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CASE REPORT

Hepatocellular Carcinoma with Peritoneal Dissemination

which was Regressed during Vitamin K2 and Vitamin E

Administration

Toshiyuki Otsuka 1, Satoshi Hagiwara 1, Hiroki Tojima 1, Hiroaki Yoshida 1,

Tetsushi Takahashi 1, Kazumi Nagasaka 1, Shinichi Tomioka 1, Tetsu Ando 2,

Kunio Takeuchi 2, Takayuki Kori 2, Yoshihiro Ohno 3, Satoru Kakizaki 4,

Hitoshi Takagi 4 and Masatomo Mori 4

Abstract

A 65-year-old man with positive anti-hepatitis C antibody and chronic renal failure was diagnosed as hav-

ing a ruptured hepatocellular carcinoma (HCC) based on computed tomography (CT). The patient underwent

transcatheter arterial embolization (TAE) for the HCC. After one more session of TAE, the patient underwent

surgery. But HCC seeding peritoneally was pointed out. Vitamin K2 and vitamin E were administered as a

conservative treatment. Six months after starting vitamins K2 and E, the primary tumor did not increase in

size and intraperitoneal dissemination disappeared on CT with a significant decrease of alpha-fetoprotein.

Even though this is only one case, combination therapy of vitamin K2 and E may induce growth suppression

of HCC.

Key words: hepatocellular carcinoma, vitamin K2, vitamin E

(DOI: 10.2169/internalmedicine.46.6131)

Introduction

Hepatocellular carcinoma (HCC) is a common malig-

nancy in Japan and the diagnosis and treatment of HCC has

progressed (1). Although curative treatment is available and

the survival of patients with an early stage of HCC in-

creases, curative treatment is difficult and the prognosis is

poor at advanced stage of HCC. Even in the patients with

advanced stage HCC, intraperitoneal dissemination of HCC

is rare (2). Ruptured HCC increases the risk of abdominal

dissemination and the prognosis of patients with ruptured

HCC is usually worse than that of non-ruptured HCC (3, 4).

Thus, abdominal dissemination of HCC is considered in a

terminal stage (2).

Vitamin K2 is known to inhibit the growth of a variety of

tumor cell lines by inducing apoptosis or differentiation (5,

6). Vitamin K2 was recently used for the treatment of sev-

eral human cancers including myelodysplastic syndrome (5).

Vitamin E is also known to be an apoptotic agent for tumor

cells and prevents hepatocarcinogenesis in animal models (7,

8). It is reported that administration of vitamin E for pa-

tients with liver cirrhosis and hepatitis C virus (HCV) infec-

tion resulted in a lower rate of development of HCC and a

higher cumulative survival without development of HCC (8).

In this report, we present a case of regression of perito-

neal dissemination in HCC during the administration of vita-

min K2 and vitamin E.

Case Report

A 65-year-old man was referred to Tone Chuo Hospital

for the diagnosis and treatment of a liver tumor in October

2004. The patient had received hematodialysis since 1995 in

Department of Internal Medicine, Tone Chuo Hospital, Numata, Department of Surgery, Tone Chuo Hospital, Numata, Department of Pathol-

ogy, Tone Chuo Hospital, Numata and Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine,

Maebashi

Received for publication July 18, 2006; Accepted for publication September 19, 2006

Correspondence to Dr. Toshiyuki Otsuka, tcht-otsuka@tonehoken.or.jp

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Figure 1.Demonstration of hepatocellular carcinoma (HCC) by enhanced computed tomogra-

phy (CT). A: CT shows a HCC measuring 3 cm in diameter at segment 4 of the liver (arrow) and

high-density ascites (arrowhead). B: CT shows a HCC with lipiodol deposition (arrow) and a large

amount of ascites soon after the operation. C: CT shows a HCC with lipiodol deposition (arrow)

and decreased ascites 6 months after the administration of vitamins K2 and E (C). The size of the

HCC did not change in 6 months.

another hospital. There was no history of alcohol abuse or

smoking. The patient received blood transfusion due to a

wound in 1964. Laboratory tests showed hemoglobin (Hb),

8.2 g/dL, white blood cell count (WBC), 7,500/mm 3, platelet

count (PLT), 143,000/mm3, total bilirubin (T-BIL) 0.41 mg/

dL, albumin (ALB) 3.3 g/dL, aspartate aminotransferase

(AST), 12 IU/L, alanine aminotransferase (ALT), 17 IU/L,

alpha-fetoprotein (AFP), 8,997 ng/mL, protein induced by

vitamin K absence or antagonist II (PIVKA-II), 41 mAU/

mL. Hepatitis B surface antigen was negative and anti-

hepatitis C antibody was positive. Computed tomography

(CT) demonstrated a tumor, 3 cm in diameter at segment 4

of the liver and ascites of high density (Fig. 1A). Gastro-

intestinal endoscopy showed esophageal varices. Therefore,

the patient was diagnosed with ruptured hepatocellular carci-

noma (HCC) associated with liver cirrhosis caused by HCV.

Hepatic arteriography showed tumor stain at segment 4 in

the liver (Fig. 2). Transcatheter arterial embolization (TAE)

was performed to the HCC. CT showed local recurrence of

HCC at segment 4 in January 2005 and a second TAE was

performed with 30 mg of epirubicin. However, after the sec-ond TAE, the AFP level was increased and the deposition of

lipiodol in the tumor was decreased. The diagnosis was that

the local recurrence occurred again and the patient was ad-

mitted to our hospital in June 2005.

On admission, the patient was alert and physical examina-

tion showed no abnormality. The results of routine labora-

tory tests on admission were as follows: Hb 10.7 g/dL,

WBC 5,700/mm3, PLT 124,000/mm3, Prothrombin time

82.2%, T-BIL 0.33 mg/dL, ALB 3.5 g/dL, AST 16 IU/L,

ALT 16 IU/L, ICG 15.5%, AFP 1,381 ng/mL, PIVKA-II 25

mAU/mL. Because hepatic arteriography showed no tumor

stain in the liver, we could not perform TAE. We decided to

perform surgical treatment for HCC in segment 4. Surgical

laparotomy revealed several tumors and bloody ascites in

the abdominal cavity (Fig. 3A) in July 2005. Pathologically,

one of the tumors in the omentum was revealed to be

moderately-poorly differentiated HCC (Fig. 3B). Surgical

treatment was aborted. Soon after the operation, CT demon-

strated HCC measuring 3 cm in diameter at segment 4

(Fig. 1B), disseminated tumors and ascites in the abdominal

cavity (Fig. 4A, B). Because of the advanced stage of HCC

and chronic renal failure, the patient declined interventional

therapies. Thereafter, we prescribed oral vitamin K2 (45 mg/

day) and vitamin E (150 mg/day) and the patient was dis-charged in August 1, 2005. Three months after the admini-

stration of vitamin K2 and vitamin E, the AFP level had de-

creased to 46.4 ng/mL (Fig. 5) and CT demonstrated that

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Figure 2.Hepatic arteriography shows a tumor stain (arrow). A: Early phase. B: Late phase.

Figure 3.Pathological features of disseminated tumor in the omentum at operation. A: Macro-

scopic examination shows a dark green tumor. B: Microscopic examination shows a moderately-

poorly differentiated HCC (H&E 40). Arrow shows bile.

the diameter of HCC at segment 4 was unchanged and dis-

seminated tumors disappeared and ascites was decreased.

Six months have passed and the AFP level was 56.5 ng/mL

(Fig. 5), and HCC in segment 4 did not increase in size

(Fig. 1C), ascites did not increase and disseminated tumors

disappeared on CT (Fig. 4C, D). During the six months, the

PIVKA-II level was within normal range.

Discussion

Although the recent improvements of the treatment for

HCC such as operation and radiofrequency ablation are re-

markable, a treatment for peritoneal dissemination of HCC

has not been established (9). In patients with extrahepatic

metastases of HCC, most patients with bone metastases died

from hepatic cause but approximately one-third of the pa-

tients with metastases other than bone died from extrahe-

patic causes (10). Therefore, it is important to treat extrahe-

patic HCC including peritoneal dissemination in order to

improve survival and provide a good quality of life even

when the patient is in the terminal stage of HCC. It is usu-ally difficult to completely resect peritoneal dissemination of

HCC (2, 11). However, repeated resection for peritoneal dis-

semination of HCC could contribute to the long-term sur-

vival (3, 12). Radiotherapy is used either in combination

with or as an alternative to surgery (13). For example, the

patient with HCC underwent six repeated resections and two

radiotherapy for peritoneal dissemination, and the patient re-

mained alive without any evidence of recurrence for three

years (14). Hyperthermia could be considered as one of the

multimodal treatments (11). Reportedly, the combination of

transarterial chemoembolization and hyperthermia was effec-

tive against peritoneal HCC in an animal experiment (15). A

variety of systemic chemotherapy have been tested in HCC,

including combination therapies with cisplatin, doxorubicin

and tegafur and uracil (UFT), and alpha-interferon and UFT

(16-18). The case of recurrent HCC with peritoneal dissemi-

nation and splenic metastasis which disappeared after ad-

ministration of UFT was reported (19). In the present case,

TAE was repeatedly performed for primary HCC but the

peritoneal dissemination was difficult to treat because of the

poor clinical condition even though the peritoneal dissemi-

nation was detected before surgery.

Vitamin K2 is known to inhibit the growth and invasion

of HCC cell lines in vitro (20, 21). Moreover, administrationof vitamin K2 to nude mice implanted liver tumor cells in-

hibited the growth of the liver tumor (20). Although the

mechanisms associated with the antiproliferative effects of

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Figure 4.Disseminated tumors and ascites by enhanced CT. A, B: A few disseminated tumors

(arrows) and large amount of ascites are found soon after the operation. C, D: There is no dissemi

nated tumor and only a small amount of ascites at 6 months after start of administration of vita

mins K2 and E.

Figure 5.Clinical course of the patient.

vitamin K2 against tumor cells remain unknown, it has been

proposed that the effect of vitamin K2 may occur through

activation of protein kinase A (PKA) pathway (20). PKA it-

self induces cell cycle arrest and activates downstream tran-

scriptional factors, activating enhancer-binding protein-2 andupstream transcription factor-1, which are related to growth

inhibition (20). Furthermore, Wang et al reported that vita-

min K2 induced c-myc resulted in apoptosis of hepatoma

cells (21). Clinically, vitamin K2 is known to be used in the

treatment of myelodysplastic syndrome (22). As for HCC,

administration of vitamin K2 prevents the development of

HCC in women with viral cirrhosis and that suppresses the

recurrence of HCC and improves survival in patients who

have received curative treatment of HCC (6, 22).

Vitamin E is known to induce apoptotic cell death in vari-

ous cell types in vitro and to inhibit tumorigenesis in vivo

(7, 23, 24). In the mechanisms of vitamin E-induced apopto-

sis it has been demonstrated that vitamin E restores both

transforming growth factor- and Fas/CD95-APO-1 signal-

ing pathway and activates extracellular signal-regulated

kinase-1 and c-Jun NH2-terminal kinase-1 as well as tran-

scriptional factors, c-Jun and activating transcriptional

factor-2 (7, 24). Clinical work of administration of vitamin

E to patients with viral liver cirrhosis showed that the rate

of development of HCC tended to be longer and survival

was higher in the vitamin E group compared with the con-

trol group (8).

Therefore, we prescribed oral vitamin K2 45 mg daily

and oral vitamin E 150 mg daily. Recently, vitamin K2 was

used for chemoprevention of HCC and there were no ad-

verse effects related to administration of vitamin K2 45 mgwhich is the same dosage used in the treatment of osteopo-

rosis (6). Vitamin E was also used for chemoprevention of

HCC using the same dosage for the treatment of peripheral

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nerve impediment and there were no adverse effects (8). As

a result, intraabdominal dissemination of HCC disappeared

and the primary tumor did not grow. Although the associa-

tion between vitamin K2 and E in the field of antiprolifera-

tive effect on tumor cells is not known, it is suggested that

administration of vitamin K2 and E inhibited the growth of

HCC in the present case.Although spontaneous regression of HCC is rare, several

causes of regression of HCC have been known, such as lack

of blood supply due to rapid growth of HCC, withdrawal

from steroid, abstinence of alcohol consumption (5). In the

present case, the speed of tumor growth was not rapid be-

cause the size of primary HCC and abdominal disseminated

tumors were up to 3 cm. He did not have a history of medi-

cation with steroid and alcohol abuse. Therefore, administra-

tion of vitamin K2 and E could be reason for regression in

our case. To our knowledge, this is the first case report

documenting regression of HCC during the administration of

vitamin K2 and E.

In conclusion, administration of vitamin K2 and vitaminE for patients with advanced stage of HCC, such as perito-

neal dissemination and distant metastasis, who have no indi-

cation of interventional therapy, should be considered to

prolong life and to improve quality of life. Further control

study will be needed to confirm the efficacy of vitamin K2

and vitamin E for the treatment of HCC.

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