Clin J Gastroenterol (2011) 4:43–48 DOI 10.1007/s12328-010-0195-4
CASE REPORT
Spontaneous regression of diffuse intrahepatic recurrence with portal vein tumor thrombus after resection of hepatocellular carcinoma Akihiro Okano • Hiroshi Takakuwa Takefumi Nakamura
•
Received: 6 July 2010 / Accepted: 14 November 2010 / Published online: 14 December 2010 Ó Springer 2010
Abstract We report a rare case of spontaneous regression of diffuse intrahepatic recurrence with portal vein tumor thrombus (PVTT) after resection of hepatocellular carcinoma (HCC). A 68-year-old man with hepatitis C virusrelated liver cirrhosis presented with a 40 mm tumor in the right anterior segment of the liver. The tumor was diagnosed as HCC by typical imaging findings and elevated serum alpha-fetoprotein (AFP) (716 ng/ml) and protein induced by vitamin K absence II (PIVKA II) (8,100 ng/ ml). A right anterior sectionectomy of the liver was performed. Microscopically, the tumor was moderately differentiated HCC. Four months after resection, a computed tomography (CT) scan showed diffuse intrahepatic recurrence with PVTT. Serum AFP was 12,319 ng/ml and PIVKA II was 168,000 ng/ml. The patient did not receive any further treatment for HCC including herbal medicine, and stopped smoking. Two years and 5 months later, no lesion was detected on a CT scan when serum AFP was 1.9 ng/ml. Ischemia due to main portal vein occlusion and rapid tumor growth might have induced tumor regression in the present case. Moreover, abstention from smoking might have improved his immunological function.
Introduction
Keywords Spontaneous regression Hepatocellular carcinoma Diffuse recurrence Portal vein tumor thrombus
A 68-year-old man was admitted to our hospital in June 2003 for work-up of hepatic mass incidentally found by abdominal ultrasonography (US). He had no history of blood transfusion. He had been a regular drinker, consuming over 100 g of alcohol daily for 20 years, but had stopped drinking 28 years ago. He had smoked 40 cigarettes per day for 50 years. He was diagnosed as type 2 diabetes mellitus at the age of 40 and had taken gliclazide orally. He took no other drugs including anticoagulant drugs and vitamin K. Examination of the head, neck, skin, chest, heart, and extremities was unremarkable. The abdomen was soft and flat, and no masses were palpable.
A. Okano (&) H. Takakuwa T. Nakamura Department of Gastroenterology, Tenri Hospital, 200 Mishima-cho, Tenri, Nara 632-8552, Japan e-mail: [email protected]
Spontaneous regression (SR) of a malignant tumor is defined as partial or complete disappearance of malignant cells without any specific treatment, such as administration of anticancer drugs or surgical resection [1]. It is a rare phenomenon and has been estimated to occur in one of 60,000–100,000 cases of malignant tumors [1]. Neuroblastoma, renal cell carcinoma, malignant melanoma, malignant lymphoma, and leukemia are well known to regress spontaneously. SR of hepatocellular carcinoma (HCC) is an unusual phenomenon; however, tumor regression seems to be more frequent among patients with HCC than among patients with other neoplasms [2]. HCC has a poor prognosis, especially a diffuse-type HCC as in the present case [3]. We report a very unusual case of SR of diffuse intrahepatic recurrence with portal vein tumor thrombus (PVTT) after resection of HCC.
Case report
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Clin J Gastroenterol (2011) 4:43–48
Laboratory data on admission are shown in Table 1. Serum HCV Ab and HCV RNA were positive. Serum alpha-fetoprotein (AFP) was 716 ng/ml (normal B10 ng/ ml) and protein induced by vitamin K absence II (PIVKA II) was 8,100 ng/ml (normal B40 ng/ml). Indocyanine green elimination test showed a K value of 0.126 (normal B0.168–0.232) and retention in 15 min was 13.7% (normal B10%). Abdominal US demonstrated a hypoechoic mass with a mosaic pattern 40 mm in diameter in the right anterior superior segment of the liver [Couinaud’s segment 8 (S8)]. A dynamic contrast-enhanced computed tomography (CT) scan showed a solitary, encapsulated, hypervascular tumor located in the same area (Fig. 1a, b). Hepatic angiography disclosed a tumor stain in the arterial phase in the same area. The tumor was described as a low-density lesion on CT during arterial portography and as an enhanced lesion on CT arteriography. The findings of the above laboratory data and imaging examinations were consistent with HCC, classified as stage II (T2N0M0) according to the TNM classification of the Liver Cancer Study Group of Japan. In July 2003, the patient underwent a curative operation, involving right anterior sectionectomy of the liver. Macroscopically, sections of the specimen revealed a welldefined encapsulated solid tumor measuring 40 9 40 9 38 mm in size. Microscopically, the tumor was composed of moderately differentiated trabecular HCC cells (Fig. 2) without portal vein invasion. There was evidence of liver cirrhosis in the remaining part of the liver parenchyma. Table 1 Laboratory data on the first admission Hemoglobin
17.5 g/dl
HBs Ag (-)
Platelets
118,000/mm3
HBs Ab (-)
White blood cells
6,000/mm3
HBe Ag (-)
PT
11.4 s (control 10.6 s)
HBe Ab (-)
Albumin
4.1 g/dl
HBc Ab (-)
Globulin
3.6 g/dl
HCV Ab (?)
AST
23 IU/l
HCV RNA (?)
ALT
26 IU/l
AFP 716 ng/ml
Total bilirubin
0.8 mg/dl
PIVKA II 8,100 ng/ml
c-GTP
37 IU/l
ICG test
ALP
253 IU/l
K value 0.126
Glucose
163 mg/dl
R15 13.7%
HbA1c
8.4%
PT prothrombin time, AST aspartate aminotransferase, ALT alanine aminotransferase, c-GTP c-glutamyl transpeptidase, ALP alkaline phosphatase, HBs Ag hepatitis B surface antigen, Ab antibody, HBe hepatitis B envelope, HBc hepatitis B core, HCV hepatitis C virus, RNA ribonucleic acid, AFP alpha-fetoprotein, PIVKA II protein induced by vitamin K absence II, ICG indocyanine green, R15 retention in 15 min
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Fig. 1 Dynamic CT scan showed a 40 mm high and isodensity mass in the early phase (a) and a low and isodensity mass in the delayed phase (b) in the liver (S8)
Fig. 2 Microscopic examination of the tumor revealed moderately differentiated trabecular HCC (H&E, 9200)
Clin J Gastroenterol (2011) 4:43–48
Four months after the operation, in November 2003, a follow-up dynamic CT scan showed diffuse intrahepatic tumors in the right and left lobe of the remnant liver. The tumor infiltrated the main trunk and left and right branch of the portal vein (Fig. 3a–c). Serum AFP was 12,319 ng/ml and PIVKA II was 168,000 ng/ml at that time. The findings of the above imaging examinations and laboratory data were consistent with recurrent HCC classified as stage IV A (T4N0M0). The patient refused any treatment for HCC and was followed-up as an outpatient. He did not take herbal medicine and did not take any drugs except gliclazide; he also stopped smoking. Five months after the recurrence, in April 2004, a follow-up abdominal US scan showed diffuse tumors in the liver with main PVTT. Over the next 2 years, no cancer treatment was administered and no blood chemistry and imaging examinations were performed. The patient was asymptomatic without abdominal pain, ascites, edema, and jaundice during this period. In April 2006, an abdominal CT scan revealed no tumors in the liver, except a portal vein linear lesion that was probably a scar
45
(Fig. 4a–c). Serum AFP had decreased dramatically to the normal range (1.9 ng/ml) Unfortunately the tumor regression was not confirmed histologically. One year later, in May 2007, a new hypervascular lesion that measured 15 mm was detected in the right anterior inferior segment of the liver (S5) (Fig. 5a, b). Serum AFP was 1.3 ng/ml. The lesion was diagnosed as recurrent HCC by the imaging findings. Transcatheter arterial chemoembolization (TACE) was performed using an emulsion of 3 ml lipiodol and 30 mg epirubicin with gelfoam. Percutaneous radiofrequency ablation (RFA) was also performed. An abdominal CT scan after the treatment showed complete remission (Fig. 5c). Since then, the patient has been followed up at our clinic without any signs of recurrence for 3 years.
Discussion Here we report a rare case of SR of diffuse intrahepatic recurrence with PVTT after resection of HCC. For
Fig. 3 CT scan showed diffuse-type low density masses in the right and left lobe of the liver (a–c) in the delayed phase. The tumor thrombus was noticed in the main trunk (b, c), umbilical portion (a, c), and right branch (c) of the portal vein
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Clin J Gastroenterol (2011) 4:43–48
Fig. 4 CT scan revealed no lesions in the liver (a–c) and the main trunk (b, c) (except linear scar), umbilical portion (a, c), and right branch (c) of the portal vein
diagnosis of SR, it is important to prove the presence of malignant cells morphologically. In this case, the recurrence after resection of HCC was not proved histologically; however, the findings of the abdominal CT scan (Fig. 3a–c) and the elevation of serum AFP and PIVKA II levels supported the diagnosis of HCC. In the previous reports of SR of HCC, clinical profiles vary widely. Tumor regression has been reported in patients with single or multiple lesions, with or without extrahepatic metastases, and with or without having received prior ineffective antineoplastic therapies [4]. The possibility of SR may not be related to size of mass, causative liver disease, and the level of tumor markers [4]. The causative factors and mechanism leading to SR of HCC are not clearly known. Various factors have been suggested. Two possible causes have been considered in previous literature [5]. Firstly, ischemia due to injuries of the feeding arteries associated with angiography and arterial thrombosis [6, 7], the occlusion of the feeders caused by cancerous invasion [8], PVTT [9, 10], deprivation of
123
oxygen due to rapid tumor growth [11], and gastrointestinal bleeding [12] have been thought to be reasons for SR of HCC, because malignant tissue is more sensitive to ischemic change than normal hepatic tissue. HCC is fed predominantly by the hepatic artery, while normal hepatic tissue receives a dual blood supply from the hepatic artery and the portal vein. The portal venous flow does not directly affect tumor viability, but the occlusion of a portal vein branch induces atrophy of the occluded area by necrosis or apoptosis of liver cells [13]. Embolization of the portal vein alone results in minimal damage to HCC, but it has been reported that portal vein embolization increases TACE efficiency [14]. Therefore, disturbances of both the arterial and portal venous circulation might induce tumor regression. Secondly, immunological changes may be the cause of SR of HCC. Abstinence from alcohol or smoking [15, 16], operation with blood transfusion [17], the use of some herbal medicine [18], withdrawal or reduction of androgen [19], secondary bacterial infection in the tumor [20], and prolonged fever [21] induce production of cytokines such
Clin J Gastroenterol (2011) 4:43–48
47
Fig. 5 A dynamic CT scan revealed a 15 mm high density mass in the early phase (a) and a low density mass in the delayed phase (b) in the liver (S5). Follow-up CT scan after TACE and RFA showed complete necrosis of the hepatic mass in the delayed phase (c)
as tumor necrotizing factor (TNF) and TNF may play an important role in anti-tumor activities. In the cases described, the complete tumor necrosis was due to cytokines such as TNF-a and interleukin 18 [22, 23]. The prognosis of diffuse intrahepatic recurrence after resection of HCC is very poor [3]. There have been no previous reports of SR of this type of recurrence as in the present case. What factors, then, could have been involved in SR of HCC in our patient? The main mechanism of SR in this case may have been possibly related to a disturbance of the blood supply due to the PVTT [9, 10] and a deprivation of the oxygen supply due to the rapid tumor growth [11]. It is difficult to evaluate the effect of deficiency of blood and oxygen supply, even if there is evidence of PVTT and rapid tumor growth. Though PVTT and rapid tumor growth are not rare in HCC patients, SR of the tumor is unusual. Therefore, it is difficult to explain the phenomenon only by ischemia due to PVTT and rapid tumor growth. We assume that systemic as well as local effects are involved in the mechanism of SR. Not only did the multiple diffuse intrahepatic tumor regress in this patient but the PVTT also regressed; this phenomenon cannot be
explained solely by ischemic effects. In such instances, immunological mechanisms may play an important role in SR. Abstinence from smoking might have improved his immunological function [16]; however, it is difficult to prove this, because of a lack of definitive evidence. The precise mechanism of SR cannot be fully explained in the present case. This is the first case of SR of a diffuse-type recurrence after resection of HCC. We consider that the accumulation and analysis of clinical data obtained from patients with SR of HCC will contribute to the understanding of this phenomenon and also to the further development in the treatment of HCC.
References 1. Cole WH. Efforts to explain spontaneous regression of cancer. J Surg Oncol. 1981;17:201–9. 2. Epstein RJ, Leung TW. Reversing hepatocellular carcinoma progression by using networked biological therapies. Clin Cancer Res. 2007;13:11–7.
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48 3. Okano A, Hajiro K, Takakuwa H, Nishio A, Matsusue S, Sano A, et al. Diffuse intrahepatic recurrence after resection of hepatocellular carcinoma. Hepatogastroenterology. 2000;47:1356–9. 4. Oquinena S, Inarrairaegui M, Vila JJ, Alegre F, Zozaya JM, Sangro B. Spontaneous regression of hepatocellular carcinoma: three case reports and a categorized review of the literature. Dig Dis Sci. 2009;54:1147–53. 5. Oquinena S, Guillen-Grima F, Inarrairaegui M, Zozaya JM, Sangro B. Spontaneous regression of hepatocellular carcinoma: a systematic review. Euro J Gastroenterol Hepatol. 2009;21:254–7. 6. Imaoka S, Sasaki Y, Masutani S, Ishikawa O, Furukawa H, Kabuto T, et al. Necrosis of hepatocellular carcinoma caused by spontaneously arising arterial thrombus. Hepatogastroenterology. 1994;41:359–62. 7. Takayasu K, Muramatsu Y, Shima Y, Moriyama N, Yamada T, Yoshida T, et al. Necrosis of hepatocellular carcinoma as a result of subintimal injury incurred by hepatic angiography: report of two cases. Am J Gastroenterol. 1986;81:979–83. 8. Kato H, Nakamura M, Muramatsu M, Orito E, Ueda R, Mizokami M. Spontaneous regression of hepatocellular carcinoma: two case reports and a literature review. Hepatol Res. 2004;29:180–90. 9. Uenishi T, Hirohashi K, Tanaka H, Ikebe T, Kinoshita H. Spontaneous regression of a large hepatocellular carcinoma with portal vein tumor thrombi: report of a case. Surg Today. 2000;30:82–5. 10. Iiai T, Sato Y, Nabatame N, Yamamoto S, Makino S, Hatakeyama K. Spontaneous complete regression of hepatocellular carcinoma with portal vein tumor thrombus. Hepatogastroenterology. 2003;50:1628–30. 11. Iwasaki M, Furuse J, Yoshino M, Moriyama N, Kanemoto H, Okumura H. Spontaneous regression of hepatocellular carcinoma; a case report. Jpn J Clin Oncol. 1997;27:278–81. 12. Tocci G, Conte A, Guarascio P, Visco G. Spontaneous regression of a hepatocellular carcinoma after massive gastrointestinal hemorrhage. BMJ. 1990;300:641–2. 13. Ikeda K, Kinoshita H, Hirohashi K, Kubo S, Kaneda K. The ultrastructure, kinetics and intralobular distribution of apoptotic
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14.
15.
16.
17.
18. 19.
20.
21.
22. 23.
hepatocytes after portal branch ligation, with special reference to their relationship to necrotic hepatocytes. Arch Histol Cytol. 1995;58:171–84. Nakao N, Miura K, Takahashi H, Ohnishi M, Miura T, Okamoto E, et al. Hepatocellular carcinoma: combined hepatic, arterial, and portal venous embolization. Radiology. 1986;161:303–7. Gottfried EB, Steller R, Paronetto F, Lieber CS. Spontaneous regression of hepatocellular carcinoma. Gastroenterology. 1982;82:770–4. Grossmann M, Hoermann R, Weiss M, Jauch KW, Oertel H, Staebler A, et al. Spontaneous regression of hepatocellular carcinoma. Am J Gastroenterol. 1995;90:1500–3. Sato Y, Fujiwara K, Nakagawa S. A case of spontaneous regression of hepatocellular carcinoma with bone metastasis. Cancer. 1985;56:667–71. Chien RN, Chen TJ, Liaw YF. Spontaneous regression of hepatocellular carcinoma. Am J Gastroenterol. 1992;87:903–5. McCaugan GW, Bilous MJ, Gallagher ND. Long-term survival with tumor regression in androgen-induced liver tumors. Cancer. 1985;56:2622–6. Watanabe N, Yamauchi N, Maeda M, Neda H, Tsuji Y, Okamoto T, et al. Recombinant human tumor necrosis factor causes regression in patients with advanced malignancies. Oncology. 1994;51:360–5. Jansen PM, Van der Pouw Kraan TC, de Jong IW, van Mierlo G, Wijdenes J, Chang AA, et al. Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon-gamma. Blood. 1996;87:5144–51. Hill ADK, Redmond HP, Croke DT, Grace PA, Bouchier-Hayes D. Cytokines and tumor therapy. Br J Surg. 1992;79:990–7. Abiru S, Kato Y, Hamasaki K, Nakao K, Nakata K, Eguchi K. Spontaneous regression of hepatocellular carcinoma associated with elevated levels of interleukin 18. Am J Gastroenterol. 2002;97:774–5.
CASE REPORT
Spontaneous regression of diffuse intrahepatic recurrence with portal vein tumor thrombus after resection of hepatocellular carcinoma Akihiro Okano • Hiroshi Takakuwa Takefumi Nakamura
•
Received: 6 July 2010 / Accepted: 14 November 2010 / Published online: 14 December 2010 Ó Springer 2010
Abstract We report a rare case of spontaneous regression of diffuse intrahepatic recurrence with portal vein tumor thrombus (PVTT) after resection of hepatocellular carcinoma (HCC). A 68-year-old man with hepatitis C virusrelated liver cirrhosis presented with a 40 mm tumor in the right anterior segment of the liver. The tumor was diagnosed as HCC by typical imaging findings and elevated serum alpha-fetoprotein (AFP) (716 ng/ml) and protein induced by vitamin K absence II (PIVKA II) (8,100 ng/ ml). A right anterior sectionectomy of the liver was performed. Microscopically, the tumor was moderately differentiated HCC. Four months after resection, a computed tomography (CT) scan showed diffuse intrahepatic recurrence with PVTT. Serum AFP was 12,319 ng/ml and PIVKA II was 168,000 ng/ml. The patient did not receive any further treatment for HCC including herbal medicine, and stopped smoking. Two years and 5 months later, no lesion was detected on a CT scan when serum AFP was 1.9 ng/ml. Ischemia due to main portal vein occlusion and rapid tumor growth might have induced tumor regression in the present case. Moreover, abstention from smoking might have improved his immunological function.
Introduction
Keywords Spontaneous regression Hepatocellular carcinoma Diffuse recurrence Portal vein tumor thrombus
A 68-year-old man was admitted to our hospital in June 2003 for work-up of hepatic mass incidentally found by abdominal ultrasonography (US). He had no history of blood transfusion. He had been a regular drinker, consuming over 100 g of alcohol daily for 20 years, but had stopped drinking 28 years ago. He had smoked 40 cigarettes per day for 50 years. He was diagnosed as type 2 diabetes mellitus at the age of 40 and had taken gliclazide orally. He took no other drugs including anticoagulant drugs and vitamin K. Examination of the head, neck, skin, chest, heart, and extremities was unremarkable. The abdomen was soft and flat, and no masses were palpable.
A. Okano (&) H. Takakuwa T. Nakamura Department of Gastroenterology, Tenri Hospital, 200 Mishima-cho, Tenri, Nara 632-8552, Japan e-mail: [email protected]
Spontaneous regression (SR) of a malignant tumor is defined as partial or complete disappearance of malignant cells without any specific treatment, such as administration of anticancer drugs or surgical resection [1]. It is a rare phenomenon and has been estimated to occur in one of 60,000–100,000 cases of malignant tumors [1]. Neuroblastoma, renal cell carcinoma, malignant melanoma, malignant lymphoma, and leukemia are well known to regress spontaneously. SR of hepatocellular carcinoma (HCC) is an unusual phenomenon; however, tumor regression seems to be more frequent among patients with HCC than among patients with other neoplasms [2]. HCC has a poor prognosis, especially a diffuse-type HCC as in the present case [3]. We report a very unusual case of SR of diffuse intrahepatic recurrence with portal vein tumor thrombus (PVTT) after resection of HCC.
Case report
123
44
Clin J Gastroenterol (2011) 4:43–48
Laboratory data on admission are shown in Table 1. Serum HCV Ab and HCV RNA were positive. Serum alpha-fetoprotein (AFP) was 716 ng/ml (normal B10 ng/ ml) and protein induced by vitamin K absence II (PIVKA II) was 8,100 ng/ml (normal B40 ng/ml). Indocyanine green elimination test showed a K value of 0.126 (normal B0.168–0.232) and retention in 15 min was 13.7% (normal B10%). Abdominal US demonstrated a hypoechoic mass with a mosaic pattern 40 mm in diameter in the right anterior superior segment of the liver [Couinaud’s segment 8 (S8)]. A dynamic contrast-enhanced computed tomography (CT) scan showed a solitary, encapsulated, hypervascular tumor located in the same area (Fig. 1a, b). Hepatic angiography disclosed a tumor stain in the arterial phase in the same area. The tumor was described as a low-density lesion on CT during arterial portography and as an enhanced lesion on CT arteriography. The findings of the above laboratory data and imaging examinations were consistent with HCC, classified as stage II (T2N0M0) according to the TNM classification of the Liver Cancer Study Group of Japan. In July 2003, the patient underwent a curative operation, involving right anterior sectionectomy of the liver. Macroscopically, sections of the specimen revealed a welldefined encapsulated solid tumor measuring 40 9 40 9 38 mm in size. Microscopically, the tumor was composed of moderately differentiated trabecular HCC cells (Fig. 2) without portal vein invasion. There was evidence of liver cirrhosis in the remaining part of the liver parenchyma. Table 1 Laboratory data on the first admission Hemoglobin
17.5 g/dl
HBs Ag (-)
Platelets
118,000/mm3
HBs Ab (-)
White blood cells
6,000/mm3
HBe Ag (-)
PT
11.4 s (control 10.6 s)
HBe Ab (-)
Albumin
4.1 g/dl
HBc Ab (-)
Globulin
3.6 g/dl
HCV Ab (?)
AST
23 IU/l
HCV RNA (?)
ALT
26 IU/l
AFP 716 ng/ml
Total bilirubin
0.8 mg/dl
PIVKA II 8,100 ng/ml
c-GTP
37 IU/l
ICG test
ALP
253 IU/l
K value 0.126
Glucose
163 mg/dl
R15 13.7%
HbA1c
8.4%
PT prothrombin time, AST aspartate aminotransferase, ALT alanine aminotransferase, c-GTP c-glutamyl transpeptidase, ALP alkaline phosphatase, HBs Ag hepatitis B surface antigen, Ab antibody, HBe hepatitis B envelope, HBc hepatitis B core, HCV hepatitis C virus, RNA ribonucleic acid, AFP alpha-fetoprotein, PIVKA II protein induced by vitamin K absence II, ICG indocyanine green, R15 retention in 15 min
123
Fig. 1 Dynamic CT scan showed a 40 mm high and isodensity mass in the early phase (a) and a low and isodensity mass in the delayed phase (b) in the liver (S8)
Fig. 2 Microscopic examination of the tumor revealed moderately differentiated trabecular HCC (H&E, 9200)
Clin J Gastroenterol (2011) 4:43–48
Four months after the operation, in November 2003, a follow-up dynamic CT scan showed diffuse intrahepatic tumors in the right and left lobe of the remnant liver. The tumor infiltrated the main trunk and left and right branch of the portal vein (Fig. 3a–c). Serum AFP was 12,319 ng/ml and PIVKA II was 168,000 ng/ml at that time. The findings of the above imaging examinations and laboratory data were consistent with recurrent HCC classified as stage IV A (T4N0M0). The patient refused any treatment for HCC and was followed-up as an outpatient. He did not take herbal medicine and did not take any drugs except gliclazide; he also stopped smoking. Five months after the recurrence, in April 2004, a follow-up abdominal US scan showed diffuse tumors in the liver with main PVTT. Over the next 2 years, no cancer treatment was administered and no blood chemistry and imaging examinations were performed. The patient was asymptomatic without abdominal pain, ascites, edema, and jaundice during this period. In April 2006, an abdominal CT scan revealed no tumors in the liver, except a portal vein linear lesion that was probably a scar
45
(Fig. 4a–c). Serum AFP had decreased dramatically to the normal range (1.9 ng/ml) Unfortunately the tumor regression was not confirmed histologically. One year later, in May 2007, a new hypervascular lesion that measured 15 mm was detected in the right anterior inferior segment of the liver (S5) (Fig. 5a, b). Serum AFP was 1.3 ng/ml. The lesion was diagnosed as recurrent HCC by the imaging findings. Transcatheter arterial chemoembolization (TACE) was performed using an emulsion of 3 ml lipiodol and 30 mg epirubicin with gelfoam. Percutaneous radiofrequency ablation (RFA) was also performed. An abdominal CT scan after the treatment showed complete remission (Fig. 5c). Since then, the patient has been followed up at our clinic without any signs of recurrence for 3 years.
Discussion Here we report a rare case of SR of diffuse intrahepatic recurrence with PVTT after resection of HCC. For
Fig. 3 CT scan showed diffuse-type low density masses in the right and left lobe of the liver (a–c) in the delayed phase. The tumor thrombus was noticed in the main trunk (b, c), umbilical portion (a, c), and right branch (c) of the portal vein
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Clin J Gastroenterol (2011) 4:43–48
Fig. 4 CT scan revealed no lesions in the liver (a–c) and the main trunk (b, c) (except linear scar), umbilical portion (a, c), and right branch (c) of the portal vein
diagnosis of SR, it is important to prove the presence of malignant cells morphologically. In this case, the recurrence after resection of HCC was not proved histologically; however, the findings of the abdominal CT scan (Fig. 3a–c) and the elevation of serum AFP and PIVKA II levels supported the diagnosis of HCC. In the previous reports of SR of HCC, clinical profiles vary widely. Tumor regression has been reported in patients with single or multiple lesions, with or without extrahepatic metastases, and with or without having received prior ineffective antineoplastic therapies [4]. The possibility of SR may not be related to size of mass, causative liver disease, and the level of tumor markers [4]. The causative factors and mechanism leading to SR of HCC are not clearly known. Various factors have been suggested. Two possible causes have been considered in previous literature [5]. Firstly, ischemia due to injuries of the feeding arteries associated with angiography and arterial thrombosis [6, 7], the occlusion of the feeders caused by cancerous invasion [8], PVTT [9, 10], deprivation of
123
oxygen due to rapid tumor growth [11], and gastrointestinal bleeding [12] have been thought to be reasons for SR of HCC, because malignant tissue is more sensitive to ischemic change than normal hepatic tissue. HCC is fed predominantly by the hepatic artery, while normal hepatic tissue receives a dual blood supply from the hepatic artery and the portal vein. The portal venous flow does not directly affect tumor viability, but the occlusion of a portal vein branch induces atrophy of the occluded area by necrosis or apoptosis of liver cells [13]. Embolization of the portal vein alone results in minimal damage to HCC, but it has been reported that portal vein embolization increases TACE efficiency [14]. Therefore, disturbances of both the arterial and portal venous circulation might induce tumor regression. Secondly, immunological changes may be the cause of SR of HCC. Abstinence from alcohol or smoking [15, 16], operation with blood transfusion [17], the use of some herbal medicine [18], withdrawal or reduction of androgen [19], secondary bacterial infection in the tumor [20], and prolonged fever [21] induce production of cytokines such
Clin J Gastroenterol (2011) 4:43–48
47
Fig. 5 A dynamic CT scan revealed a 15 mm high density mass in the early phase (a) and a low density mass in the delayed phase (b) in the liver (S5). Follow-up CT scan after TACE and RFA showed complete necrosis of the hepatic mass in the delayed phase (c)
as tumor necrotizing factor (TNF) and TNF may play an important role in anti-tumor activities. In the cases described, the complete tumor necrosis was due to cytokines such as TNF-a and interleukin 18 [22, 23]. The prognosis of diffuse intrahepatic recurrence after resection of HCC is very poor [3]. There have been no previous reports of SR of this type of recurrence as in the present case. What factors, then, could have been involved in SR of HCC in our patient? The main mechanism of SR in this case may have been possibly related to a disturbance of the blood supply due to the PVTT [9, 10] and a deprivation of the oxygen supply due to the rapid tumor growth [11]. It is difficult to evaluate the effect of deficiency of blood and oxygen supply, even if there is evidence of PVTT and rapid tumor growth. Though PVTT and rapid tumor growth are not rare in HCC patients, SR of the tumor is unusual. Therefore, it is difficult to explain the phenomenon only by ischemia due to PVTT and rapid tumor growth. We assume that systemic as well as local effects are involved in the mechanism of SR. Not only did the multiple diffuse intrahepatic tumor regress in this patient but the PVTT also regressed; this phenomenon cannot be
explained solely by ischemic effects. In such instances, immunological mechanisms may play an important role in SR. Abstinence from smoking might have improved his immunological function [16]; however, it is difficult to prove this, because of a lack of definitive evidence. The precise mechanism of SR cannot be fully explained in the present case. This is the first case of SR of a diffuse-type recurrence after resection of HCC. We consider that the accumulation and analysis of clinical data obtained from patients with SR of HCC will contribute to the understanding of this phenomenon and also to the further development in the treatment of HCC.
References 1. Cole WH. Efforts to explain spontaneous regression of cancer. J Surg Oncol. 1981;17:201–9. 2. Epstein RJ, Leung TW. Reversing hepatocellular carcinoma progression by using networked biological therapies. Clin Cancer Res. 2007;13:11–7.
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