Clin J Gastroenterol (2013) 6:424–428 DOI 10.1007/s12328-013-0420-z
CASE REPORT
Elevated paraneoplastic hypercholesterolemia in a case of hepatoid adenocarcinoma of the stomach with liver metastasis Tetsuro Sohda • Hiroyuki Kusuhara • Yoshiki Egashira Keisuke Egashira • Koichi Eguchi • Kunihiko Aoyagi • Shotaro Sakisaka
•
Received: 15 May 2013 / Accepted: 24 August 2013 / Published online: 14 September 2013 Ó Springer Japan 2013
Abstract A 67-year-old man was admitted to our hospital because of a large liver tumor revealed by ultrasonography. Laboratory data showed increased serum levels of alphafetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), which are tumor markers for hepatocellular carcinoma. In addition, the serum cholesterol level was extremely high. Endoscopic examination revealed advanced gastric cancer. Histological findings of the stomach and liver tumor showed they were both hepatoid adenocarcinomas and were both positive for antibodies against AFP as well as DCP, suggesting that the tumors were gastric cancer with liver metastasis. Moreover, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme for regulation of cholesterol synthesis, was upregulated in the tumor tissues. Accordingly, we diagnosed this patient with AFP- and DCP-producing gastric cancer accompanied by paraneoplastic hypercholesterolemia. Paraneoplastic hypercholesterolemia is sometimes seen in hepatocellular carcinoma, but never in gastric cancer. This case is interesting because of the feature of hepatoid adenocarcinoma. Keywords Alpha-fetoprotein (AFP) Des-gammacarboxy prothrombin (DCP) Hepatoid adenocarcinoma Hypercholesterolemia Paraneoplastic syndrome 3-hydroxyl-3methylglutaryl coenzyme A (HMG-CoA) reductase T. Sohda (&) K. Eguchi K. Aoyagi S. Sakisaka Department of Gastroenterology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan e-mail: [email protected] H. Kusuhara Y. Egashira K. Egashira Sakura Hospital, 4-16-15 Katae, Jonan-ku, Fukuoka 814-0142, Japan
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Introduction Serum alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) are recognized as being useful markers in the diagnosis of hepatocellular carcinoma (HCC). When elevated, these tumor markers in serum are also seen in patients with gastric cancer, albeit rarely [1–3]. Moreover, AFP- and DCP-producing gastric cancer is sometimes morphologically similar to HCC [4]. Advanced malignancies are sometimes associated with paraneoplastic syndrome. In the syndrome, hypercholesterolemia is known to be a unique complication in HCC [5, 6]; however, it is unknown whether paraneoplastic hypercholesterolemia is associated with AFP- and DCP-producing cancers other than HCC. Here, we report a patient who had AFP- and DCP-producing hepatoid adenocarcinoma of the stomach together with liver metastasis. In this case, the serum cholesterol level was extremely high. Furthermore, we demonstrated overproduction of cholesterol in cancer cells by immunohistochemistry.
Case report A 67-year-old male was admitted to our hospital with a liver tumor. He had neither past history nor family history of hypercholesterolemia. On physical examination, an elastic firm liver was palpable 5 cm below the right costal margin. The laboratory data were as follows. Serum levels of transaminase, alkaline phosphatase and bilirubin were within the normal range, whereas the level of lactate dehydrogenase was high. Serum level of cholesterol was extremely high at 470 mg/dl. Hepatitis C virus (HCV)
Clin J Gastroenterol (2013) 6:424–428
425
Table 1 Laboratory data on admission WBC
9,200/ll
HBs Ag
(-) HBc Ab (-)
Hb
16.3 g/dl
HCV Ab
(-)
Plt
34.5 9 104/ll 1.4 ng/ml
TP
8.1 g/dl
CEA
Alb
4.1 g/dl
CA19-9
4 U/ml
T Bil
0.7 mg/dl
AFP
720,000 ng/ml
AST
24 IU/l
(L3 43.7 %)
ALT
15 IU/l
DCP
LDH
634 IU/l
ALP
313 IU/l
r-GTP
139 IU/l
T Chol
470 mg/dl
HDL-C
46 mg/dl
TG
109 mg/dl
1,525,000 mAU/ml
antibody, HCV-RNA, hepatitis B virus surface (HBs) antigen and hepatitis B virus core (HBc) antibody were all negative. As for tumor markers, serum AFP and DCP levels were both extremely high, whereas serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were normal (Table 1). A computed tomography (CT) scan showed large nodules in the right lobe of the liver (Fig. 1). Endoscopic examination revealed the simultaneous presence of Borrmann III type advanced cancer extending from the body to the antrum of the stomach (Fig. 2). Gastric biopsy demonstrated hepatoid adenocarcinoma. The patient’s performance status was not good because of a previous cerebral infarction. Therefore, the patient and his family did not desire active treatment. The stomach and liver tumors progressively enlarged, resulting in death 2 months after admission. To distinguish metastatic liver lesions of gastric cancer from gastric cancer complicated with HCC, we performed liver necropsy. The liver tissue showed hepatoid adenocarcinoma, as was seen in the gastric lesion (Fig. 3). Immunohistochemical analysis was performed using an anti-alpha-1-fetoprotein polyclonal antibody (DakoCytomation A/S, Copenhagen, Denmark) for AFP and a MU-3 monoclonal antibody (Eisai, Tokyo, Japan) for DCP. Immunoreaction for both AFP and DCP was clearly shown in both the gastric cancer and in the metastatic lesion of the liver, suggesting AFP- and DCP-producing gastric cancer with liver metastasis (Fig. 4). To study the origin of the elevated serum cholesterol level, we also performed immunohistochemical analysis using a rabbit antibody against a human 3-hydroxyl-3methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme for regulation of cholesterol synthesis (United States Biological, Swampscott, MA, USA) as described in
Fig. 1 Computed tomography scan shows large nodules in the right lobe of the liver
Fig. 2 Endoscopic examination reveals the simultaneous presence of Borrmann III type advanced cancer from the body to the antrum of the stomach
a previous report [7]. HMG-CoA reductase was clearly stained in both the primary gastric lesion and the metastatic liver lesion, whereas the signal was significantly suppressed in the non-tumorous liver (Fig. 5).
Discussion We demonstrated the first case of AFP- and DCP-producing gastric cancer with liver metastasis accompanied by paraneolpastic hypercholesterolemia. Immunohistochemical analysis revealed that the hepatoid adenocarcinoma cells in the stomach and metastatic liver lesions were producing cholesterol.
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Fig. 3 Histological examination demonstrates that both stomach (a) and liver lesions (b) were hepatoid adenocarcinoma (H&E staining 9200)
Fig. 4 Immunoreaction for both AFP (a, c) and DCP (b, d) was significantly demonstrated in the primary gastric lesion (a, b) and the metastatic lesion of the liver (c, d) (9200)
Cholesterol is usually synthesized in hepatocytes. Since some HCC are thought to maintain this function, HCC is sometimes accompanied by hypercholesterolemia [5, 6]. Thus, paraneoplastic hypercholesterolemia is thought to be a unique complication in HCC, and raised levels in malignancies other than HCC are extremely rare. Many cases of AFP- and DCP-producing gastric cancer have been reported [8, 9]. These gastric cancers sometimes show histological findings similar to HCC. However, it is
123
not known whether this special gastric cancer has any functional common features, including cholesterol synthesis, with HCC. It is well known that low-density lipoprotein receptor (LDL-R) and HMG-CoA reductase play a central role in the regulation of cholesterol synthesis in hepatocytes [10]. We reported reduced expression of LDL-R in cases of HCC with paraneoplastic hypercholesterolemia [11]. When the HCC expresses only low levels of LDL-R, HMG-CoA
Clin J Gastroenterol (2013) 6:424–428
427
Fig. 5 HMG-CoA reductase was clearly stained in both the primary gastric lesion (a) and the metastatic liver lesion (b), whereas the signal was significantly suppressed in the non-tumorous liver (c) (9200)
reductase may become increased due to a lack of negative feedback, resulting in upregulation of cholesterol synthesis. Since gastric cancer usually does not synthesize cholesterol, increased cholesterol levels due to the oppression of small bile ducts by the tumor must be considered in metastatic liver cancer accompanied by hypercholesterolemia. Thus, the crucial point to consider is whether cholesterol synthesis in gastric cancer tissue is increasing. To clarify this problem, we performed immunohistochemistry for HMG-CoA reductase. We have already reported on the significance of immunohistochemistry for HMG-CoA reductase in the diagnosis of paraneoplastic hypercholesterolemia [7]. AFP-producing gastric cancer sometimes presents hepatoid adenocarcinoma which is morphologically similar to HCC. Hepatoid adenocarcinoma of the stomach or AFPproducing gastric cancer, which differs from common gastric adenocarcinoma, has the same hypervascularity as HCC, and has been reported to rupture spontaneously in metastatic liver lesions as is often seen in HCC [12]. Although hepatoid adenocarcinoma has the potential to produce albumin as well as tumor markers such as AFP and DCP, hepatoid adenocarcinoma also seems to be similar to HCC in function [13]. Furthermore, Caruso et al. [14] reported upregulation of HMG-CoA reductase activity and LDL-R expression in some types of gastric cancer. Thus, gastric cancer is expected to have the potential of cholesterol synthesis like HCC. When the cholesterol regulation system via LDL-R fails in gastric cancer with such function, paraneoplastic hypercholesterolemia occurs.
In this report, we have proven the overproduction of cholesterol in hepatoid adenocarcinoma of the stomach and its metastatic liver lesion. This case is interesting because of the feature of hepatoid adenocarcinoma. Disclosures Conflict of Interest: The authors 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 all patients for being included in the study.
References 1. McIntire KR, Waldmann TA, Moertel CG, Go VL. Serum alphafetoprotein in patients with neoplasms of the gastrointestinal tract. Cancer Res. 1975;35:991–6. 2. Chang YC, Nagasue N, Abe S, Kohno H, Kumar DD, Nakamura T. alpha Fetoprotein producing early gastric cancer with liver metastasis: report of three cases. Gut. 1991;32:542–5. 3. Chang YC, Nagasue N, Abe S, Taniura H, Kumar DD, Nakamura T. Comparison between the clinicopathologic features of AFPpositive and AFP-negative gastric cancers. Am J Gastroenterol. 1992;87:321–5. 4. Ishikura H, Kirimoto K, Shamoto M, Miyamoto Y, Yamagiwa H, Itoh T, Aizawa M. Hepatoid adenocarcinomas of the stomach. An analysis of seven cases. Cancer. 1986;58:119–26. 5. Luo JC, Hwang SJ, Wu JC, Li CP, Hsiao LT, Lai CR, Chiang JH, Lui WY, Chang FY, Lee SD. Paraneoplastic syndromes in patients with hepatocellular carcinoma in Taiwan. Cancer. 1999;86:799–804.
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428 6. Hwang SJ, Lee SD, Chang CF, Wu JC, Tsay SH, Lui WY, Chiang JH, Lo KJ. Hypercholesterolaemia in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 1992;7:491–6. 7. Sohda T, Iwata K, Hirano G, Sakurai K, Yokoyama K, Morihara D, Takeyama Y, Irie M, Shakado S, Sakisaka S. 3-Hydroxyl-3methylglutaryl-coenzyme A reductase is up regulated in hepatocellular carcinoma associated with paraneoplastic hypercholesterolemia. Med Mol Morphol. 2013 (in press). 8. Sohda T, Tomioka Y, Inomata S, Morita I, Eguchi K, Aoyagi K, Watanabe H, Nakamura S, Sakisaka S. Alpha-fetoprotein (AFP)and des-gamma-carboxy prothrombin (DCP)-producing adenocarcinoma of the stomach with liver metastasis in a patient with chronic hepatitis C. Intern Med. 2005;44:294–8. 9. Ye MF, Tao F, Liu F, Sun AJ. Hepatoid adenocarcinoma of the stomach: a report of three cases. World J Gastroenterol. 2013;19:4437–42. 10. Rodwell VW. Cholesterol regulation of hepatic 3-hydroxy-3methylglutaryl-coenzyme A reductase. Biochem J. 1972;128:16.
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Clin J Gastroenterol (2013) 6:424–428 11. Sohda T, Iwata K, Kitamura Y, Suzuki N, Takeyama Y, Irie M, Anan A, Nakane H, Yoshikane M, Watanabe H, Sakisaka S. Reduced expression of low-density lipoprotein receptor in hepatocellular carcinoma with paraneoplastic hypercholesterolemia. J Gastroenterol Hepatol. 2008;23:e153–6. 12. Sohda T, Hanano T, Miyamoto H, Kitano Y, Iwata K, Yokoyama M, Irie M, Takeyama Y, Shakado S, Sakisaka S. Spontaneous rupture of metastatic alpha-fetoprotein-producing gastric cancer of the liver. Hepatol Int. 2008;2:258–61. 13. Foschini MP, Baccarini P, Dal Monte PR, Sinard J, Eusebi V, Rosai J. Albumin gene expression in adenocarcinomas with hepatoid differentiation. Virchows Arch. 1998;433:537–41. 14. Caruso MG, Notarnicola M, Cavallini A, Di Leo A. 3-Hydroxy3-methylglutaryl coenzyme A reductase activity and low-density lipoprotein receptor expression in diffuse-type and intestinal-type human gastric cancer. J Gastroenterol. 2002;37:504–8.
CASE REPORT
Elevated paraneoplastic hypercholesterolemia in a case of hepatoid adenocarcinoma of the stomach with liver metastasis Tetsuro Sohda • Hiroyuki Kusuhara • Yoshiki Egashira Keisuke Egashira • Koichi Eguchi • Kunihiko Aoyagi • Shotaro Sakisaka
•
Received: 15 May 2013 / Accepted: 24 August 2013 / Published online: 14 September 2013 Ó Springer Japan 2013
Abstract A 67-year-old man was admitted to our hospital because of a large liver tumor revealed by ultrasonography. Laboratory data showed increased serum levels of alphafetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), which are tumor markers for hepatocellular carcinoma. In addition, the serum cholesterol level was extremely high. Endoscopic examination revealed advanced gastric cancer. Histological findings of the stomach and liver tumor showed they were both hepatoid adenocarcinomas and were both positive for antibodies against AFP as well as DCP, suggesting that the tumors were gastric cancer with liver metastasis. Moreover, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme for regulation of cholesterol synthesis, was upregulated in the tumor tissues. Accordingly, we diagnosed this patient with AFP- and DCP-producing gastric cancer accompanied by paraneoplastic hypercholesterolemia. Paraneoplastic hypercholesterolemia is sometimes seen in hepatocellular carcinoma, but never in gastric cancer. This case is interesting because of the feature of hepatoid adenocarcinoma. Keywords Alpha-fetoprotein (AFP) Des-gammacarboxy prothrombin (DCP) Hepatoid adenocarcinoma Hypercholesterolemia Paraneoplastic syndrome 3-hydroxyl-3methylglutaryl coenzyme A (HMG-CoA) reductase T. Sohda (&) K. Eguchi K. Aoyagi S. Sakisaka Department of Gastroenterology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan e-mail: [email protected] H. Kusuhara Y. Egashira K. Egashira Sakura Hospital, 4-16-15 Katae, Jonan-ku, Fukuoka 814-0142, Japan
123
Introduction Serum alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) are recognized as being useful markers in the diagnosis of hepatocellular carcinoma (HCC). When elevated, these tumor markers in serum are also seen in patients with gastric cancer, albeit rarely [1–3]. Moreover, AFP- and DCP-producing gastric cancer is sometimes morphologically similar to HCC [4]. Advanced malignancies are sometimes associated with paraneoplastic syndrome. In the syndrome, hypercholesterolemia is known to be a unique complication in HCC [5, 6]; however, it is unknown whether paraneoplastic hypercholesterolemia is associated with AFP- and DCP-producing cancers other than HCC. Here, we report a patient who had AFP- and DCP-producing hepatoid adenocarcinoma of the stomach together with liver metastasis. In this case, the serum cholesterol level was extremely high. Furthermore, we demonstrated overproduction of cholesterol in cancer cells by immunohistochemistry.
Case report A 67-year-old male was admitted to our hospital with a liver tumor. He had neither past history nor family history of hypercholesterolemia. On physical examination, an elastic firm liver was palpable 5 cm below the right costal margin. The laboratory data were as follows. Serum levels of transaminase, alkaline phosphatase and bilirubin were within the normal range, whereas the level of lactate dehydrogenase was high. Serum level of cholesterol was extremely high at 470 mg/dl. Hepatitis C virus (HCV)
Clin J Gastroenterol (2013) 6:424–428
425
Table 1 Laboratory data on admission WBC
9,200/ll
HBs Ag
(-) HBc Ab (-)
Hb
16.3 g/dl
HCV Ab
(-)
Plt
34.5 9 104/ll 1.4 ng/ml
TP
8.1 g/dl
CEA
Alb
4.1 g/dl
CA19-9
4 U/ml
T Bil
0.7 mg/dl
AFP
720,000 ng/ml
AST
24 IU/l
(L3 43.7 %)
ALT
15 IU/l
DCP
LDH
634 IU/l
ALP
313 IU/l
r-GTP
139 IU/l
T Chol
470 mg/dl
HDL-C
46 mg/dl
TG
109 mg/dl
1,525,000 mAU/ml
antibody, HCV-RNA, hepatitis B virus surface (HBs) antigen and hepatitis B virus core (HBc) antibody were all negative. As for tumor markers, serum AFP and DCP levels were both extremely high, whereas serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were normal (Table 1). A computed tomography (CT) scan showed large nodules in the right lobe of the liver (Fig. 1). Endoscopic examination revealed the simultaneous presence of Borrmann III type advanced cancer extending from the body to the antrum of the stomach (Fig. 2). Gastric biopsy demonstrated hepatoid adenocarcinoma. The patient’s performance status was not good because of a previous cerebral infarction. Therefore, the patient and his family did not desire active treatment. The stomach and liver tumors progressively enlarged, resulting in death 2 months after admission. To distinguish metastatic liver lesions of gastric cancer from gastric cancer complicated with HCC, we performed liver necropsy. The liver tissue showed hepatoid adenocarcinoma, as was seen in the gastric lesion (Fig. 3). Immunohistochemical analysis was performed using an anti-alpha-1-fetoprotein polyclonal antibody (DakoCytomation A/S, Copenhagen, Denmark) for AFP and a MU-3 monoclonal antibody (Eisai, Tokyo, Japan) for DCP. Immunoreaction for both AFP and DCP was clearly shown in both the gastric cancer and in the metastatic lesion of the liver, suggesting AFP- and DCP-producing gastric cancer with liver metastasis (Fig. 4). To study the origin of the elevated serum cholesterol level, we also performed immunohistochemical analysis using a rabbit antibody against a human 3-hydroxyl-3methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme for regulation of cholesterol synthesis (United States Biological, Swampscott, MA, USA) as described in
Fig. 1 Computed tomography scan shows large nodules in the right lobe of the liver
Fig. 2 Endoscopic examination reveals the simultaneous presence of Borrmann III type advanced cancer from the body to the antrum of the stomach
a previous report [7]. HMG-CoA reductase was clearly stained in both the primary gastric lesion and the metastatic liver lesion, whereas the signal was significantly suppressed in the non-tumorous liver (Fig. 5).
Discussion We demonstrated the first case of AFP- and DCP-producing gastric cancer with liver metastasis accompanied by paraneolpastic hypercholesterolemia. Immunohistochemical analysis revealed that the hepatoid adenocarcinoma cells in the stomach and metastatic liver lesions were producing cholesterol.
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Fig. 3 Histological examination demonstrates that both stomach (a) and liver lesions (b) were hepatoid adenocarcinoma (H&E staining 9200)
Fig. 4 Immunoreaction for both AFP (a, c) and DCP (b, d) was significantly demonstrated in the primary gastric lesion (a, b) and the metastatic lesion of the liver (c, d) (9200)
Cholesterol is usually synthesized in hepatocytes. Since some HCC are thought to maintain this function, HCC is sometimes accompanied by hypercholesterolemia [5, 6]. Thus, paraneoplastic hypercholesterolemia is thought to be a unique complication in HCC, and raised levels in malignancies other than HCC are extremely rare. Many cases of AFP- and DCP-producing gastric cancer have been reported [8, 9]. These gastric cancers sometimes show histological findings similar to HCC. However, it is
123
not known whether this special gastric cancer has any functional common features, including cholesterol synthesis, with HCC. It is well known that low-density lipoprotein receptor (LDL-R) and HMG-CoA reductase play a central role in the regulation of cholesterol synthesis in hepatocytes [10]. We reported reduced expression of LDL-R in cases of HCC with paraneoplastic hypercholesterolemia [11]. When the HCC expresses only low levels of LDL-R, HMG-CoA
Clin J Gastroenterol (2013) 6:424–428
427
Fig. 5 HMG-CoA reductase was clearly stained in both the primary gastric lesion (a) and the metastatic liver lesion (b), whereas the signal was significantly suppressed in the non-tumorous liver (c) (9200)
reductase may become increased due to a lack of negative feedback, resulting in upregulation of cholesterol synthesis. Since gastric cancer usually does not synthesize cholesterol, increased cholesterol levels due to the oppression of small bile ducts by the tumor must be considered in metastatic liver cancer accompanied by hypercholesterolemia. Thus, the crucial point to consider is whether cholesterol synthesis in gastric cancer tissue is increasing. To clarify this problem, we performed immunohistochemistry for HMG-CoA reductase. We have already reported on the significance of immunohistochemistry for HMG-CoA reductase in the diagnosis of paraneoplastic hypercholesterolemia [7]. AFP-producing gastric cancer sometimes presents hepatoid adenocarcinoma which is morphologically similar to HCC. Hepatoid adenocarcinoma of the stomach or AFPproducing gastric cancer, which differs from common gastric adenocarcinoma, has the same hypervascularity as HCC, and has been reported to rupture spontaneously in metastatic liver lesions as is often seen in HCC [12]. Although hepatoid adenocarcinoma has the potential to produce albumin as well as tumor markers such as AFP and DCP, hepatoid adenocarcinoma also seems to be similar to HCC in function [13]. Furthermore, Caruso et al. [14] reported upregulation of HMG-CoA reductase activity and LDL-R expression in some types of gastric cancer. Thus, gastric cancer is expected to have the potential of cholesterol synthesis like HCC. When the cholesterol regulation system via LDL-R fails in gastric cancer with such function, paraneoplastic hypercholesterolemia occurs.
In this report, we have proven the overproduction of cholesterol in hepatoid adenocarcinoma of the stomach and its metastatic liver lesion. This case is interesting because of the feature of hepatoid adenocarcinoma. Disclosures Conflict of Interest: The authors 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 all patients for being included in the study.
References 1. McIntire KR, Waldmann TA, Moertel CG, Go VL. Serum alphafetoprotein in patients with neoplasms of the gastrointestinal tract. Cancer Res. 1975;35:991–6. 2. Chang YC, Nagasue N, Abe S, Kohno H, Kumar DD, Nakamura T. alpha Fetoprotein producing early gastric cancer with liver metastasis: report of three cases. Gut. 1991;32:542–5. 3. Chang YC, Nagasue N, Abe S, Taniura H, Kumar DD, Nakamura T. Comparison between the clinicopathologic features of AFPpositive and AFP-negative gastric cancers. Am J Gastroenterol. 1992;87:321–5. 4. Ishikura H, Kirimoto K, Shamoto M, Miyamoto Y, Yamagiwa H, Itoh T, Aizawa M. Hepatoid adenocarcinomas of the stomach. An analysis of seven cases. Cancer. 1986;58:119–26. 5. Luo JC, Hwang SJ, Wu JC, Li CP, Hsiao LT, Lai CR, Chiang JH, Lui WY, Chang FY, Lee SD. Paraneoplastic syndromes in patients with hepatocellular carcinoma in Taiwan. Cancer. 1999;86:799–804.
123
428 6. Hwang SJ, Lee SD, Chang CF, Wu JC, Tsay SH, Lui WY, Chiang JH, Lo KJ. Hypercholesterolaemia in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 1992;7:491–6. 7. Sohda T, Iwata K, Hirano G, Sakurai K, Yokoyama K, Morihara D, Takeyama Y, Irie M, Shakado S, Sakisaka S. 3-Hydroxyl-3methylglutaryl-coenzyme A reductase is up regulated in hepatocellular carcinoma associated with paraneoplastic hypercholesterolemia. Med Mol Morphol. 2013 (in press). 8. Sohda T, Tomioka Y, Inomata S, Morita I, Eguchi K, Aoyagi K, Watanabe H, Nakamura S, Sakisaka S. Alpha-fetoprotein (AFP)and des-gamma-carboxy prothrombin (DCP)-producing adenocarcinoma of the stomach with liver metastasis in a patient with chronic hepatitis C. Intern Med. 2005;44:294–8. 9. Ye MF, Tao F, Liu F, Sun AJ. Hepatoid adenocarcinoma of the stomach: a report of three cases. World J Gastroenterol. 2013;19:4437–42. 10. Rodwell VW. Cholesterol regulation of hepatic 3-hydroxy-3methylglutaryl-coenzyme A reductase. Biochem J. 1972;128:16.
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Clin J Gastroenterol (2013) 6:424–428 11. Sohda T, Iwata K, Kitamura Y, Suzuki N, Takeyama Y, Irie M, Anan A, Nakane H, Yoshikane M, Watanabe H, Sakisaka S. Reduced expression of low-density lipoprotein receptor in hepatocellular carcinoma with paraneoplastic hypercholesterolemia. J Gastroenterol Hepatol. 2008;23:e153–6. 12. Sohda T, Hanano T, Miyamoto H, Kitano Y, Iwata K, Yokoyama M, Irie M, Takeyama Y, Shakado S, Sakisaka S. Spontaneous rupture of metastatic alpha-fetoprotein-producing gastric cancer of the liver. Hepatol Int. 2008;2:258–61. 13. Foschini MP, Baccarini P, Dal Monte PR, Sinard J, Eusebi V, Rosai J. Albumin gene expression in adenocarcinomas with hepatoid differentiation. Virchows Arch. 1998;433:537–41. 14. Caruso MG, Notarnicola M, Cavallini A, Di Leo A. 3-Hydroxy3-methylglutaryl coenzyme A reductase activity and low-density lipoprotein receptor expression in diffuse-type and intestinal-type human gastric cancer. J Gastroenterol. 2002;37:504–8.
