Kaohsiung Journal of Medical Sciences (2015) 31, 621e625
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ORIGINAL ARTICLE
Variable uptake feature of focal nodular hyperplasia in Tc-99m phytate hepatic scintigraphy/single-photon emission computed tomographydA parametric analysis Yu-Ling Hsu a, Yu-Wen Chen a,d,*, Chia-Yang Lin a, Yun-Chang Lai a,c, Shinn-Cherng Chen b,d, Zu-Yau Lin b,d a
Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan b Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan c Department of Public Health College of Health Science, Kaohsiung Medical University, Taiwan d Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Received 26 December 2014; accepted 25 September 2015
Available online 23 November 2015
KEYWORDS Focal nodular hyperplasia; Kupffer cells; Tc-99m phytate scintigraphy/singlephoton emission computed tomography
Abstract Tc-99m phytate hepatic scintigraphy remains the standard method for evaluating the functional features of Kupffer cells. In this study, we demonstrate the variable uptake feature of focal nodular hyperplasia (FNH) in Tc-99m phytate scintigraphy. We reviewed all patients who underwent Tc-99m phytate hepatic scintigraphy between 2008 and 2012 in Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Cases with FNH were diagnosed on the basis of pathology or at least one or more prior imaging with a periodic clinical follow-up. All patients received a standard protocol of dynamic flow study and planar and Tc-99m phytate single-photon emission computed tomography (E. CAM; Siemens). The correlation of variable nodular radioactivity with parameters such as tumor size and localization was analyzed. In total, 15 lesions of 14 patients in the clinic were diagnosed as FNH. The tumor size was approximately 2.9e7.4 cm (mean size 4.6 cm). Four lesions were larger than 5 cm. The major anatomic distribution was in the right hepatic lobe (10 lesions), particularly in the superior segments (7 lesions). Tc-99m phytate single-photon emission computed tomography imaging for determining the functional features of Kupffer cells included cool/ cold (8 lesions), isoradioactive/warm (6 lesions), and hot (1 lesion) patterns of uptake. We did not observe any statistically significant correlation between variable nodular
Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. E-mail address:
[email protected] (Y.-W. Chen). http://dx.doi.org/10.1016/j.kjms.2015.09.010 1607-551X/Copyright ª 2015, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
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Y.-L. Hsu et al. radioactivity and tumor size (p Z 0.68) or localization (p Z 0.04). Herein, we demonstrate the variable uptake feature of FNH in Tc-99m phytate scintigraphy. In small FNH tumors (< 5 cm), increased or equal uptake still provided specificity for the differential diagnosis of hepatic solid tumors. Copyright ª 2015, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
Introduction Focal nodular hyperplasia (FNH) is the second most common benign solid liver tumor; it constitutes approximately 8% of all primary hepatic neoplasms and is present in 0.3e3% of the general population [1e3]. These tumors are most frequently diagnosed in women (10:1) aged 20e50 years [4]. At present, the pathophysiology of FNH remains unclear. However, a new hypothesis posits that FNH genesis is secondary to vascular malformation, which produces hyperperfusion in the area of hepatic parenchyma, which determines a hyperplastic response to this phenomenon without the risk of malignant transformation [1,5] or bleeding, thus eliminating the need for aggressive treatment [6,7]. Patients with FNH are asymptomatic and identified incidentally during imaging. However, approximately 25% of patients initially exhibit related symptoms, such as epigastric pain or a palpable mass. The absolute differential diagnosis with other solid hypervascular hepatic tumors, such as hepatic cellular adenoma or hepatic cellular carcinoma, remains difficult. Contrast computed tomography (CT) and magnetic resonance imaging (MRI) scans are the choices for detecting the typical features, such as a uniform pattern of hypervascularity after contrast enhancement and a central scar of fibrovascular tissue, for FNH diagnosis. Unfortunately, these typical features are not always present [8,9]. In a study of 305 patients with FNH, Nguyen et al. [10] reported that a central scar was only found in approximately 50% of the cases. Hepatic scintigraphy with Tc-99m sulfur colloid or phytate provides specificity for FNH diagnosis. Findings revealed that, compared with CT, MRI, or ultrasound, phytate imaging reveals the typical characteristics of solid tumors more effectively because of the increased or equal uptake of radiopharmaceuticals by the tumors, called “hot or warm nodules,” compared with adjacent hepatic tissues. Although its use in Taiwan is decreasing, Tc-99m phytate hepatic scintigraphy remains an excellent tool for evaluating the functional status of Kupffer cells. In this paper, we include several cases with FNH demonstrating the variable uptake feature in Tc-99m phytate hepatic scintigraphy and propose a hypothesis for these phenomena according to a recent literature review.
Methods We reviewed all patients who underwent Tc-99m phytate (off-label usage) hepatic scintigraphy in Kaohsiung Medical
University Hospital, Kaohsiung, Taiwan, between 2008 and 2012. In total, 25 patients were reviewed. Among them, five patients, diagnosed with hepatocellular carcinoma (HCC), were excluded. The inclusion criteria for FNH included cases diagnosed on the basis of pathology; those with at least one CT, MRI, or ultrasound supporting diagnosis; or those clinically treated for FNH with a long-term follow-up. In total, 14 patients with 15 lesions were included. After intravenous injection of 6mCi Tc-99m phytate, all patients underwent a standard protocol of Tc-99m phytate hepatic scintigraphy as a dynamic flow study (2 seconds per frame, 32 frames), planar imaging (anterior, posterior, and lateral views), and single-photon emission computed tomography (SPECT; E. CAM; Siemens, Cleveland, Ohio, USA). All imaging was reviewed by at least two experienced nuclear medicine physicians. According to the tumor sphere-growth theory, the size of the mass is represented as a volume estimated on the basis of the greatest length of the mass in ultrasound or CT imaging. Compared with adjacent hepatic parenchyma, tumor masses were classified on a 5-point scale as exhibiting a cold, cool, isoradioactive, warm, or hot pattern on the basis of their radioactivity uptake in single-photon imaging. Following a statistical analysis, we performed a Chi-square test and multiple linear regressions to analyze correlations between all the parameters.
Results We recruited 14 patients diagnosed with FNH who had a total of 15 lesions. Nine of the patients (64%) were women and the rest (36%) were men. One woman had two lesions. The age range was from 23 years to 45 years, with a mean age of 31.6 6.2 years. The tumor size ranged from 2.9 cm to 7.4 cm, with a mean size of 4.6 1.5 cm. Among the lesions, 11 were smaller than 5 cm (73%). In the dynamic flow study, we found that only two lesions (13%) had a hyperhepatic flow. The lesions were classified among five groups by comparing their uptake features with those of hepatic parenchyma: four (26.7%) were cold lesions, four (26.7%) cool lesions, three (20%) isoradioactive lesions, three (20%) warm lesions, and one (6.7%) a hot lesion. Thus, seven lesions (46.7%) satisfied the diagnostic criteria for FNH. Figure 1 shows the typical features of “warm and cold nodules.” The anatomical distribution of these lesions is as follows: one in the liver segment S1/2 (7%); four in S3/4 (27%); three in S5/6 (20%); and seven in S7/8 (46%) of the liver. Most of the lesions were located in the liver segment S7/8 (Figure 2).
FNH variable feature on Tc99m phytate scan
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Figure 1. (A) Case with an “isoradioactive or warm” lesion in S5 (as indicated by the arrow); labeled as “score 3.” (B) Case with a “cold” pattern in S7 (as indicated by the arrow); labeled as “score 1.”
We defined multiple parameters in our study, such as patient age, tumor location, tumor size, and tumor radioactivity. We analyzed the correlation between all these parameters by performing the Chi-square test and multiple linear regressions. All the tumors were given one of the five scores: score 1 (cold), 2 (cool), 3 (isoradioactive), 4 (warm), or 5 (hot). Various cutoff values were used for the statistical analysis. The p values were also calculated. No statistically
Figure 2. Distribution of tumors: most focal nodular hyperplasia lesions in our cases are localized in superior segments of the right hepatic lobe.
significant correlation was observed between the radioactivity uptake feature of hepatic tumors and tumor size or localization (Figures 3 and 4).
Discussion Kupffer cells in hepatic sinusoids were first discovered by Carl Wilhelm von Kupffer (1865). These cells, belonging to the mononuclear phagocyte system, constitute the largest tissue macrophage population in the body (80e90%) [11]. Thus, hepatic uptake is the major uptake seen after
Figure 3. score.
Correlation between tumor size and radioactivity
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Figure 4. Correlation between segments with localized hepatic tumors and radioactivity scores.
intravenous injection of Tc-99m sulfur colloid or phytate in healthy people. The liver is an immunological organ [12]. Kupffer cells exhibit various mechanisms, such as phagocytosis, metabolism, cytokine generation, and antitumor effects. In addition, these cells play a crucial role in the host defense mechanism and in maintaining homeostasis [13e15]. Kupffer cells can be classified into two types on the basis of topological and functional heterogeneity. Large Kupffer cells are located in the periportal zone and respond to incoming molecular signals; therefore, they exhibit higher phagocytosis, lysosomal protease activity, and output of biologically active mediators than smaller Kupffer cells in the midzonal and perivenous areas [15e17]. A liver impairment (e.g., hepatitis or cirrhosis) is speculated to reduce the functional capacity of Kupffer cells [18]. Recently, the functional capacity of M1/M2 Kupffer cells was found to play a role in the potential mechanism of alcoholic/nonalcoholic fatty liver disease [15,19,20]. As mentioned, a new hypothesis posits that FNH genesis is secondary to vascular malformation, which produce hyperperfusion in the area of hepatic parenchyma. Therefore, alternative Kupffer cells in the affected region will likely change in number or functional capacity. The functional features of Kupffer cells in FNH can be properly demonstrated using Tc-99m phytate hepatic scintigraphy. Phytate uptake was normal in approximately 60e75% of cases, reduced in 25e30% of cases, and increased in 5e10% of cases, reflecting a variable number of Kupffer cells [21e24]. Among our 15 cases, eight (53%) exhibited reduced phytate uptake, three (20%) normal uptake, and four (27%) increased uptake. The varied distribution could be due to a variation in the population. The reason for the increased or equal uptake of Tc-99m phytate (sulfur colloid) in FNH compared with that in hepatic adenoma remains contentious. According to traditional concepts, hepatic cellular adenomas tend to be cold because of the loss of their Kupffer cell content. However, a study conducted by the Armed Forces Institute of Pathology (Washington, DC, USA) demonstrated the presence of Kupffer cells in 12 cases with hepatic adenoma [25]. Among them, 10 were shown, by hepatic scintigraphy, to be cold nodules and two to be cool or isoradioactive nodules. An analysis of the 10 cold nodules revealed that six had a normal number of Kupffer cells, which was related to a normal liver, whereas the remaining four nodules had a decreased number of Kupffer cells. No direct relationship
Y.-L. Hsu et al. was observed in hepatic scintigraphy between the number of Kupffer cells and the uptake feature of the nodules. Therefore, the uptake feature of lesions in hepatic scintigraphy is likely related to a combination of factors, such as the number and functional status of Kupffer cells in these lesions and blood flow. In our dynamic flow study, we examined two cases with hypervascularity and the uptake of the colloid still varied. We could not find strong evidence of a correlation between tumor size or localization and its radioactivity uptake. Notably, almost half of the lesions of our patients were found in the right hepatic lobe (S7/8), consistent with the literature (Figures 2 and 4). To our knowledge, there are no reports with exact declaration. As the hepatic right lobe constitutes the largest part of the liver, the incidence of FNH is probably greatest in it. Most of the FNH tumors in this study (11 of 15) were smaller than 5 cm (Figure 3). The small FNH tumors (< 5 cm) predominantly exhibited increased or equal uptake (7 of 11; 64%) for scores above 3. By contrast, the large FNH tumors (> 5 cm) exhibited a decreased uptake (3 of 4). In our study, 27% of FNH tumors were large (> 5 cm); therefore, we observed fewer tumors (47%) with isoradioactivity or increased radioactivity uptake. In addition, a change in the microenvironment with the growth of a tumor will be one of the potential factors contributing to the alteration of the functional capacity of Kupffer cells. No statistically significant correlation was observed between radioactivity uptake and tumor size. However, small FNH tumors (< 5 cm) seem to exhibit a trend of increased or equal uptake, providing specificity for differentiating between solid tumors in CT or MRI imaging. As Tc-99m phytate or colloid has been used in hepatology for decades, this method remains the standard method for evaluating the functional features of Kupffer cells. We demonstrated the variable uptake feature of FNH; however, the traditional warm/hot pattern was exhibited by only 47% of FNH tumors. This does not suggest that the Tc-99m phytate or colloid study is no longer helpful in the differential diagnosis of FNH. We emphasize that the cold/cool tumors cannot be ruled out as FNH. Tumor size and localization are also provided as reference parameters. The only limitation of our study was the small sample size. Therefore, we must include more cases to increase our sample size and further analyze the molecular status of Kupffer cells in the future. Herein, we demonstrated the variable uptake feature of FNH in Tc-99m phytate scintigraphy. The increased or equal uptake by small FNH tumors (< 5 cm) still provides specificity for the differential diagnosis of hepatic solid tumors.
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