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doi: 10.1111/hepr.12366
Hepatology Research 2015; 45: 494–499
Case Report
Case of cholangiocellular carcinoma in a patient with glycogen storage disease type Ia Hiroyuki Kanamori,1 Yukiomi Nakade,1 Takaya Yamamoto,1 Yuji Kobayashi,1 Ken Sato,1 Kiyoaki Ito,1 Tomohiko Ohashi,1 Noiku Nakao,2 Norimitsu Ishii,1 Emiko Takahashi,3 Toyoharu Yokoi,3 Haruhisa Nakao,1 Tsuyoshi Kurokawa,4 Chikara Yamaguchi5 and Masashi Yoneda1 Departments of 1Internal Medicine and 2Surgery, Division of Gastroenterology, 3Department of Pathology, Aichi Medical University, Nagakute, 4Masuko Hospital, Nagoya and 5Setoguchi Psychosomatic Clinic, Seto, Japan
Glycogen storage disease (GSD) type Ia is caused by a deficiency in glucose-6-phosphatase. Long-term complications, including renal disease, gout, osteoporosis and pulmonary hypertension, develop in patients with GSD type Ia. In the second or third decade, 22–75% of GSD type Ia patients develop hepatocellular adenoma (HCA). In some of these patients, the HCA evolves into hepatocellular carcinoma.
However, little is known about GSD type Ia patients with HCA who develop cholangiocellular carcinoma (CCC). Here, we report for the first time, a patient with GSD type Ia with HCA, in whom intrahepatic CCC was developed.
INTRODUCTION
(CCC). Here, we report for the first time a patient with GSD type Ia complicated with HCA, in whom intrahepatic CCC was developed.
G
LYCOGEN STORAGE DISEASE (GSD) type Ia, or von Gierke’s disease, is known to be caused by deficient glucose-6-phosphatase activity resulting from mutations in the G6PC gene.1 Patients with GSD type Ia present in infancy with hypoglycemia, growth retardation, hepatomegaly, lactic acidosis, hyperlipidemia and hyperuricemia.1 Long-term complications, including renal disease, gout, osteoporosis and pulmonary hypertension, are experienced by GSD type Ia patients.2 In the second or third decade of life, 22–75% of patients with GSD type Ia develop hepatocellular adenoma (HCA).3 In some of the patients with GSD type Ia, the HCA evolves into hepatocellular carcinoma (HCC).4 However, little is known about GSD type Ia patients with HCA who develop cholangiocellular carcinoma
Correspondence: Dr Yukiomi Nakade, Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University, 1-1 Karimata Yazako Nagakute, Aichi 480-1195, Japan. Email: [email protected] Conflict of interest: The authors have no financial or other conflicts of interest. Received 27 April 2014; revision 26 May 2014; accepted 27 May 2014.
494
Key words: cholangiocellular carcinoma, glycogen storage disease, hepatocellular adenoma
CASE REPORT
A
39-YEAR-OLD MAN, who had been diagnosed with GSD type Ia in the department of pediatrics in another hospital at the age of 2 years, was examined at a follow-up visit at our hospital on 11 August 2005. He had no history of alcohol abuse, and did not smoke. No remarkable familial history existed. On physical examination, his height was 163 cm and weight was 50 kg. His face seemed to look young. His bulbar conjunctiva showed no icterus, and heart and respiratory sounds were normal. His liver and spleen were not palpable. Laboratory work-up revealed that serum low-density lipoprotein cholesterol, triglycerides, lactic acid, acetoisobutyric acid, 3-hydroxybutyric acid, and acetic acid levels were also elevated (Table 1). Serum α-fetoprotein was within the normal range; however, protein induced by vitamin K absence/antagonist-II (PIVKA-II) was slightly elevated at 50 mAU/mL (Table 1). We had recognized multiple HCA in his liver since 2005. Magnetic resonance imaging (MRI) revealed
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 494–499
CCC in glycogen storage disease type Ia
Table 1 Laboratory data on admission Laboratory data Total protein Albumin Total bilirubin BUN Creatinine AST ALT ALP LDH γ-GT Amylase Total cholesterol LDL cholesterol Triglycerides lactic acid Acetoisobutyric acid 3-Hydroxybutyric acid Glucose HbA1c
Hemogram 8 g/dL 4.6 g/dL 0.7 g/dL 10.5 mg/dL 0.64 mg/dL 28 IU/L 17 IU/L 232 IU/L 124 IU/L 47 IU/L 140 mg/dL 212 mg/dL 150 mg/dL 523 mg/dL 38.4 mg/dL 313 μM
WBC RBC Hb Ht Plt PT% AFP PIVKA-II CEA HBsAg HBsAb HBcAb HCVAb
6300/μL 373 × 104/μL 11 g/dL 31.9% 363 × 104/μL 95% 2.4 ng/dL 50 mAU/mL 2 ng/mL (−) (−) (−) (−)
ICG-R15
2%
721 μM 122 mg/dL 4.4
γ-GT, γ-glutamyltransferase; AFP, α-fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CEA, carcinoembryonic antigen; Hb, hemoglobin; HbA1c, hemoglobin A1c; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HCVAb, hepatitis C antibody; HDL, high-density lipoprotein; Ht, hematocrits; ICG-R15, indocyanine green retention rate at 15 min; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; PIVKA-II, protein induced by vitamin K absence/ antagonist-II; Plt, platelets; PT, prothrombin time; RBC, red blood cells; WBC, white blood cells.
multiple high- or isointense lesions on T1-weighted imaging (WI), high- or isointense lesions on T2-WI, and significant enhancement on T1-WI after contrast medium administration (Fig. 1). His HCA had been examined by MRI annually from 2005 to 2008. In August 2009, one of the liver tumors located in the left medial lobe enlarged from 10 mm to 23 mm in diameter, as seen on dynamic contrast-enhanced MRI with gadopentetic acid by 12 months (Fig. 2a,b). The enlarged liver tumor showed partial enhancement in the arterial phase, and low signal intensity on hepatobiliary phase images on dynamic contrast-enhanced MRI with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) (Fig. 2c,d). A dynamic computed tomography (CT) scan showed that the peripheral part of the enlarged liver tumor was contrasted in mod-
495
erate high density in the early phase and that it was contrasted in iso-low density in the late phase (Fig. 2e,f). Early phase images by CT during hepatic arteriography (CTHA) revealed that the peripheral part of the enlarged liver tumor was well stained, whereas the internal side of the liver tumor was faintly stained (Fig. 2g). CT during arterial portography (CTAP) revealed that the liver tumor was contrasted in low density (Fig. 2H). From these findings, the enlarged liver tumor was suspected to be transformed to a malignant tumor, and ultrasonography-guided fine-needle aspiration was performed. Microscopic findings showed moderately differentiated intrahepatic CCC, and we diagnosed the enlarged liver tumor as intrahepatic CCC. Because the patient had normal hepatic function, resection of subsegment 4 in his liver was performed on 5 January 2010. The resected specimen revealed a tumor measuring 23 mm in diameter on the cut surface (Fig. 3a). Serum PIVKA-II level was not significantly changed compared with that before tumor resection. Hematoxylin–eosin staining showed that dysplastic columnar epithelial cells contained in the large nucleus had proliferated in a tubular and papillary formation (Fig. 3b). Immunohistochemical examination of the resected tumor stained positively for cytokeratin 7 (Fig. 3c). Histology of the tumor was consistent with moderately differentiated CCC, whereas no HCA components were observed. Cells with enlarged clear cytoplasm were observed in the non-tumorous portions of the liver parenchyma, which stained positively for periodic acid-Schiff (PAS) and PAS diastase (Fig. 3d,e). Hepatocellular ballooning, inflammation and fibrosis were not emerged in the nontumorous portions of the liver parenchyma (Fig. 3d,e). These findings were consistent with the livers of patients with GSD Ia.
DISCUSSION
H
EPATOCELLULAR ADENOMA IS a frequent longterm complication of patients with GSD type Ia.5 Malignant transformation from HCA to HCC in these patients has been documented in several reports.5,6 With prevalence ranging 22–75% of patients with GSD type Ia, HCA typically emerges by the second or third decade of life. HCA formation in GSD type I is reported to be associated with constant hormonal stimulation of the liver.3,7 It has been reported that hyperglucagonemia and hypoinsulinemia may contribute to the development of HCA.8 On the other hand, there have been few reports of GSD type Ia patients with HCA who develop
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 494–499
496 H. Kanamori et al.
T1WI
T2WI
Figure 1 Arrows show multiple highor isointense lesions on T1-WI, and high or isointense lesions on T2-WI in the liver. These lesions were significantly enhanced on T1-WI after contrast medium administration. WI, weighted imaging.
T1WI (enhance)
CCC. Whether the above-mentioned hormonal balances are involved in the occurrence of CCC remains to be elucidated. With the development of new imaging modalities, liver tumors, especially HCC, are being detected at an earlier stage.9 Gd-EOB-DTPA is a relatively new and well-tolerated liver-specific contrast agent, known to have a beneficial role in evaluating both dynamic and hepatobiliary phase images.10 Gd-EOB-DTPA is taken up into bile, and improves lesion detection and characterization by increasing liver-to-lesion conspicuity in the added hepatobiliary phase image.11 Although the usefulness of detecting hypervascular HCC has been reported, neither hypovascular lesions nor lesions with weakly increased arterial flow are able to be imaged currently. Typical HCC show prominent enhancement on arterial phase images, and low signal intensity on hepatobiliary phase images.11 However, in the present case, the liver tumor did not show prominent enhancement on the arterial phase
image, and showed low signal intensity on the hepatobiliary phase image. A previous study reported that some dysplastic nodules also revealed levels of hypointensity in the hepatobiliary phase similar to that of HCC.12 The differential diagnosis between HCC and other liver tumors remains obscure in MRI with Gd-EOB-DTPA. Computed tomographic arterial portography and CTHA are performed to distinguish between HCC and dysplastic nodules in the liver.13 CTAP is known to reveal the vascularity in portal phase images, whereas CTHA is known to display the vascularity in arterial phase images. In the present case, early phase images by CTHA revealed that only the peripheral part of the liver tumor was well stained, and CTAP showed that the liver tumor was contrasted in low density. These findings indicated that the liver tumor was a hypovascular nodule, and thus fine-needle aspiration was performed. We diagnosed the enlarged liver tumor as an intrahepatic CCC.
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 494–499
a
c
CCC in glycogen storage disease type Ia
497
b
d
e
f
g
h
Specific chromosomal and genetic alterations could contribute to the development of HCA. Chromosomal abnormalities have been identified in 20–89% of HCA.14–16 Chromosomal aberrations were found in 60% of the HCA taken from GSD type Ia patients and 57% of
Figure 2 Arrows show the liver tumor. Dynamic contrast-enhanced MRI imaging in (a) 2008 and (b) 2009 showed that a hypointense lesion located in the left median lobe on T1WI enlarged from 10 to 23 mm in diameter over a period of 1 year. (c) Dynamic contrastenhanced MRI with Gd-EOB-DTPA revealed that the liver tumor showed partial enhancement on arterial phase imaging, and (d) low signal intensity on hepatobiliary phase imaging. (e) Dynamic contrast-enhanced CT revealed that the enlarged liver tumor did not show prominent enhancement on arterial phase imaging, and (f) isodensity on portal phase imaging. (g) Early phase CTHA revealed that the peripheral part of the enlarged liver tumor was well stained, whereas the internal side of the liver tumor was faintly stained. (h) CTAP revealed that the liver tumor was contrasted in low density. CT, computed tomography; CTAP, CT arterial portography; CTHA, CT during hepatic arteriography; Gd-EOB-DTPA, gadoliniumethoxybenzyl-diethylenetriamine pentaacetic acid; MRI, magnetic resonance imaging; WI, weighted imaging.
the HCA obtained from the general population.16 Kishnani et al. also showed that alterations in chromosome 6 could be an early event in liver tumorigenesis in GSD type I.16 The genomic alterations in HCA are much fewer than those in HCC.14 It has been showed that a
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 494–499
498 H. Kanamori et al.
a
Figure 3 (a) Macroscopic findings of the resected specimen revealed a tumor 23 mm in diameter on the cut surface. (b) Microscopic examination showed that dysplastic columnar epithelial cells contained in a large nucleus proliferated in tubular and papillary formation. Histology of the tumor revealed moderately differentiated cholangiocellular carcinoma, whereas no hepatocellular adenoma components were observed (hematoxylin–eosin, original magnification ×100). (c) Immunohistochemical examination of the tumor showed that cells positive for cytokeratin 7 had emerged (original magnification ×100). (d,e) PAS and PAS diastase stained cells had emerged (original magnification ×200). PAS, periodic acid-Schiff.
b
c
d
e
mean of 7.2 chromosomal aberrations were present in well HCC patients, whereas only two chromosomal aberrations were seen in HCA patients.14 Mutation studies have indicated that a group of HCA, representing 15% of cases exhibiting activating mutations of β-catenin, were generally characterized by a high risk of malignant transformation to HCC.4 However, whether chromosomal aberrations or mutations of β-catenin in
© 2014 The Japan Society of Hepatology
HCA contribute to the occurrence of CCC remains unclear. In conclusion, we have described a case of GSD Ia with progression of HCA to CCC. GSD Ia patients should be paid attention to for not only HCC but also CCC development. Further studies are needed to investigate the mechanism of the development of CCC in patients with GSD Ia.
Hepatology Research 2015; 45: 494–499
REFERENCES 1 Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GP. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I). Eur J Pediatr 2002; 161 (Suppl 1): S20–34. 2 Yiu WH, Pan CJ, Ruef RA et al. Angiotensin mediates renal fibrosis in the nephropathy of glycogen storage disease type Ia. Kidney Int 2008; 73: 716–23. 3 Coire CI, Qizilbash AH, Castelli MF. Hepatic adenomata in type Ia glycogen storage disease. Arch Pathol Lab Med 1987; 111: 166–9. 4 Cassiman D, Libbrecht L, Verslype C et al. An adult male patient with multiple adenomas and a hepatocellular carcinoma: mild glycogen storage disease type Ia. J Hepatol 2010; 53: 213–7. 5 Bianchi L. Glycogen storage disease I and hepatocellular tumours. Eur J Pediatr 1993; 152 (Suppl 1): S63– 70. 6 Ochi H, Hiraoka A, Uehara T et al. Abdominal imaging findings of a patient with hepatocellular carcinoma associated with glycogen storage disease type 1a. Intern Med 2011; 50: 2317–22. 7 Kharsa G, Degott C, Filoche B, Hedde JP, Potet F, Benhamou JP. [Hepatic adenoma and hepatocellular carcinoma in 3 brothers with type I glycogenosis]. Gastroenterol Clin Biol 1990; 14: 84–9. 8 Parker P, Burr I, Slonim A, Ghishan FK, Greene H. Regression of hepatic adenomas in type Ia glycogen storage disease with dietary therapy. Gastroenterology 1981; 81: 534–6.
CCC in glycogen storage disease type Ia
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9 Pauleit D, Textor J, Bachmann R et al. Hepatocellular carcinoma: detection with gadolinium- and ferumoxidesenhanced MR imaging of the liver. Radiology 2002; 222: 73–80. 10 Weinmann HJ, Schuhmann-Giampieri G, Schmitt-Willich H, Vogler H, Frenzel T, Gries H. A new lipophilic gadolinium chelate as a tissue-specific contrast medium for MRI. Magn Reson Med 1991; 22: 233–7; discussion 42. 11 Reimer P, Rummeny EJ, Shamsi K et al. Phase II clinical evaluation of Gd-EOB-DTPA: dose, safety aspects, and pulse sequence. Radiology 1996; 199: 177–83. 12 Earls JP, Theise ND, Weinreb JC et al. Dysplastic nodules and hepatocellular carcinoma: thin-section MR imaging of explanted cirrhotic livers with pathologic correlation. Radiology 1996; 201: 207–14. 13 Hayashi M, Matsui O, Ueda K et al. Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium. AJR Am J Roentgenol 1999; 172: 969–76. 14 Wilkens L, Bredt M, Flemming P, Becker T, Klempnauer J, Kreipe HH. Differentiation of liver cell adenomas from well-differentiated hepatocellular carcinomas by comparative genomic hybridization. J Pathol 2001; 193: 476–82. 15 Steinemann D, Skawran B, Becker T et al. Assessment of differentiation and progression of hepatic tumors using array-based comparative genomic hybridization. Clin Gastroenterol Hepatol 2006; 4: 1283–91. 16 Kishnani PS, Chuang TP, Bali D et al. Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease. Hum Mol Genet 2009; 18: 4781–90.
© 2014 The Japan Society of Hepatology
doi: 10.1111/hepr.12366
Hepatology Research 2015; 45: 494–499
Case Report
Case of cholangiocellular carcinoma in a patient with glycogen storage disease type Ia Hiroyuki Kanamori,1 Yukiomi Nakade,1 Takaya Yamamoto,1 Yuji Kobayashi,1 Ken Sato,1 Kiyoaki Ito,1 Tomohiko Ohashi,1 Noiku Nakao,2 Norimitsu Ishii,1 Emiko Takahashi,3 Toyoharu Yokoi,3 Haruhisa Nakao,1 Tsuyoshi Kurokawa,4 Chikara Yamaguchi5 and Masashi Yoneda1 Departments of 1Internal Medicine and 2Surgery, Division of Gastroenterology, 3Department of Pathology, Aichi Medical University, Nagakute, 4Masuko Hospital, Nagoya and 5Setoguchi Psychosomatic Clinic, Seto, Japan
Glycogen storage disease (GSD) type Ia is caused by a deficiency in glucose-6-phosphatase. Long-term complications, including renal disease, gout, osteoporosis and pulmonary hypertension, develop in patients with GSD type Ia. In the second or third decade, 22–75% of GSD type Ia patients develop hepatocellular adenoma (HCA). In some of these patients, the HCA evolves into hepatocellular carcinoma.
However, little is known about GSD type Ia patients with HCA who develop cholangiocellular carcinoma (CCC). Here, we report for the first time, a patient with GSD type Ia with HCA, in whom intrahepatic CCC was developed.
INTRODUCTION
(CCC). Here, we report for the first time a patient with GSD type Ia complicated with HCA, in whom intrahepatic CCC was developed.
G
LYCOGEN STORAGE DISEASE (GSD) type Ia, or von Gierke’s disease, is known to be caused by deficient glucose-6-phosphatase activity resulting from mutations in the G6PC gene.1 Patients with GSD type Ia present in infancy with hypoglycemia, growth retardation, hepatomegaly, lactic acidosis, hyperlipidemia and hyperuricemia.1 Long-term complications, including renal disease, gout, osteoporosis and pulmonary hypertension, are experienced by GSD type Ia patients.2 In the second or third decade of life, 22–75% of patients with GSD type Ia develop hepatocellular adenoma (HCA).3 In some of the patients with GSD type Ia, the HCA evolves into hepatocellular carcinoma (HCC).4 However, little is known about GSD type Ia patients with HCA who develop cholangiocellular carcinoma
Correspondence: Dr Yukiomi Nakade, Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University, 1-1 Karimata Yazako Nagakute, Aichi 480-1195, Japan. Email: [email protected] Conflict of interest: The authors have no financial or other conflicts of interest. Received 27 April 2014; revision 26 May 2014; accepted 27 May 2014.
494
Key words: cholangiocellular carcinoma, glycogen storage disease, hepatocellular adenoma
CASE REPORT
A
39-YEAR-OLD MAN, who had been diagnosed with GSD type Ia in the department of pediatrics in another hospital at the age of 2 years, was examined at a follow-up visit at our hospital on 11 August 2005. He had no history of alcohol abuse, and did not smoke. No remarkable familial history existed. On physical examination, his height was 163 cm and weight was 50 kg. His face seemed to look young. His bulbar conjunctiva showed no icterus, and heart and respiratory sounds were normal. His liver and spleen were not palpable. Laboratory work-up revealed that serum low-density lipoprotein cholesterol, triglycerides, lactic acid, acetoisobutyric acid, 3-hydroxybutyric acid, and acetic acid levels were also elevated (Table 1). Serum α-fetoprotein was within the normal range; however, protein induced by vitamin K absence/antagonist-II (PIVKA-II) was slightly elevated at 50 mAU/mL (Table 1). We had recognized multiple HCA in his liver since 2005. Magnetic resonance imaging (MRI) revealed
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 494–499
CCC in glycogen storage disease type Ia
Table 1 Laboratory data on admission Laboratory data Total protein Albumin Total bilirubin BUN Creatinine AST ALT ALP LDH γ-GT Amylase Total cholesterol LDL cholesterol Triglycerides lactic acid Acetoisobutyric acid 3-Hydroxybutyric acid Glucose HbA1c
Hemogram 8 g/dL 4.6 g/dL 0.7 g/dL 10.5 mg/dL 0.64 mg/dL 28 IU/L 17 IU/L 232 IU/L 124 IU/L 47 IU/L 140 mg/dL 212 mg/dL 150 mg/dL 523 mg/dL 38.4 mg/dL 313 μM
WBC RBC Hb Ht Plt PT% AFP PIVKA-II CEA HBsAg HBsAb HBcAb HCVAb
6300/μL 373 × 104/μL 11 g/dL 31.9% 363 × 104/μL 95% 2.4 ng/dL 50 mAU/mL 2 ng/mL (−) (−) (−) (−)
ICG-R15
2%
721 μM 122 mg/dL 4.4
γ-GT, γ-glutamyltransferase; AFP, α-fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CEA, carcinoembryonic antigen; Hb, hemoglobin; HbA1c, hemoglobin A1c; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HCVAb, hepatitis C antibody; HDL, high-density lipoprotein; Ht, hematocrits; ICG-R15, indocyanine green retention rate at 15 min; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; PIVKA-II, protein induced by vitamin K absence/ antagonist-II; Plt, platelets; PT, prothrombin time; RBC, red blood cells; WBC, white blood cells.
multiple high- or isointense lesions on T1-weighted imaging (WI), high- or isointense lesions on T2-WI, and significant enhancement on T1-WI after contrast medium administration (Fig. 1). His HCA had been examined by MRI annually from 2005 to 2008. In August 2009, one of the liver tumors located in the left medial lobe enlarged from 10 mm to 23 mm in diameter, as seen on dynamic contrast-enhanced MRI with gadopentetic acid by 12 months (Fig. 2a,b). The enlarged liver tumor showed partial enhancement in the arterial phase, and low signal intensity on hepatobiliary phase images on dynamic contrast-enhanced MRI with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) (Fig. 2c,d). A dynamic computed tomography (CT) scan showed that the peripheral part of the enlarged liver tumor was contrasted in mod-
495
erate high density in the early phase and that it was contrasted in iso-low density in the late phase (Fig. 2e,f). Early phase images by CT during hepatic arteriography (CTHA) revealed that the peripheral part of the enlarged liver tumor was well stained, whereas the internal side of the liver tumor was faintly stained (Fig. 2g). CT during arterial portography (CTAP) revealed that the liver tumor was contrasted in low density (Fig. 2H). From these findings, the enlarged liver tumor was suspected to be transformed to a malignant tumor, and ultrasonography-guided fine-needle aspiration was performed. Microscopic findings showed moderately differentiated intrahepatic CCC, and we diagnosed the enlarged liver tumor as intrahepatic CCC. Because the patient had normal hepatic function, resection of subsegment 4 in his liver was performed on 5 January 2010. The resected specimen revealed a tumor measuring 23 mm in diameter on the cut surface (Fig. 3a). Serum PIVKA-II level was not significantly changed compared with that before tumor resection. Hematoxylin–eosin staining showed that dysplastic columnar epithelial cells contained in the large nucleus had proliferated in a tubular and papillary formation (Fig. 3b). Immunohistochemical examination of the resected tumor stained positively for cytokeratin 7 (Fig. 3c). Histology of the tumor was consistent with moderately differentiated CCC, whereas no HCA components were observed. Cells with enlarged clear cytoplasm were observed in the non-tumorous portions of the liver parenchyma, which stained positively for periodic acid-Schiff (PAS) and PAS diastase (Fig. 3d,e). Hepatocellular ballooning, inflammation and fibrosis were not emerged in the nontumorous portions of the liver parenchyma (Fig. 3d,e). These findings were consistent with the livers of patients with GSD Ia.
DISCUSSION
H
EPATOCELLULAR ADENOMA IS a frequent longterm complication of patients with GSD type Ia.5 Malignant transformation from HCA to HCC in these patients has been documented in several reports.5,6 With prevalence ranging 22–75% of patients with GSD type Ia, HCA typically emerges by the second or third decade of life. HCA formation in GSD type I is reported to be associated with constant hormonal stimulation of the liver.3,7 It has been reported that hyperglucagonemia and hypoinsulinemia may contribute to the development of HCA.8 On the other hand, there have been few reports of GSD type Ia patients with HCA who develop
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 494–499
496 H. Kanamori et al.
T1WI
T2WI
Figure 1 Arrows show multiple highor isointense lesions on T1-WI, and high or isointense lesions on T2-WI in the liver. These lesions were significantly enhanced on T1-WI after contrast medium administration. WI, weighted imaging.
T1WI (enhance)
CCC. Whether the above-mentioned hormonal balances are involved in the occurrence of CCC remains to be elucidated. With the development of new imaging modalities, liver tumors, especially HCC, are being detected at an earlier stage.9 Gd-EOB-DTPA is a relatively new and well-tolerated liver-specific contrast agent, known to have a beneficial role in evaluating both dynamic and hepatobiliary phase images.10 Gd-EOB-DTPA is taken up into bile, and improves lesion detection and characterization by increasing liver-to-lesion conspicuity in the added hepatobiliary phase image.11 Although the usefulness of detecting hypervascular HCC has been reported, neither hypovascular lesions nor lesions with weakly increased arterial flow are able to be imaged currently. Typical HCC show prominent enhancement on arterial phase images, and low signal intensity on hepatobiliary phase images.11 However, in the present case, the liver tumor did not show prominent enhancement on the arterial phase
image, and showed low signal intensity on the hepatobiliary phase image. A previous study reported that some dysplastic nodules also revealed levels of hypointensity in the hepatobiliary phase similar to that of HCC.12 The differential diagnosis between HCC and other liver tumors remains obscure in MRI with Gd-EOB-DTPA. Computed tomographic arterial portography and CTHA are performed to distinguish between HCC and dysplastic nodules in the liver.13 CTAP is known to reveal the vascularity in portal phase images, whereas CTHA is known to display the vascularity in arterial phase images. In the present case, early phase images by CTHA revealed that only the peripheral part of the liver tumor was well stained, and CTAP showed that the liver tumor was contrasted in low density. These findings indicated that the liver tumor was a hypovascular nodule, and thus fine-needle aspiration was performed. We diagnosed the enlarged liver tumor as an intrahepatic CCC.
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 494–499
a
c
CCC in glycogen storage disease type Ia
497
b
d
e
f
g
h
Specific chromosomal and genetic alterations could contribute to the development of HCA. Chromosomal abnormalities have been identified in 20–89% of HCA.14–16 Chromosomal aberrations were found in 60% of the HCA taken from GSD type Ia patients and 57% of
Figure 2 Arrows show the liver tumor. Dynamic contrast-enhanced MRI imaging in (a) 2008 and (b) 2009 showed that a hypointense lesion located in the left median lobe on T1WI enlarged from 10 to 23 mm in diameter over a period of 1 year. (c) Dynamic contrastenhanced MRI with Gd-EOB-DTPA revealed that the liver tumor showed partial enhancement on arterial phase imaging, and (d) low signal intensity on hepatobiliary phase imaging. (e) Dynamic contrast-enhanced CT revealed that the enlarged liver tumor did not show prominent enhancement on arterial phase imaging, and (f) isodensity on portal phase imaging. (g) Early phase CTHA revealed that the peripheral part of the enlarged liver tumor was well stained, whereas the internal side of the liver tumor was faintly stained. (h) CTAP revealed that the liver tumor was contrasted in low density. CT, computed tomography; CTAP, CT arterial portography; CTHA, CT during hepatic arteriography; Gd-EOB-DTPA, gadoliniumethoxybenzyl-diethylenetriamine pentaacetic acid; MRI, magnetic resonance imaging; WI, weighted imaging.
the HCA obtained from the general population.16 Kishnani et al. also showed that alterations in chromosome 6 could be an early event in liver tumorigenesis in GSD type I.16 The genomic alterations in HCA are much fewer than those in HCC.14 It has been showed that a
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: 494–499
498 H. Kanamori et al.
a
Figure 3 (a) Macroscopic findings of the resected specimen revealed a tumor 23 mm in diameter on the cut surface. (b) Microscopic examination showed that dysplastic columnar epithelial cells contained in a large nucleus proliferated in tubular and papillary formation. Histology of the tumor revealed moderately differentiated cholangiocellular carcinoma, whereas no hepatocellular adenoma components were observed (hematoxylin–eosin, original magnification ×100). (c) Immunohistochemical examination of the tumor showed that cells positive for cytokeratin 7 had emerged (original magnification ×100). (d,e) PAS and PAS diastase stained cells had emerged (original magnification ×200). PAS, periodic acid-Schiff.
b
c
d
e
mean of 7.2 chromosomal aberrations were present in well HCC patients, whereas only two chromosomal aberrations were seen in HCA patients.14 Mutation studies have indicated that a group of HCA, representing 15% of cases exhibiting activating mutations of β-catenin, were generally characterized by a high risk of malignant transformation to HCC.4 However, whether chromosomal aberrations or mutations of β-catenin in
© 2014 The Japan Society of Hepatology
HCA contribute to the occurrence of CCC remains unclear. In conclusion, we have described a case of GSD Ia with progression of HCA to CCC. GSD Ia patients should be paid attention to for not only HCC but also CCC development. Further studies are needed to investigate the mechanism of the development of CCC in patients with GSD Ia.
Hepatology Research 2015; 45: 494–499
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