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Resection of peritoneal metastases in patients with hepatocellular carcinoma
Brief Clinical Report Resection of peritoneal metastases in patients with hepatocellular carcinoma Masaji Hashimoto, MD, Kazunari Sasaki, MD, Jin Moriyama, MD, Masamichi Matsuda, MD, and Goro Watanabe, MD, Tokyo, Japan
Background. Peritoneal metastases from hepatocellular carcinoma are common; they are found in as many as 18% of autopsy cases. Effective treatment for peritoneal metastases, however, has not yet been established. Methods. We resected peritoneal metastases 12 times in 9 patients with hepatocellular carcinoma. We assessed the clinical course and outcome of these patients to determine the effectiveness of resecting peritoneal metastases and the factors related to survival. Results. The 1-, 3-, and 5-year survival rates were 58%, 52%, and 42%, respectively. Four patients survived for longer than 2 years without recurrence or with controlled recurrence confined to the liver. Three patients receiving palliative resection had a poor prognosis, with survivals of only 4, 9, and 12 months. Conclusion. Operative resection should be an option for selected patients with peritoneal metastases from hepatocellular carcinoma. Resection of peritoneal metastases should be considered in patients whose primary liver neoplasm is under control and who have no metastases in other organs. (Surgery 2013;153:727-31.) From the Department of Digestive Surgery, Toranomon Hospital and Okinaka Memorial Institute of Medical Research, Tokyo, Japan
THE
MAIN SITES OF METASTASIS FROM HEPATOCELLULAR
(HCC) are the lungs, bone, lymph nodes, and adrenal glands.1-3 Peritoneal metastases from HCC are found at autopsy in up to 18% of patients with HCC.1 In contrast, a prevalence of only 6.3% was reported for postoperative peritoneal metastases in Japanese patients who underwent hepatic resection.4 In general, when present, peritoneal metastases arising from intra-abdominal malignancies are disseminated widely with numerous tumor nodules and malignant ascites. Resection of such metastases is not indicated to improve the patient’s quality of life. In contrast, several groups have reported that resection of peritoneal metastases arising from HCC may be of value,5,6 but the operative treatment of peritoneal metastases is not well established. CARCINOMA
Accepted for publication March 30, 2012. Reprint requests: Masaji Hashimoto, MD, Department of Digestive Surgery, Toranomon Hospital, 2-2-2 Toranomon, Minatoku, Tokyo 105-8470, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2012.03.031
Although the prognosis of patients with HCC with peritoneal metastases is generally poor,7 we evaluated the clinicopathologic characteristics and outcome of 9 selected patients with HCC and peritoneal metastases treated in our department during an 8-year period. PATIENTS AND METHODS Between 2003 and 2010, we performed 500 hepatic resections for HCC, including repeat hepatectomy. Patients who were found to have peritoneal metastases by follow-up imaging were assessed for possible resection of their metastatic tumors. Resection of peritoneal metastases was performed 12 times in 9 patients (Table I). The selection criteria of these patients included a limited number of peritoneal metastatic nodules, harmful symptoms, and HCC in the liver being under control. In 7 of the 12 operations, no residual HCC was seen in the liver or at other sites macroscopically. These patients had undergone hepatectomy previously (not via a laparoscopic approach), percutaneous radiofrequency ablation therapy (RFA), or transarterial chemoembolization (TACE). Four patients, 2 of whom were only treated by TACE (cases 8 and 9) and 2 of whom had multiple lung metastases (cases SURGERY 727
Case
Age
Sex
Virus
Liver status
Child–Pugh class
1
72 79 52 53 54 60 40 66 74 58 76 64
F
No
NOR
A
M
B
CH
A
M F M M M M M
C B C C B, C No C
CH CH LC LC CH NOR LC
A A B A A A B
2
3 4 5 6 7 8 9
Location RUQ LLQ Umbilicus RUQ LUQ LUQ RFA site LUQ LUQ LUQ Umbilicus LUQ
Other site
Initial symptoms
N N N Y (lung) Y (lung) N N Y (lung) N N Y (liver) Y (liver)
N N N Y (tumor) Y (tumor) N N Y (pain) N N Y (tumor) Y (tumor)
Combined resection
Jejunum
HTX (S6) HTX (S3) Abdominal wall
AFP, mg/L
PIVKA-II, AU/L
138 1,055 7 6 5 8 3,068 4,140 3 8 50,260 47,000 (<20)
610 315 21 21 21 21 166 1060 431 99 115 531 (<30)
Former treatment HTX (1) HTX (1)
HTX (1) – HTX (1) – HTX (3) – HTX (1) HTX (1) – HTX (2) – TACE (1)
TACE (2) RFA (2) TACE (11) TACE (1) TACE (6)
Interval (initial treat to peritoneal ope)
No. metastases
Size, mm
5m 7 yr 3 yr 6 yr, 6 m 7 yr 11 m 1 yr, 3 m 11yr 11 m 1 yr 3yr 1 yr, 6 m
1 1 1 2 2 1 3 1 3 1 1 1
20 50 50 54, 11 70, 68 60 5, 3, 2 80 20, 15, 10 20 60 145
Surgical margin of peritoneal resection [R]
Survival, month
0 1 1 1 2 0 1 2 1 1 0 1
91 9 55 13 7 35 29 12 10 10 9 4
728 Hashimoto et al
Table I. Clinicopathologic characteristics of the patients with resected peritoneal dissemination
Alive/dead Alive
Dead Alive Alive Dead Alive Dead Dead Dead
Numbers in parentheses indicate number of times. CH, Chronic hepatitis; HTX, hepatectomy; LC, liver cirrhosis; LLQ , left under quadrant; LUQ , left upper quadrant; NOR, normal liver; ope, operation; PIVKA-II, serum des-gamma-carboxy prothorombin; RFA, radiofrequency ablation; RUQ , right upper quadrant; TACE, transarterial chemoembolization.
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Hashimoto et al 729
2 and 5) at the time of detection of the peritoneal metastases, did not show complete control of their liver tumors. Complete control of their tumors means the treatment of HCC with hepatectomy or radiofrequency ablation (RFA) therapy, not with transarterial chemoembolization (TACE) therapy. None of these patients had adjuvant chemotherapy or radiation therapy before or after the resection of the peritoneal metastases. None underwent percutaneous biopsy for diagnosis. RESULTS The mean age of the 9 patients at the initial resection of their peritoneal metastases was 64 years, with a range of 40–76 years. The male to female ratio was 7:2. Positive hepatitis B serology was found in 2 patients, hepatitis C serology in 4 patients, both viruses in 1 patient, and neither virus in 2 patients. The nonmalignant liver parenchyma contained chronic active hepatitis in 4 patients, cirrhosis in 3, and was normal in 2. According to the Child–Pugh classification, 8 patients were in class A and 1 patient was in class B.8,9 Six of 9 patients had poorly differentiated HCC. Five patients had increased serum alphafetoprotein, and 7 had increased serum desgamma-carboxy prothorombin at the time of peritoneal surgery. Previous treatment of the HCC included hepatectomy in 8 patients, RFA in 1 patient, and TACE in 5 patients. The interval from initial treatment for the primary HCC to resection of the peritoneal metastases was 5 months to 11 years, with an average of 31 months. Case 2 underwent resection of peritoneal metastases 3 times, and case 1 had 2 resections. The interval from the first operation to the second operation for peritoneal metastases was 7 years in case 1, in whom the increase in serum tumor marker occurred 2 years before the detection of the second peritoneal recurrence; because the tumor was located in the lower left abdomen, the computed tomography (CT) targeting the remnant liver missed this peritoneal metastasis. After resection of the second peritoneal resection there was no recurrence at 9 months (Fig 1). The number of peritoneal metastases ranged from 1 to 3, with an average of 2, and the maximum diameter of these tumors ranged from 2 to 145 mm (mean, 44 mm) on preoperative imaging. The number of resected nodules also ranged from 1 to 3, with an average of 2 (equal or more than on preoperative imaging), and their average maximum diameter was 40 mm (2;145 mm). Peritoneal metastases were located in the left upper quadrant in 7 cases, the right upper
Fig 1. Case 1 had 2 resections of peritoneal metastases. The interval from the first operation to the second operation was 7 years. Serum tumor marker elevation occurred 2 years before the detection of the second peritoneal recurrence because the tumor was located in the lower left abdomen (A) and PET/CT was effective in diagnosis (B).
quadrant in 2 cases, the periumbilical region in 2 cases, and near the primary neoplasm or the RFA therapy site in 1 case each (Table I). We tried to perform resection of all visible peritoneal metastases with a negative surgical margin (R0-R1 resection), which was achieved in 10 operations performed on 8 patients. In the other 2 operations, we could not remove the peritoneal metastases completely because of local extension and vascular invasion in 2 patients who had multiple lung metastases and symptoms caused by the peritoneal tumors (Table I). The primary HCC was moderately to poorly differentiated HCC in all patients. Pathologic examination of the resected peritoneal metastases showed histologically compatible with the metastases from HCC in all cases. After resection of the peritoneal metastases, the survival rate for patients was 58% after 1 year, 50% after 3 years, and 42% after 5 years, with a mean follow-up period of 28 months (4;91 months; Fig 2, Table I). Four patients died as the result of HCC recurrence in this series. With respect to prognostic factors, because no patient had more
730 Hashimoto et al
Fig 2. The survival rate after resection of the peritoneal dissemination was 58% after 1 year, 50% after 3 years, and 42% after 5 years.
than 3 peritoneal metastases and there were only 9 patients, we could not evaluate the role of the number of peritoneal metastases on survival. Distant metastases at operation and incomplete control of HCC in the liver which was treated other than with hepatectomy or RFA therapy, appeared to be adverse prognostic factors (Table I). DISCUSSION In general, except for ovarian cancer and pseudomyxoma peritonei, the resection of peritoneal tumors arising from other abdominal malignancies10,11 is not indicated for improving the patient’s quality of life because such peritoneal metastases are not localized and are disseminated throughout the peritoneal cavity.12 For example, cholangiocellular carcinoma causes more extensive peritoneal metastases than HCC, and the prognosis of cholangiocellular carcinoma patients with such metastases is poor.13 Although peritoneal metastases arising from HCC have been reported in 18% of patients at autopsy,1 such metastases are found much less frequently at the time of initial hepatectomy. The risk factors for peritoneal metastasis of HCC have not all been clarified. Hepatitis B and C infection are known to play an important role in the development of HCC, and 7 of our 9 patients had hepatitis virus infection. There was no clear relationship between the type of viral infection and the occurrence of peritoneal metastases.4 Regarding to the pathologic features of the primary
Surgery May 2013
hepatic HCC, poorly differentiated HCC is reported to be associated with a greater risk of peritoneal metastasis.14 In this series, 6 of the 9 patients had poorly differentiated HCC, and such neoplasms are usually more advanced. Although the mechanism of peritoneal metastasis has not been elucidated, spontaneous rupture of the primary tumor, percutaneous tumor biopsy, and percutaneous local ablation therapy (percutaneous ethanol injection and radiofrequency ablation) appear to play an important role in peritoneal dissemination.14-16 Detection of peritoneal metastases arising from HCC has been aided by recent advances in imaging techniques. The diagnosis of peritoneal metastases is facilitated because metastatic nodules are hypervascular, provided the tumor is of sufficient diameter to be visible on contrast-enhanced computed tomography. Because the site of the recurrence of HCC is usually in the remnant liver, it is important to extend the field of the surveillance CT to detect peritoneal metastases. Fludeoxyglucose positron emission tomography (PET)/CT is very effective for the diagnosis of progression of HCC.17 Tumor markers for HCC, alpha-fetoprotein, and serum des-gamma-carboxy prothorombin were increased in approximately one-half of our patients. In case 1, the surveillance CT targeting the remnant liver did not extend to the lower abdomen, and thus this lower abdominal metastasis was missed; the use of PET/CT allowed the detection of neoplasm tumor 2 years after the initial increase in serum tumor markers. This observation questions whether it may be standard care to perform abdominal/pelvic CT when recurrence of HCC is suspected because of tumor marker elevation. Effective treatment of peritoneal metastases from HCC remains to be established. Because such metastases are thought by many groups to represent disseminated disease, resection or radiation therapy is not thought to improve the prognosis, and systemic chemotherapy is recommended. New effective chemotherapy for HCC has been widely used and also can be used for peritoneal metastases.18 Median overall survival was 10.7 months in the sorafenib group with advanced HCC. Although patients in this series mostly had peritoneal metastases, 1-year survival rate was 58%, which might be comparable with the systemic chemotherapy. In contrast, resection of peritoneal metastases of HCC has been reported previously in Japan.5 Makino and colleagues6 reviewed 47 patients with HCC with resection of peritoneal metastases, among whom 31 patients (66%) had only 1 peritoneal metastasis macroscopically. The prognosis of
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Surgery Volume 153, Number 5
HCC patients with extrahepatic metastases is generally poor,1 with a 1-year survival rate of 20% a 3-year survival of 0% without resection.6,19 Although our numbers are small, after resection of peritoneal metastases in the present series, the survival rate was 58% after 1 year, 50% after 3 years, and 42% after 5 years (Fig 2). Incomplete control of the HCC in the liver, the presence of extrahepatic metastases other than the peritoneum, or an R2 resection of the peritoneal metastases may be the prognostic factors. Because 1 patient with 3 peritoneal metastases had a good prognosis, ie, 29 months of disease-free survival, the number of peritoneal metastases might not be a prognostic factor. Although the number of the peritoneal metastases detected during laparotomy was equal or more than that of preoperative imaging, laparoscopic observation may be effective in evaluation of the peritoneal metastases, but complete removal of peritoneal metastases may still have a beneficial effect (Table I). In conclusion Resection may be an option for selected patients with peritoneal metastases from HCC because complete removals of such metastases appear to improve survival in patients with controlled HCC in the liver and without other distant metastases. REFERENCES 1. Ikai I, Arii S, Ichida T, Okita K, Omata M, Kojiro M, et al. Report of 16th follow-up survey of primary liver tumor. Hepatol Res 2005;32:163-72. 2. Nagasue N, Yukaya H, Hamada T, Hirose S, Kanashima R, Inokuchi K. The natural history of hepatocellular carcinoma. A study of 100 untreated cases. Cancer 1984;54:1461-5. 3. Katyal S, Oliver JH III, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology 2000;216:698-703. 4. Nakashima T, Okuda K, Kojiro M, Jimi A, Yamaguchi R, Sakamoto K, et al. Pathology of hepatocellular carcinoma in Japan, 232 consecutive cases autopsied in ten years. Cancer 1983;51:863-77. 5. Nakayama H, Takayama T, Makuuchi M, Yamazaki S, Kosuge T, Shimada K, et al. Resection of peritoneal metastases
6.
7. 8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
18.
19.
from hepatocellular carcinoma. Hepatogastroenterology 1999;46:1049-52. Makino I, Hojo S, Terada I, Note M, Sawasaki K, Fujita H. A case of peritoneal dissemination of ruputured hepatocellular carcinoma (HCC) resected three times [in Japanese]. J Jpn Surg Assoc 2004;65:1397-402. Lee YT, Geer DA. Primary liver cancer: pattern of metastasis. J Surg Oncol 1987;36:26-31. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG III, editor. The liver and portal hypertension. Philadelphia: W.B. Saunders; 1964. p. 50. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-69. Witkamp AJ, de Bree E, Kaag MM, van Slooten GW, van Coevorden F, Zoetmulder FA. Extensive surgical cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in patients with pseudomyxoma peritonei. Br J Surg 2001;88:458-63. Suh-Burgmann E, Powell CB. Cytoreductive surgery for gynecologica malignancies–new standards of care. Surg Oncol Clin N Am 2007;16:667-82. Yamaguchi A, Tsukioka Y, Fushida S, Kurosaka Y, Kanno M, Yonemura Y, et al. Intraperitoneal hyperthermic treatment for peritoneal dissemination of colorectal cancers. Dis Colon Rectum 1992;35:964-8. Lazaridis KN, Gores GJ. Cholangiocarcinoma. Gastroenterology 2005;128:1655-67. Sonoda T, Kanematsu T, Takenaka K, Sugimachi K. Ruptured hepatocellular carcinoma evokes risk of implanted metastases. J Surg Oncol 1989;41:183-6. Sakurai M, Okamura J, Seki K, Kuroda C. Needle tract implantation of hepatocellular carcinoma after percutaneous liver biopsy. Am J Surg Pathol 1983;7:191-5. Llovet JM, Vilana R, Bru C, Bianchi L, Salmeron JM, Boix L, et al. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001;33:1124-9. Han AR, Gwak GY, Choi MS, Lee JH, Koh KC, Paik SW, et al. The clinical value of 18F-FDG PET/CT for investigating unexplained serum AFP elevation following interventional therapy for hepatocellular carcinoma. Hepatogastroenterology 2009;56:1111-6. Liovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90. Sakamoto K, Nakashima K, Migo S, Hasuda K, Anai H. A study of treatment for extrahepatic metastasis after treatment of hepatocellular carcinoma [in Japanese]. Jpn J Gastroenterol Surg 2002;35:116-9.
Background. Peritoneal metastases from hepatocellular carcinoma are common; they are found in as many as 18% of autopsy cases. Effective treatment for peritoneal metastases, however, has not yet been established. Methods. We resected peritoneal metastases 12 times in 9 patients with hepatocellular carcinoma. We assessed the clinical course and outcome of these patients to determine the effectiveness of resecting peritoneal metastases and the factors related to survival. Results. The 1-, 3-, and 5-year survival rates were 58%, 52%, and 42%, respectively. Four patients survived for longer than 2 years without recurrence or with controlled recurrence confined to the liver. Three patients receiving palliative resection had a poor prognosis, with survivals of only 4, 9, and 12 months. Conclusion. Operative resection should be an option for selected patients with peritoneal metastases from hepatocellular carcinoma. Resection of peritoneal metastases should be considered in patients whose primary liver neoplasm is under control and who have no metastases in other organs. (Surgery 2013;153:727-31.) From the Department of Digestive Surgery, Toranomon Hospital and Okinaka Memorial Institute of Medical Research, Tokyo, Japan
THE
MAIN SITES OF METASTASIS FROM HEPATOCELLULAR
(HCC) are the lungs, bone, lymph nodes, and adrenal glands.1-3 Peritoneal metastases from HCC are found at autopsy in up to 18% of patients with HCC.1 In contrast, a prevalence of only 6.3% was reported for postoperative peritoneal metastases in Japanese patients who underwent hepatic resection.4 In general, when present, peritoneal metastases arising from intra-abdominal malignancies are disseminated widely with numerous tumor nodules and malignant ascites. Resection of such metastases is not indicated to improve the patient’s quality of life. In contrast, several groups have reported that resection of peritoneal metastases arising from HCC may be of value,5,6 but the operative treatment of peritoneal metastases is not well established. CARCINOMA
Accepted for publication March 30, 2012. Reprint requests: Masaji Hashimoto, MD, Department of Digestive Surgery, Toranomon Hospital, 2-2-2 Toranomon, Minatoku, Tokyo 105-8470, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2012.03.031
Although the prognosis of patients with HCC with peritoneal metastases is generally poor,7 we evaluated the clinicopathologic characteristics and outcome of 9 selected patients with HCC and peritoneal metastases treated in our department during an 8-year period. PATIENTS AND METHODS Between 2003 and 2010, we performed 500 hepatic resections for HCC, including repeat hepatectomy. Patients who were found to have peritoneal metastases by follow-up imaging were assessed for possible resection of their metastatic tumors. Resection of peritoneal metastases was performed 12 times in 9 patients (Table I). The selection criteria of these patients included a limited number of peritoneal metastatic nodules, harmful symptoms, and HCC in the liver being under control. In 7 of the 12 operations, no residual HCC was seen in the liver or at other sites macroscopically. These patients had undergone hepatectomy previously (not via a laparoscopic approach), percutaneous radiofrequency ablation therapy (RFA), or transarterial chemoembolization (TACE). Four patients, 2 of whom were only treated by TACE (cases 8 and 9) and 2 of whom had multiple lung metastases (cases SURGERY 727
Case
Age
Sex
Virus
Liver status
Child–Pugh class
1
72 79 52 53 54 60 40 66 74 58 76 64
F
No
NOR
A
M
B
CH
A
M F M M M M M
C B C C B, C No C
CH CH LC LC CH NOR LC
A A B A A A B
2
3 4 5 6 7 8 9
Location RUQ LLQ Umbilicus RUQ LUQ LUQ RFA site LUQ LUQ LUQ Umbilicus LUQ
Other site
Initial symptoms
N N N Y (lung) Y (lung) N N Y (lung) N N Y (liver) Y (liver)
N N N Y (tumor) Y (tumor) N N Y (pain) N N Y (tumor) Y (tumor)
Combined resection
Jejunum
HTX (S6) HTX (S3) Abdominal wall
AFP, mg/L
PIVKA-II, AU/L
138 1,055 7 6 5 8 3,068 4,140 3 8 50,260 47,000 (<20)
610 315 21 21 21 21 166 1060 431 99 115 531 (<30)
Former treatment HTX (1) HTX (1)
HTX (1) – HTX (1) – HTX (3) – HTX (1) HTX (1) – HTX (2) – TACE (1)
TACE (2) RFA (2) TACE (11) TACE (1) TACE (6)
Interval (initial treat to peritoneal ope)
No. metastases
Size, mm
5m 7 yr 3 yr 6 yr, 6 m 7 yr 11 m 1 yr, 3 m 11yr 11 m 1 yr 3yr 1 yr, 6 m
1 1 1 2 2 1 3 1 3 1 1 1
20 50 50 54, 11 70, 68 60 5, 3, 2 80 20, 15, 10 20 60 145
Surgical margin of peritoneal resection [R]
Survival, month
0 1 1 1 2 0 1 2 1 1 0 1
91 9 55 13 7 35 29 12 10 10 9 4
728 Hashimoto et al
Table I. Clinicopathologic characteristics of the patients with resected peritoneal dissemination
Alive/dead Alive
Dead Alive Alive Dead Alive Dead Dead Dead
Numbers in parentheses indicate number of times. CH, Chronic hepatitis; HTX, hepatectomy; LC, liver cirrhosis; LLQ , left under quadrant; LUQ , left upper quadrant; NOR, normal liver; ope, operation; PIVKA-II, serum des-gamma-carboxy prothorombin; RFA, radiofrequency ablation; RUQ , right upper quadrant; TACE, transarterial chemoembolization.
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Hashimoto et al 729
2 and 5) at the time of detection of the peritoneal metastases, did not show complete control of their liver tumors. Complete control of their tumors means the treatment of HCC with hepatectomy or radiofrequency ablation (RFA) therapy, not with transarterial chemoembolization (TACE) therapy. None of these patients had adjuvant chemotherapy or radiation therapy before or after the resection of the peritoneal metastases. None underwent percutaneous biopsy for diagnosis. RESULTS The mean age of the 9 patients at the initial resection of their peritoneal metastases was 64 years, with a range of 40–76 years. The male to female ratio was 7:2. Positive hepatitis B serology was found in 2 patients, hepatitis C serology in 4 patients, both viruses in 1 patient, and neither virus in 2 patients. The nonmalignant liver parenchyma contained chronic active hepatitis in 4 patients, cirrhosis in 3, and was normal in 2. According to the Child–Pugh classification, 8 patients were in class A and 1 patient was in class B.8,9 Six of 9 patients had poorly differentiated HCC. Five patients had increased serum alphafetoprotein, and 7 had increased serum desgamma-carboxy prothorombin at the time of peritoneal surgery. Previous treatment of the HCC included hepatectomy in 8 patients, RFA in 1 patient, and TACE in 5 patients. The interval from initial treatment for the primary HCC to resection of the peritoneal metastases was 5 months to 11 years, with an average of 31 months. Case 2 underwent resection of peritoneal metastases 3 times, and case 1 had 2 resections. The interval from the first operation to the second operation for peritoneal metastases was 7 years in case 1, in whom the increase in serum tumor marker occurred 2 years before the detection of the second peritoneal recurrence; because the tumor was located in the lower left abdomen, the computed tomography (CT) targeting the remnant liver missed this peritoneal metastasis. After resection of the second peritoneal resection there was no recurrence at 9 months (Fig 1). The number of peritoneal metastases ranged from 1 to 3, with an average of 2, and the maximum diameter of these tumors ranged from 2 to 145 mm (mean, 44 mm) on preoperative imaging. The number of resected nodules also ranged from 1 to 3, with an average of 2 (equal or more than on preoperative imaging), and their average maximum diameter was 40 mm (2;145 mm). Peritoneal metastases were located in the left upper quadrant in 7 cases, the right upper
Fig 1. Case 1 had 2 resections of peritoneal metastases. The interval from the first operation to the second operation was 7 years. Serum tumor marker elevation occurred 2 years before the detection of the second peritoneal recurrence because the tumor was located in the lower left abdomen (A) and PET/CT was effective in diagnosis (B).
quadrant in 2 cases, the periumbilical region in 2 cases, and near the primary neoplasm or the RFA therapy site in 1 case each (Table I). We tried to perform resection of all visible peritoneal metastases with a negative surgical margin (R0-R1 resection), which was achieved in 10 operations performed on 8 patients. In the other 2 operations, we could not remove the peritoneal metastases completely because of local extension and vascular invasion in 2 patients who had multiple lung metastases and symptoms caused by the peritoneal tumors (Table I). The primary HCC was moderately to poorly differentiated HCC in all patients. Pathologic examination of the resected peritoneal metastases showed histologically compatible with the metastases from HCC in all cases. After resection of the peritoneal metastases, the survival rate for patients was 58% after 1 year, 50% after 3 years, and 42% after 5 years, with a mean follow-up period of 28 months (4;91 months; Fig 2, Table I). Four patients died as the result of HCC recurrence in this series. With respect to prognostic factors, because no patient had more
730 Hashimoto et al
Fig 2. The survival rate after resection of the peritoneal dissemination was 58% after 1 year, 50% after 3 years, and 42% after 5 years.
than 3 peritoneal metastases and there were only 9 patients, we could not evaluate the role of the number of peritoneal metastases on survival. Distant metastases at operation and incomplete control of HCC in the liver which was treated other than with hepatectomy or RFA therapy, appeared to be adverse prognostic factors (Table I). DISCUSSION In general, except for ovarian cancer and pseudomyxoma peritonei, the resection of peritoneal tumors arising from other abdominal malignancies10,11 is not indicated for improving the patient’s quality of life because such peritoneal metastases are not localized and are disseminated throughout the peritoneal cavity.12 For example, cholangiocellular carcinoma causes more extensive peritoneal metastases than HCC, and the prognosis of cholangiocellular carcinoma patients with such metastases is poor.13 Although peritoneal metastases arising from HCC have been reported in 18% of patients at autopsy,1 such metastases are found much less frequently at the time of initial hepatectomy. The risk factors for peritoneal metastasis of HCC have not all been clarified. Hepatitis B and C infection are known to play an important role in the development of HCC, and 7 of our 9 patients had hepatitis virus infection. There was no clear relationship between the type of viral infection and the occurrence of peritoneal metastases.4 Regarding to the pathologic features of the primary
Surgery May 2013
hepatic HCC, poorly differentiated HCC is reported to be associated with a greater risk of peritoneal metastasis.14 In this series, 6 of the 9 patients had poorly differentiated HCC, and such neoplasms are usually more advanced. Although the mechanism of peritoneal metastasis has not been elucidated, spontaneous rupture of the primary tumor, percutaneous tumor biopsy, and percutaneous local ablation therapy (percutaneous ethanol injection and radiofrequency ablation) appear to play an important role in peritoneal dissemination.14-16 Detection of peritoneal metastases arising from HCC has been aided by recent advances in imaging techniques. The diagnosis of peritoneal metastases is facilitated because metastatic nodules are hypervascular, provided the tumor is of sufficient diameter to be visible on contrast-enhanced computed tomography. Because the site of the recurrence of HCC is usually in the remnant liver, it is important to extend the field of the surveillance CT to detect peritoneal metastases. Fludeoxyglucose positron emission tomography (PET)/CT is very effective for the diagnosis of progression of HCC.17 Tumor markers for HCC, alpha-fetoprotein, and serum des-gamma-carboxy prothorombin were increased in approximately one-half of our patients. In case 1, the surveillance CT targeting the remnant liver did not extend to the lower abdomen, and thus this lower abdominal metastasis was missed; the use of PET/CT allowed the detection of neoplasm tumor 2 years after the initial increase in serum tumor markers. This observation questions whether it may be standard care to perform abdominal/pelvic CT when recurrence of HCC is suspected because of tumor marker elevation. Effective treatment of peritoneal metastases from HCC remains to be established. Because such metastases are thought by many groups to represent disseminated disease, resection or radiation therapy is not thought to improve the prognosis, and systemic chemotherapy is recommended. New effective chemotherapy for HCC has been widely used and also can be used for peritoneal metastases.18 Median overall survival was 10.7 months in the sorafenib group with advanced HCC. Although patients in this series mostly had peritoneal metastases, 1-year survival rate was 58%, which might be comparable with the systemic chemotherapy. In contrast, resection of peritoneal metastases of HCC has been reported previously in Japan.5 Makino and colleagues6 reviewed 47 patients with HCC with resection of peritoneal metastases, among whom 31 patients (66%) had only 1 peritoneal metastasis macroscopically. The prognosis of
Hashimoto et al 731
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HCC patients with extrahepatic metastases is generally poor,1 with a 1-year survival rate of 20% a 3-year survival of 0% without resection.6,19 Although our numbers are small, after resection of peritoneal metastases in the present series, the survival rate was 58% after 1 year, 50% after 3 years, and 42% after 5 years (Fig 2). Incomplete control of the HCC in the liver, the presence of extrahepatic metastases other than the peritoneum, or an R2 resection of the peritoneal metastases may be the prognostic factors. Because 1 patient with 3 peritoneal metastases had a good prognosis, ie, 29 months of disease-free survival, the number of peritoneal metastases might not be a prognostic factor. Although the number of the peritoneal metastases detected during laparotomy was equal or more than that of preoperative imaging, laparoscopic observation may be effective in evaluation of the peritoneal metastases, but complete removal of peritoneal metastases may still have a beneficial effect (Table I). In conclusion Resection may be an option for selected patients with peritoneal metastases from HCC because complete removals of such metastases appear to improve survival in patients with controlled HCC in the liver and without other distant metastases. REFERENCES 1. Ikai I, Arii S, Ichida T, Okita K, Omata M, Kojiro M, et al. Report of 16th follow-up survey of primary liver tumor. Hepatol Res 2005;32:163-72. 2. Nagasue N, Yukaya H, Hamada T, Hirose S, Kanashima R, Inokuchi K. The natural history of hepatocellular carcinoma. A study of 100 untreated cases. Cancer 1984;54:1461-5. 3. Katyal S, Oliver JH III, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology 2000;216:698-703. 4. Nakashima T, Okuda K, Kojiro M, Jimi A, Yamaguchi R, Sakamoto K, et al. Pathology of hepatocellular carcinoma in Japan, 232 consecutive cases autopsied in ten years. Cancer 1983;51:863-77. 5. Nakayama H, Takayama T, Makuuchi M, Yamazaki S, Kosuge T, Shimada K, et al. Resection of peritoneal metastases
6.
7. 8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
18.
19.
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