growth has been considered an atypical or worrisome finding. Oral contraceptive use is not responsible for the development of FNH, but they probably stimulate its growth. Mathieu et al (10) examined 216 women with FNH and found a correlation between cessation of oral contraceptive use and regression in size of FNH in two. We also report two patients in whom the FNH decreased from 11.0 to 6.5 cm in diameter and from 10 to 4 cm following cessation of oral contraceptive use. In most patients, regardless of whether oral contraceptives or other steroids are being used, most FNH appear to remain stable in size and number, while a few can be expected to show modest interval growth or decrease in size (10). FNH detectability and apparent size are clearly affected by the imaging protocol used. Variation in the volume of intravenously administered contrast material and rate of injection, CT scanning delays, and other technical factors surely account for some of the increased number and multiplicity of FNH cases that we and other investigators have found recently (11,12).
We continue to regard calcification as a rare finding in FNH, and such lesions would require further documentation of benignity in our practice. Caseiro-Alves et al (13) reported five FNH lesions with calcification in a series of 295 patients, and another isolated case was recently reported (2).
The differential diagnosis for FNH includes other hypervascular tumors such as adenoma, fibrolamellar and conventional hepatocellular carcinoma (HCC), small hemangiomas, and hypervascular metastases. While adenomas are also benign, they have a low-grade–malignancy potential, may bleed spontaneously, and are usually resected if large or if the diagnosis is in doubt (14). While adenomas are also most common in women of reproductive age, adenomas are more likely than FNH to contain areas of heterogeneity, fat, necrosis, hemorrhage, and calcification. Adenomas usually enhance less brightly and less homogeneously than FNH (14).
Fibrolamellar HCC is another hypervascular tumor occurring in young adults and usually contains a fibrotic scar. Despite these similarities, we believe that the differentiation of these malignant tumors from FNH is usually not difficult. Fibrolamellar HCC is usually first detected on images as a large (>10-cm), heterogeneous, lobulated mass with broad central or eccentric scars and radiating septa. Calcifications are found in 68% of fibrolamellar HCC, and obvious signs of malignancy such as lymphadenopathy (65%), metastases, and biliary and vascular invasion are found in the majority of cases (15). We did encounter two patients with large exophytic FNH lesions having lobulated margins and a broad scar resembling fibrolamellar HCC. Such cases require a higher standard of proof including core biopsy and close follow-up.
Most large (>3-cm) FNH lesions are easy to diagnose with confidence, in our experience, because they demonstrate the characteristic thin central scar (65%) and homogeneous hypervascularity. FNH lesions smaller than 3 cm less often have a visible scar (35%) and may be more difficult to distinguish from other hypervascular tumors. Clinical information and common sense, however, allow confident management in most cases.
Conventional HCC usually occurs in a setting of chronic liver disease, causes elevated serum tumor markers, and usually has different imaging characteristics than those of FNH. HCC is typically heterogeneous and hypoattenuating to normal liver on nonenhanced, delayed, and some PVP scans, while FNH is usually homogeneous and isoattenuating on these scans. HCC is often accompanied by other signs of malignancy, including vascular invasion and metastases (16).
Hypervascular metastases usually occur in the setting of a known malignancy or one evident on the CT scan demonstrating the liver lesion. Metastases, as compared with FNH, are more often multiple, heterogeneous, and less likely to be isoattenuating to liver on nonenhanced, PVP, and delayed CT scans (17).
Most hemangiomas are easily diagnosed with CT due to characteristic nodular, peripheral, and progressive enhancement. Small hemangiomas may be uniformly hyperattenuating on HAP scans but are usually similar to blood pool attenuation on all phases of enhanced and nonenhanced CT, unlike FNH (18).
When CT findings are not considered diagnostic of FNH, or in the presence of a known or suspected hypervascular malignancy, further evaluation may be necessary. Technetium hepatobiliary scintigraphy, or 99mTc HIDA, will demonstrate uptake and delayed excretion of the radiotracer in about 90% of FNH lesions (19). Core-needle biopsy is the most definitive test, but it is essential to acquire tissue from the center of the FNH lesion where the presence of bile ductules along with other hepatic tissue is diagnostic of FNH.
Our study has several limitations, including lack of histologic proof of every lesion in every patient. However, within the limits of ethical patient care, we believe that we have compelling evidence of the benign nature and likely histologic characteristics in all our cases. Ours was a retrospective descriptive study meant to establish reliable CT criteria for identifying FNH with optimized CT techniques. With the recent publication of a series of articles (14–18) with substantial numbers of patients with other hypervascular liver tumors examined at helical multiphasic CT, we believe that we now have the basis to conduct a prospective or carefully designed retrospective trial to test the accuracy of CT in this setting.
In conclusion, FNH has become a more common diagnostic consideration in the helical CT era. FNH is a benign-appearing homogeneous mass with attenuation similar to that of normal liver on nonenhanced, PVP, and delayed phase scans; however, it enhances brightly and homogeneously on HAP scans. Lesions larger than 3 cm in diameter usually demonstrate a thin scar, and all FNH lesions typically have a smooth though ill-defined margin and are usually subcapsular. Exophytic growth, presence of a pseudocapsule, peritumoral vessels, and hyperattentuation to fatty liver should not mitigate against this diagnosis. When helical multiphasic CT demonstrates findings characteristic of FNH, further evaluation is often not necessary.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, G.B., M.P.F.; study concepts and design, M.P.F.; definition of intellectual content, G.B., M.P.F.; literature research, G.B.; clinical studies, all authors; data acquisition, all authors; data analysis, G.B., M.P.F.; manuscript preparation, all authors; manuscript editing, M.P.F.; manuscript review, M.P.F.; manuscript final version approval, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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