British Journal of Radiology (2007) 80, e317-e320
© 2007 British Institute of Radiology
doi: 10.1259/bjr/97773297
Hepatoid adenocarcinoma of the gallbladder: a mimicker of hepatocellular carcinoma
I C van den Bos, MD, PhD
1
S M Hussain, MD, PhD
1,4
R S Dwarkasing, MD
1
H Stoop, MSC
2
P E Zondervan, MD
2
G P Krestin, MD, PhD
1 and
R A de Man, MD, PhD
3
Departments of 1 Radiology, 2 Pathology and 3 Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands and 4 Department of Radiology, University of Nebraska Medical Center, Omaha, NE, USA
Correspondence: Indra C van den Bos, MD, Department of Radiology, Erasmus MC, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: vandenbos.ic{at}gmail.com
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Abstract
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We present a case of a large gallbladder tumour in a patient with no known liver disease and elevated 
-fetoprotein (AFP), in whom a differential diagnosis from hepatocellular carcinoma (HCC) in a non-cirrhotic liver was particularly difficult given the combination of the size of the tumour, solitary nature, elevated AFP and striking resemblance with HCC at histology. In presenting this patient, we would like to emphasise the role of MRI as a problem-solving tool for analysis of rare tumours of non-hepatocellular origin, including hepatoid adenocarcinoma of the gallbladder.
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Introduction
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Hepatoid adenocarcinoma (HAC) is a rare variant of extrahepatic adenocarcinoma, consisting of foci of both adenomatous and hepatocellular differentiation that behave like hepatocellular carcinoma (HCC) in morphology and functionality [1]. It occurs in a multitude of organs: most frequently in the stomach [2, 3], but also rarely in other areas, including the lung [4], kidney [5], female reproductive tract [6, 7], pancreas [8] and gallbladder [1, 9]. Typically, an elevated level of serum -fetoprotein (AFP) is detected, although normal levels have also been described [2, 3]. We report a patient with a large tumour in the gallbladder detected on MRI combined with an elevated serum AFP. Differential diagnosis from HCC in a non-cirrhotic liver was particularly difficult given the combination of the size of the tumour with invasion of the surrounding liver, solitary nature, elevated AFP, and striking resemblance with HCC at histology.
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Case report
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A 55-year-old woman was referred to our hospital for evaluation of a hepatic mass. The lesion was discovered on ultrasound performed in another clinic for work-up of right upper quadrant abdominal pain. Previous history was unremarkable. At physical examination, no abnormalities were noted. Routine laboratory investigations were performed, showing slightly elevated liver enzymes and abnormally elevated AFP (511 µg ml–1; normal values <20 µg ml–1). Hepatitis B and C serology tests were negative. MRI was performed for further characterization of the lesion, which confirmed the presence of a well-demarcated tumour adjacent to the gallbladder, with a diameter of 7 cm (see Figure 1
). The liver demonstrated normal size and morphology, without signs of cirrhosis.
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Figure 1. (a) Axial opposed-phase T1 weighted gradient-echo (GRE) (shortest/2.3) shows hypointensity of the lesion compared with the surrounding liver, and shows that the lesion originates in the fundus of the gallbladder. (b) Axial fat-suppressed T2 weighted fast spin-echo (3000/80) shows faint hyperintensity of the lesion. (c) Axial arterial phase gadolinium-enhanced T1 weighted GRE (shortest/shortest) shows patchy, predominantly peripheral enhancement of the lesion. (d) Axial three-dimensional delayed phase fat-suppressed T1 weighted GRE (shortest/shortest) shows that the lesion retains the contrast material with a patchy distribution.
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MRI findings
On T1 weighted gradient-echo images, the lesion was hypointense to the surrounding liver parenchyma (Figure 1a
). The tumour was located in the gallbladder fossa, with a slightly bilobar shape, causing narrowing of the gallbladder lumen. The gallbladder wall showed discontinuity, which confirmed that the lesion originated in the gallbladder (Figure 1b,d). Fat-suppressed T2 weighted fast spin-echo (FSE) images showed hyperintensity of the tumour, without evidence of internal nodules or internal heterogeneity (Figure 1b). Specifically, the signal intensity was higher in the periphery of the lesion, with slightly lower values in the centre, suggestive of central fibrosis. After intravenous administration of non-liver-specific gadolinium chelate (Magnevist (gadopentetate dimeglumine); Schering, Berlin, Germany), the lesion enhanced predominantly in the periphery (Figure 1c). Dynamic gadolinium-enhanced images revealed peripheral enhancement in the arterial phase, slowly progressing centripetally (Figure 1c,d). In the delayed phase, no clear washout of contrast material was seen, and no tumour capsule could be detected. In addition, three small lesions with diameter <1 cm were observed in the proximity of the tumour, with identical signal intensity at fat-suppressed T2 weighted imaging and after contrast administration. These alterations were suspect for metastases and satellite lesions. For further characterization of the tumour, additional imaging using a liver-specific contrast medium was performed (superparamagnetic iron oxide particle (SPIO) contrast agent, Resovist; Schering). After uptake of SPIO, fat-suppressed T2 weighted FSE showed no evident decrease in signal intensity within the lesion, indicating that it was not a primary tumour with an abundant amount of Kupffer cells. This finding virtually excluded the possibility of well-differentiated HCC, hepatocellular adenoma and focal nodular hyperplasia. The findings of the MRI examination posed a diagnostic dilemma: the combination of signal intensity, morphology of the tumour, close proximity to the gallbladder and enhancement pattern was strongly suggestive of a cholangiocarcinoma or another type of malignant lesion originating from the gallbladder. However, the elevated serum AFP, solitary nature, large size, non-cirrhotic liver suggested HCC as the most likely diagnosis. Therefore, the final differential diagnosis comprised HAC of the gallbladder, cholangiocarcinoma and HCC. We considered HAC the most likely diagnosis because this entity shows hepatoid differentiation and can present with a liver tumour and elevated AFP [1].
Histology
Subsequently, ultrasound-guided percutaneous liver biopsy was performed. At microscopic evaluation, a combination of hepatocyte-like structures and adeno-structures was observed embedded in a fibrous tissue matrix (Figure 2a). Some trabecular formations were present. Immunohistochemical analysis showed positivity for cytokeratin CK7 and CK19 in all areas, whereas CK20 was negative. These findings by themselves supported the general diagnosis of a carcinoma. In addition, CD10 positivity was observed, which indicated sporadic canalicular differentiation (Figure 2b,c). Staining with AFP showed cytoplasm positivity (Figure 2d). CD56 staining showed slight positivity in the cell membrane in more solid areas. These findings provided evidence for hepatocellular differentiation of the tumour, suggesting HCC or perhaps HCC combined with cholangiocarcinoma (CC). However, the combination of (i) immunohistochemical results with positivity for CD10, (ii) the canalicular formation of some cells together with high serum AFP and (iii) the location of the tumour was atypical for diagnosis of either HCC or HCC-CC. Therefore, the most likely histological diagnosis was HAC.
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Figure 2. (a) Photomicrograph (haematoxylin and eosin stain, original magnification x200) shows a detailed view of the tumour with solid areas and adeno structures. (b) Photomicrograph (stained with endothelial marker CD 10, x400) shows positivity (arrows), indicating canalicular differentiation of areas within the tumour. (c) Photomicrograph (stained with cytokeratin CK 7, x200) shows abundant positive staining, indicating epithelial differentiation. (d) Photomicrograph (stained with -fetoprotein, x200) shows widespread positivity, and hence a hepatocellular origin of the tumour.
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Even though the location of the tumour was problematic for successful resection, it was decided to perform exploratory hepatic surgery to assess operability. At surgery, however, liver metastases were detected, confirming the MRI findings of suspected metastases in proximity to the tumour. Currently, the patient is undergoing palliative chemotherapy and is in reasonable condition.
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Discussion
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HAC is a rare form of adenocarcinoma with hepatoid differentiation of the tumour cells. In this report, we describe a patient with a large gallbladder tumour in combination with high AFP, for which the signal intensity on T2 weighted images showed predominantly high signal intensity in the periphery of the lesion, and hypointensity in the center of the lesion, without clear heterogeneity. The enhancement pattern on dynamic gadolinium-enhanced images showed slow peripheral enhancement with centripetal progression over time, without washout or capsule enhancement. Given the combination of tumour morphology and location, signal intensity, contrast enhancement and high AFP in the absence of cirrhosis, HAC of the gallbladder was the most likely diagnosis. HCC in a non-cirrhotic liver was less likely, as these tumours are usually very large at presentation, with striking heterogeneity and capsule formation [10, 11].
These findings are clinically relevant, as HCC, combined HCC-CC with peripheral localization or HAC all have a different therapeutic approach, especially in a non-cirrhotic liver. As in our patient, because of localization of the tumour within the gallbladder wall, differentiation from HCC or combined HCC-CC is challenging. Additional immunohistochemistry is often helpful for tumour characterization [1, 3, 9, 12]. In our patient, diffuse positivity with CK7 and CK19 was observed, which suggested the presence of an adenocarcinoma. In addition, CD10 was sporadically positive, indicating canalicular differentiation and thus hepatocellular origin. This was also supported by positivity for AFP, although some rare cases of AFP-negative HAC in the gallbladder have been described [9]. The combination of positivity for CD10, the canalicular formation of some cells in combination with high serum AFP, and the location of the tumour supported hepatoid adenocarcinoma as the most likely diagnosis. As has been described by Sakamoto et al [12], HCC or combined HCC-CC invading the gallbladder is the main differential diagnosis for gallbladder HAC. In these cases, considering the clinical presentation can be helpful, as HCC occurring in a non-cirrhotic liver is typically very large, with striking heterogeneity and capsule formation.
The present case demonstrates the value of MRI for lesion characterization. The unique ability to detect intrinsic cellular characteristics, combined with dynamic contrast-enhanced imaging, render MRI superior for detection and characterization of focal liver lesions [13]. MRI findings of HCC in non-cirrhotic liver tissue are well known [10, 11]. Typically, a solitary large tumour is observed with striking heterogeneity, inhomogeneous enhancement, capsule formation and often a central scar [10, 11]. HCC in a cirrhotic liver, however, has quite different imaging characteristics, including a mosaic pattern or multinodularity, hyperintense signal intensity on T2 weighted images, intense arterial enhancement with washout in delayed phase contrast-enhanced imaging, and delayed enhancement of a tumour capsule [11]. Larger HCC often show a multinodular or mosaic pattern within the lesion, with fibrous septa surrounding the nodules, which enhance in the portal and delayed phases after contrast administration [14]. Typical imaging findings of cholangiocarcinoma include hypointensity on T1 weighted images, hyperintensity on T2 weighted images with central hypointensity and peripheral enhancement, and centripetal progression on delayed phase images [15]. Imaging findings of primary gallbladder carcinoma are different, with eccentric tumour formation in 76% of cases, liver invasion in 91% of cases, and marked heterogeneity and inhomogeneous enhancement after contrast administration [16]. As demonstrated in our case, the combination of imaging findings before and after contrast administration did not fit the diagnosis of HCC, cholangiocarcinoma or primary gallbladder carcinoma. Given the combination of tumour morphology and location, signal intensity, contrast enhancement and high AFP in absence of cirrhosis, HAC of the gallbladder was the most likely diagnosis at MRI, and was subsequently confirmed by histoimmunochemical analysis of the tumour.
In presenting this patient, we would like to emphasise the role of MRI as a problem-solving tool for analysis of rare tumours of non-hepatocellular origin, including HAC of the gallbladder.
Received for publication May 30, 2006.
Revision received August 30, 2006.
Accepted for publication September 7, 2006.
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Abstract
Introduction
