Clin J Gastroenterol (2014) 7:271–277 DOI 10.1007/s12328-014-0483-5
CASE REPORT
A case of progressing focal nodular hyperplasia and its molecular expression pattern Kazuto Tajiri • Koichi Tsuneyama • Kengo Kawai • Yoshinari Atarashi • Masami Minemura • Shigeaki Sawada Kazuhiro Tsukada • Johji Imura • Toshiro Sugiyama
•
Received: 17 January 2014 / Accepted: 23 March 2014 / Published online: 12 April 2014 Ó Springer Japan 2014
Abstract We report the case of an adult male with progressing focal nodular hyperplasia (FNH). Although imaging studies suggested that the tumor was a classical FNH, the tumor biopsy showed glutamine synthetase expression and heat shock protein 70 in part of the tumor. As we could not definitely distinguish this case of FNH from early hepatocellular carcinoma (HCC), we performed laparoscopic partial hepatectomy. The surgical resected specimen showed that the tumor had a central scar with vascular and cholangiolar proliferation, which is compatible with FNH. Immunohistochemical analysis showed that the molecular expression pattern was compatible with FNH in the center of the tumor, whereas it partly resembled early HCC in the periphery of the tumor. FNH progression is occasionally found, and the molecular pattern of the progressing area in FNH might resemble that of early HCC due to morphologic and phenotypic changes induced by the regenerative mechanism and the alteration of blood flow. We should carefully observe progressing FNH.
K. Tajiri (&) K. Kawai M. Minemura T. Sugiyama Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama 930-0194, Japan e-mail: [email protected] K. Tsuneyama J. Imura Diagnostic Pathology, University of Toyama, 2630 Sugitani, Toyama, Japan Y. Atarashi Department of Gastroenterology, Toyama Rosai Hospital, 992 Rokuroumaru, Uozu, Japan S. Sawada K. Tsukada The Second Department of Surgery, Toyama University Hospital, 2630 Sugitani, Toyama, Japan
Keywords Progressing focal nodular hyperplasia Glutamine synthetase Immunohistochemistry
Introduction Focal nodular hyperplasia (FNH) is the second most common benign hepatic tumor after hemangioma [1, 2]. FNH is found predominantly in females between 30 and 50 years of age [1, 3]. FNH is characterized by a stellate central scar and hyperplastic nodules, and FNH nodules are usually solitary but may be multiple in about 20 % of cases [1]. Furthermore, most FNH are asymptomatic and do not require invasive therapy. Imaging studies such as ultrasonography (US), computed tomography (CT), or magnetic resonance imaging (MRI), are used for the diagnosis of FNH, and among them contrast-enhanced MRI has been shown to be the most sensitive modality for the diagnosis [4]. However, some FNH are difficult to definitely diagnose and progress with pain or abdominal hemorrhage in a few cases; therefore, invasive treatments involving surgical resection may be required [5, 6]. Recently, molecular pathogenesis of benign hepatocellular tumors has been explored and applied to clinical classification [7–10]. Glutamine synthetase (GS) has been reported to be a useful marker in differentiating hepatic nodules including FNH, hepatocellular adenoma (HCA), and nodules in cirrhosis [9, 10]. The combination of GS and heat shock protein 70 (HSP70) or glypican 3 (GPC3) had been reported to be useful to differentiate benign nodules and early hepatocellular carcinoma [10, 11]. Furthermore, the expression of molecular markers such as liver fatty acid binding protein (LFABP), serum amyloid A (SAA), C reactive protein (CRP), and b-catenin, are useful to classify hepatocellular benign tumors and apply to personalized clinical care [7, 8].
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272 Fig. 1 CT findings. (A) Dynamic CT findings. Each panel represents the indicated phase. After bolus administration of contrast medium, 30 s, 60 s, and 180 s represent artery phase, portal phase, and delayed phase, respectively. (B) CT angiography findings. Each panel represents the indicated phase. CT-arterial portography (CT-AP) shows the image approximately 20 s after bolus administration of contrast medium to superior mesenteric artery. After bolus administration of contrast medium to hepatic artery, 7 s, 20 s, and 180 s represent early artery phase, late artery phase, and delayed phase, respectively. (C) MRI findings of the tumor. Images of T1- and T2-weighted MRI are shown in the upper column. Images in Gd-EOBDTPA-enhanced MRI at indicated time
Clin J Gastroenterol (2014) 7:271–277
A
B
Plain
CT-AP
C
Artery phase
Portal phase
Early artery phase
Late artery phase
Delayed phase
T2
T1 In
Delayed phase
Diffusion
Opposed
EOB-Primovist pre
Here, we report the case of a young adult male showing liver tumor progression which was compatible with FNH by imaging studies. He had undergone surgical resection
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65sec
5min
15min
because we could not rule out the possibility of malignancy due to tumor growth and the molecular pattern found on tumor biopsy.
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Fig. 2 Liver biopsy findings. (A) HE staining, 9 40. (B) HE staining, 9 400. (C) GS, 9 4. (D) HSP70, 9 4. T, Tumor area, N, normal parenchyma area
Case Report A 35-year-old Japanese male was referred to our hospital for evaluation of a progressing liver tumor. A 2-cm diameter liver tumor was accidentally found by CT when he was admitted for diverticulitis. He had been observed every 3-6 months because enhanced CT and MRI findings suggested that the liver tumor was FNH. Although he had been healthy and asymptomatic, CT examination showed that the liver tumor has increased to a diameter of 3 cm over 6 months. On dynamic CT study, the tumor in segment 8 showed hypo-attenuation in the plain phase, hyperattenuation in the artery phase, slight hyper-attenuation in the portal phase, and iso-attenuation in the late phase (Fig. 1A). On Angio-CT, the tumor showed hypo-attenuation on CT arterial portography, hyper-attenuation from the center to the whole of tumor on CT hepatic arteriography, and central stellate and corona-like enhancement in the delayed phase (Fig. 1B). These CT findings showed the tumor was a hyper-vascular tumor with a central scar, compatible to FNH. MRI examination implied that the tumor was hyper-vascular, of little fat composition, and of gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) uptake except for the central stellate
lesion (Fig. 1C). The patient had a mild drinking habit, but the consumption of alcohol was \20 g/day. Furthermore, biochemical examination of his blood concerning liver function was normal (aspartate aminotransferase 21 U/L, alanine aminotransferase 23 U/L, gamma-glutamyl transpeptidase 50 U/L, alkaline phosphatase 234 U/L, albumin 4.2 g/dL, total bilirubin 0.6 mg/dL). He showed neither hepatitis virus B nor hepatitis virus C infection (hepatitis B surface antigen, anti-hepatitis B core antibody, and antihepatitis C antibody were negative), and his serum alphafetoprotein and des-gamma carboxyprothrombin levels were normal. These findings also supported the diagnosis of FNH. US-guided percutaneous tumor biopsy was performed because the tumor was increasing in size; this showed thickening of the liver cell plate and pseudocholangiolar proliferation (Fig. 2A, B). When we immunohistochemically analyzed the expression of glutamine synthetase (GS) and heat-shock protein (HSP) 70 to rule out early hepatocellular carcinoma (HCC), both were diffusely found in the tumor (Fig. 2C and D, respectively). Finally, we could not rule out the possibility of early HCC. Therefore, laparoscopic partial hepatectomy was performed after informed consent was provided. Macroscopic findings showed the
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274 Fig. 3 Surgical specimen findings. (A) Macroscopic findings. (B) H&E staining at the center of the tumor. Fibrous scar and cholangiolar proliferation were found, 9 100. (C) H&E staining at the periphery of the tumor, 9 400. (D) H&E staining at the edge of tumor and background liver. Arrows represent the margin of the tumor, 9 400. (E) - (G) right upper inset represents the image of the center of the tumor [C] at high magnification, and right lower inset represents the periphery of the tumor [P] at high magnification. (E) GS staining. (F) HSP70 staining. (G) OATP1B3 staining
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Table 1 Molecular expression patterns of hepatic tumors Tumor
GS
HSP70
LFABP
SAA
CRP
b-Catenin
OATP
HCC
?
?
?
-
-
?
-
HNF1a-inactivated HCA
-
-?
-
-
-
-
;
b-Catenin-activated HCA
?
-?
?
-
-
?
?
Inflammatory HCA
-
-?
?
??
??
-
;
Unclassified HCA
-
-?
?
-
-
-
- *?
FNH
Map like
-?
?
-
-
-
?
Our case periphery center
?
?
?
-
-
-
?
Map like
-
?
-
-
-
Map like
GS, glutamine synthetase; HSP, heat shock protein; LFABP, liver fatty acid-binding protein; SAA, serum amyloid A; CRP, c-reactive protein; OATP, organic anion transporter; HCC, hepatocellular carcinoma; HNF, hepatocyte nuclear factor; HCA, hepatocellular adenoma; FNH, focal nodular hyperplasia
tumor was 4 9 3 cm in diameter with a relatively clear margin against the surrounding liver tissue (Fig. 3A). A gray or white-yellowish nodule was collecting, and a central scar was seen. In the periphery of the tumor, cholestasis was seen (Fig. 3A). In the center of tumor, a central scar with vascular and cholangiolar proliferation was found, which is compatible with FNH (Fig. 3B). Thickening of the liver cell plate and pseudocholangiolar proliferation were found in the periphery of the tumor (Fig. 3C). Portal invasion and fibrous capsular formation were not present (Fig. 3D). Steatosis, inflammation or fibrosis was not found in the background liver (Fig. 3D). In immunohistochemical analysis, GS was highly and diffusely expressed in the periphery, although map-like in the center which was compatible with FNH (Fig. 3E). Expression of HSP70 was found in the periphery, not in the center (Fig. 3F). Expression of GPC3 was not found in the tumor. Expression of OATP1B3 was preserved in the periphery of the tumor although map-like in the center (Fig. 3G). Expression of LFABP was present, and SAA and CRP were both absent in the tumor (Table 1). Nuclear translocation of b-catenin was not found in the tumor (Table 1). The clinical course after partial hepatectomy was good, and there has been no recurrence of the tumor had for 2 years after the operation.
Discussion In this case, imaging studies such as CT or MRI showed findings compatible with FNH, but the tumor biopsy examination for evaluation of the tumor enlargement made it difficult for us to diagnose because the molecular expression pattern resembled that of early HCC. Laparoscopic partial hepatic resection and histological analysis suggested that the peripheral area of the progressing FNH resembled early HCC whereas the center area was compatible with FNH.
Tumor progression has been reported in a few limited cases with FNH [12–15]. In progressive cases with FNH, hemodynamic changes such as proliferation and enlargement of the arterial vessels or hyperplastic reactions during growth and regenerative process of the liver due to underlying hepatic conditions such as decreased portal blood or oxidative stress might be found [14, 15]. In our case, although the patient was healthy and asymptomatic, any underlying alteration of portal blood or oxidative stress might have been found. A recent study of a relatively large cohort showed tumor enlargement in 4 % of those observed [16]. We should consider that some cases of FNH might progress and be symptomatic. In the present case, increased GS and HSP70 expression of the tumor biopsy specimen, which had been performed to rule out early HCC, made it difficult to diagnose this case with FNH. In the central area of the present case, the map-like expression of GS that was seen is also known to be found in FNH. However, the peripheral area of the present case showed diffuse expression of GS as shown in other hepatic neoplasms (Table 1) [7–10]. GS has been reported to be expressed in activated hepatocyte progenitor cells as shown as perivenular expression in normal livers (Fig. 2C,3E) [17]. Regenerative mechanism may be involved in the increased GS expression. Recently peritumor hyperplasia of the liver, as a response to portal vein invasion by hypervascular neoplasms, has been reported [18], and marked diffuse expression of GS was found in peritumor hyperplasia [19]. In FNH, increased arterial blood flow and/or decreased portal blood have been suggested to activate the Wnt/b-catenin/GS pathway [20–22]. The Wnt/b-catenin/GS pathway has also been reported to be associated with cholestasis [23]. On the other hand, cholestasis has been reported to induce OATP expression [24] and HSP70 [25]. Although the precise mechanism is unknown, cholestasis, found in the periphery area of tumor, might affect the findings of imaging studies (e.g., delayed phase of CT-HA or hepatobiliary phase of EOB-MRI) or
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276
the immunohistological findings (GS and HSP expression) as seen in this present case. FNH is a hyperplastic hepatocellular lesion probably related to increased arterial blood flow, and we should therefore consider the morphologic and phenotypic changes. Molecular expression analysis for such hyperplastic tumors might make it difficult to distinguish them from neoplastic tumors. In such cases of progressing FNH, it might not be possible to clearly distinguish them from early HCC even if a tumor biopsy is performed. We should carefully observe progressing cases. Further studies including whole genome sequencing of those tumors with a larger cohort might be required in the future.
Conclusion We reported a case of progressing FNH showing increased expression of GS and HSP70 in the periphery area of the tumor. Some genetic alteration due to alteration of blood flow might be suggested in progressing FNH. We should carefully observe for progressing FNH. Disclosures Conflict of Interest: Kazuto Tajiri, Koichi Tsuneyama, Kengo Kawai, Yoshinari Atarashi, Masami Minemura, Shigeaki Sawada, Kazuhiro Tsukada, Johji Imura, and Toshiro Sugiyama declare that they have no conflict of interest. Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from the patient for being included in the study.
References 1. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology. 1985;5:1194–200. 2. Shen YH, Fan J, Wu ZQ, Ma ZC, Zhou XD, Zhou J, Qiu SJ, Qin LX, Ye QH, Sun HC, Huang XW, Tang ZY. Focal nodular hyperplasia of the liver in 86 patients. Hepatobiliary Pancreat Dis Int. 2007;6:52–7. 3. Luciani A, Kobeiter H, Maison P, Cherqui D, Zafrani ES, Dhumeaux D, Mathieu D. Focal nodular hyperplasia of the liver in men: is presentation the same in men and women? Gut. 2002;50:877–80. 4. Cherqui D, Rahmouni A, Charlotte F, Boulahdour H, Metreau JM, Meignan M, Fagniez PL, Zafrani ES, Mathieu D, Dhumeaux D. Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations. Hepatology. 1995;22: 1674–81. 5. Becker YT, Raiford DS, Webb L, Wright JK, Chapman WC, Pinson CW. Rupture and hemorrhage of hepatic focal nodular hyperplasia. Am Surg. 1995;61:210–4.
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Clin J Gastroenterol (2014) 7:271–277 23. Audard V, Grimber G, Elie C, Radenen B, Audebourg A, Letourneur F, Soubrane O, Vacher-Lavenu MC, Perret C, Cavard C, Terris B. Cholestasis is a marker for hepatocellular carcinomas displaying beta-catenin mutations. J Pathol. 2007;212:345–52. 24. Donner MG, Schumacher S, Warskulat U, Heinemann J, Haussinger D. Obstructive cholestasis induces TNF-alpha- and IL-1 -
277 mediated periportal downregulation of Bsep and zonal regulation of Ntcp, Oatp1a4, and Oatp1b2. Am J Physiol Gastrointest Liver Physiol. 2007;293:G1134–46. 25. Fujiwara Y, Shimada M, Yamashita Y, Adachi E, Shirabe K, Takenaka K, Sugimachi K. Cytokine characteristics of jaundice in mouse liver. Cytokine. 2001;13:188–91.
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CASE REPORT
A case of progressing focal nodular hyperplasia and its molecular expression pattern Kazuto Tajiri • Koichi Tsuneyama • Kengo Kawai • Yoshinari Atarashi • Masami Minemura • Shigeaki Sawada Kazuhiro Tsukada • Johji Imura • Toshiro Sugiyama
•
Received: 17 January 2014 / Accepted: 23 March 2014 / Published online: 12 April 2014 Ó Springer Japan 2014
Abstract We report the case of an adult male with progressing focal nodular hyperplasia (FNH). Although imaging studies suggested that the tumor was a classical FNH, the tumor biopsy showed glutamine synthetase expression and heat shock protein 70 in part of the tumor. As we could not definitely distinguish this case of FNH from early hepatocellular carcinoma (HCC), we performed laparoscopic partial hepatectomy. The surgical resected specimen showed that the tumor had a central scar with vascular and cholangiolar proliferation, which is compatible with FNH. Immunohistochemical analysis showed that the molecular expression pattern was compatible with FNH in the center of the tumor, whereas it partly resembled early HCC in the periphery of the tumor. FNH progression is occasionally found, and the molecular pattern of the progressing area in FNH might resemble that of early HCC due to morphologic and phenotypic changes induced by the regenerative mechanism and the alteration of blood flow. We should carefully observe progressing FNH.
K. Tajiri (&) K. Kawai M. Minemura T. Sugiyama Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama 930-0194, Japan e-mail: [email protected] K. Tsuneyama J. Imura Diagnostic Pathology, University of Toyama, 2630 Sugitani, Toyama, Japan Y. Atarashi Department of Gastroenterology, Toyama Rosai Hospital, 992 Rokuroumaru, Uozu, Japan S. Sawada K. Tsukada The Second Department of Surgery, Toyama University Hospital, 2630 Sugitani, Toyama, Japan
Keywords Progressing focal nodular hyperplasia Glutamine synthetase Immunohistochemistry
Introduction Focal nodular hyperplasia (FNH) is the second most common benign hepatic tumor after hemangioma [1, 2]. FNH is found predominantly in females between 30 and 50 years of age [1, 3]. FNH is characterized by a stellate central scar and hyperplastic nodules, and FNH nodules are usually solitary but may be multiple in about 20 % of cases [1]. Furthermore, most FNH are asymptomatic and do not require invasive therapy. Imaging studies such as ultrasonography (US), computed tomography (CT), or magnetic resonance imaging (MRI), are used for the diagnosis of FNH, and among them contrast-enhanced MRI has been shown to be the most sensitive modality for the diagnosis [4]. However, some FNH are difficult to definitely diagnose and progress with pain or abdominal hemorrhage in a few cases; therefore, invasive treatments involving surgical resection may be required [5, 6]. Recently, molecular pathogenesis of benign hepatocellular tumors has been explored and applied to clinical classification [7–10]. Glutamine synthetase (GS) has been reported to be a useful marker in differentiating hepatic nodules including FNH, hepatocellular adenoma (HCA), and nodules in cirrhosis [9, 10]. The combination of GS and heat shock protein 70 (HSP70) or glypican 3 (GPC3) had been reported to be useful to differentiate benign nodules and early hepatocellular carcinoma [10, 11]. Furthermore, the expression of molecular markers such as liver fatty acid binding protein (LFABP), serum amyloid A (SAA), C reactive protein (CRP), and b-catenin, are useful to classify hepatocellular benign tumors and apply to personalized clinical care [7, 8].
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272 Fig. 1 CT findings. (A) Dynamic CT findings. Each panel represents the indicated phase. After bolus administration of contrast medium, 30 s, 60 s, and 180 s represent artery phase, portal phase, and delayed phase, respectively. (B) CT angiography findings. Each panel represents the indicated phase. CT-arterial portography (CT-AP) shows the image approximately 20 s after bolus administration of contrast medium to superior mesenteric artery. After bolus administration of contrast medium to hepatic artery, 7 s, 20 s, and 180 s represent early artery phase, late artery phase, and delayed phase, respectively. (C) MRI findings of the tumor. Images of T1- and T2-weighted MRI are shown in the upper column. Images in Gd-EOBDTPA-enhanced MRI at indicated time
Clin J Gastroenterol (2014) 7:271–277
A
B
Plain
CT-AP
C
Artery phase
Portal phase
Early artery phase
Late artery phase
Delayed phase
T2
T1 In
Delayed phase
Diffusion
Opposed
EOB-Primovist pre
Here, we report the case of a young adult male showing liver tumor progression which was compatible with FNH by imaging studies. He had undergone surgical resection
123
25sec
65sec
5min
15min
because we could not rule out the possibility of malignancy due to tumor growth and the molecular pattern found on tumor biopsy.
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Fig. 2 Liver biopsy findings. (A) HE staining, 9 40. (B) HE staining, 9 400. (C) GS, 9 4. (D) HSP70, 9 4. T, Tumor area, N, normal parenchyma area
Case Report A 35-year-old Japanese male was referred to our hospital for evaluation of a progressing liver tumor. A 2-cm diameter liver tumor was accidentally found by CT when he was admitted for diverticulitis. He had been observed every 3-6 months because enhanced CT and MRI findings suggested that the liver tumor was FNH. Although he had been healthy and asymptomatic, CT examination showed that the liver tumor has increased to a diameter of 3 cm over 6 months. On dynamic CT study, the tumor in segment 8 showed hypo-attenuation in the plain phase, hyperattenuation in the artery phase, slight hyper-attenuation in the portal phase, and iso-attenuation in the late phase (Fig. 1A). On Angio-CT, the tumor showed hypo-attenuation on CT arterial portography, hyper-attenuation from the center to the whole of tumor on CT hepatic arteriography, and central stellate and corona-like enhancement in the delayed phase (Fig. 1B). These CT findings showed the tumor was a hyper-vascular tumor with a central scar, compatible to FNH. MRI examination implied that the tumor was hyper-vascular, of little fat composition, and of gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) uptake except for the central stellate
lesion (Fig. 1C). The patient had a mild drinking habit, but the consumption of alcohol was \20 g/day. Furthermore, biochemical examination of his blood concerning liver function was normal (aspartate aminotransferase 21 U/L, alanine aminotransferase 23 U/L, gamma-glutamyl transpeptidase 50 U/L, alkaline phosphatase 234 U/L, albumin 4.2 g/dL, total bilirubin 0.6 mg/dL). He showed neither hepatitis virus B nor hepatitis virus C infection (hepatitis B surface antigen, anti-hepatitis B core antibody, and antihepatitis C antibody were negative), and his serum alphafetoprotein and des-gamma carboxyprothrombin levels were normal. These findings also supported the diagnosis of FNH. US-guided percutaneous tumor biopsy was performed because the tumor was increasing in size; this showed thickening of the liver cell plate and pseudocholangiolar proliferation (Fig. 2A, B). When we immunohistochemically analyzed the expression of glutamine synthetase (GS) and heat-shock protein (HSP) 70 to rule out early hepatocellular carcinoma (HCC), both were diffusely found in the tumor (Fig. 2C and D, respectively). Finally, we could not rule out the possibility of early HCC. Therefore, laparoscopic partial hepatectomy was performed after informed consent was provided. Macroscopic findings showed the
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274 Fig. 3 Surgical specimen findings. (A) Macroscopic findings. (B) H&E staining at the center of the tumor. Fibrous scar and cholangiolar proliferation were found, 9 100. (C) H&E staining at the periphery of the tumor, 9 400. (D) H&E staining at the edge of tumor and background liver. Arrows represent the margin of the tumor, 9 400. (E) - (G) right upper inset represents the image of the center of the tumor [C] at high magnification, and right lower inset represents the periphery of the tumor [P] at high magnification. (E) GS staining. (F) HSP70 staining. (G) OATP1B3 staining
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275
Table 1 Molecular expression patterns of hepatic tumors Tumor
GS
HSP70
LFABP
SAA
CRP
b-Catenin
OATP
HCC
?
?
?
-
-
?
-
HNF1a-inactivated HCA
-
-?
-
-
-
-
;
b-Catenin-activated HCA
?
-?
?
-
-
?
?
Inflammatory HCA
-
-?
?
??
??
-
;
Unclassified HCA
-
-?
?
-
-
-
- *?
FNH
Map like
-?
?
-
-
-
?
Our case periphery center
?
?
?
-
-
-
?
Map like
-
?
-
-
-
Map like
GS, glutamine synthetase; HSP, heat shock protein; LFABP, liver fatty acid-binding protein; SAA, serum amyloid A; CRP, c-reactive protein; OATP, organic anion transporter; HCC, hepatocellular carcinoma; HNF, hepatocyte nuclear factor; HCA, hepatocellular adenoma; FNH, focal nodular hyperplasia
tumor was 4 9 3 cm in diameter with a relatively clear margin against the surrounding liver tissue (Fig. 3A). A gray or white-yellowish nodule was collecting, and a central scar was seen. In the periphery of the tumor, cholestasis was seen (Fig. 3A). In the center of tumor, a central scar with vascular and cholangiolar proliferation was found, which is compatible with FNH (Fig. 3B). Thickening of the liver cell plate and pseudocholangiolar proliferation were found in the periphery of the tumor (Fig. 3C). Portal invasion and fibrous capsular formation were not present (Fig. 3D). Steatosis, inflammation or fibrosis was not found in the background liver (Fig. 3D). In immunohistochemical analysis, GS was highly and diffusely expressed in the periphery, although map-like in the center which was compatible with FNH (Fig. 3E). Expression of HSP70 was found in the periphery, not in the center (Fig. 3F). Expression of GPC3 was not found in the tumor. Expression of OATP1B3 was preserved in the periphery of the tumor although map-like in the center (Fig. 3G). Expression of LFABP was present, and SAA and CRP were both absent in the tumor (Table 1). Nuclear translocation of b-catenin was not found in the tumor (Table 1). The clinical course after partial hepatectomy was good, and there has been no recurrence of the tumor had for 2 years after the operation.
Discussion In this case, imaging studies such as CT or MRI showed findings compatible with FNH, but the tumor biopsy examination for evaluation of the tumor enlargement made it difficult for us to diagnose because the molecular expression pattern resembled that of early HCC. Laparoscopic partial hepatic resection and histological analysis suggested that the peripheral area of the progressing FNH resembled early HCC whereas the center area was compatible with FNH.
Tumor progression has been reported in a few limited cases with FNH [12–15]. In progressive cases with FNH, hemodynamic changes such as proliferation and enlargement of the arterial vessels or hyperplastic reactions during growth and regenerative process of the liver due to underlying hepatic conditions such as decreased portal blood or oxidative stress might be found [14, 15]. In our case, although the patient was healthy and asymptomatic, any underlying alteration of portal blood or oxidative stress might have been found. A recent study of a relatively large cohort showed tumor enlargement in 4 % of those observed [16]. We should consider that some cases of FNH might progress and be symptomatic. In the present case, increased GS and HSP70 expression of the tumor biopsy specimen, which had been performed to rule out early HCC, made it difficult to diagnose this case with FNH. In the central area of the present case, the map-like expression of GS that was seen is also known to be found in FNH. However, the peripheral area of the present case showed diffuse expression of GS as shown in other hepatic neoplasms (Table 1) [7–10]. GS has been reported to be expressed in activated hepatocyte progenitor cells as shown as perivenular expression in normal livers (Fig. 2C,3E) [17]. Regenerative mechanism may be involved in the increased GS expression. Recently peritumor hyperplasia of the liver, as a response to portal vein invasion by hypervascular neoplasms, has been reported [18], and marked diffuse expression of GS was found in peritumor hyperplasia [19]. In FNH, increased arterial blood flow and/or decreased portal blood have been suggested to activate the Wnt/b-catenin/GS pathway [20–22]. The Wnt/b-catenin/GS pathway has also been reported to be associated with cholestasis [23]. On the other hand, cholestasis has been reported to induce OATP expression [24] and HSP70 [25]. Although the precise mechanism is unknown, cholestasis, found in the periphery area of tumor, might affect the findings of imaging studies (e.g., delayed phase of CT-HA or hepatobiliary phase of EOB-MRI) or
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the immunohistological findings (GS and HSP expression) as seen in this present case. FNH is a hyperplastic hepatocellular lesion probably related to increased arterial blood flow, and we should therefore consider the morphologic and phenotypic changes. Molecular expression analysis for such hyperplastic tumors might make it difficult to distinguish them from neoplastic tumors. In such cases of progressing FNH, it might not be possible to clearly distinguish them from early HCC even if a tumor biopsy is performed. We should carefully observe progressing cases. Further studies including whole genome sequencing of those tumors with a larger cohort might be required in the future.
Conclusion We reported a case of progressing FNH showing increased expression of GS and HSP70 in the periphery area of the tumor. Some genetic alteration due to alteration of blood flow might be suggested in progressing FNH. We should carefully observe for progressing FNH. Disclosures Conflict of Interest: Kazuto Tajiri, Koichi Tsuneyama, Kengo Kawai, Yoshinari Atarashi, Masami Minemura, Shigeaki Sawada, Kazuhiro Tsukada, Johji Imura, and Toshiro Sugiyama declare that they have no conflict of interest. Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from the patient for being included in the study.
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