Japanese Journal of Clinical Oncology

INTRODUCTION

Hepatocellular carcinoma infrequently metastasizes to lymph nodes. In contrast, intrahepatic cholangiocarcinoma (ICC) has been reported to metastasize to lymph nodes in 47-58% of cases (1-4). To improve outcomes after surgery for ICC, lymph node dissection is often performed. In 1997, the Liver Cancer Study Group of Japan (5) proposed a classification of regional lymph nodes in liver cancer. A study using this classification may clarify the extent of lymph node metastasis in ICC and may suggest a standard lymph node dissection for ICC. The aim of this study was to determine the extent of lymph node metastasis in ICC and to investigate the relationship between the groups of regional lymph node metastasis and surgical outcomes.

MATERIAL AND METHODS

Eighty-three patients with ICC underwent surgical resection from 27 November 1980, through 15 February 1996, at the Institute of Gastroenterology, Tokyo Women's Medical College, Tokyo. Cases of hilar cholangiocarcinoma were excluded. Five patients with peritoneal dissemination and eight patients with intrahepatic metastases in the residual liver were excluded. The remaining 70 patients were enrolled. Patients did not receive chemotherapy during the pre-operative or post-operative period.

ICCs were classified according to whether lymph node metastasis was present (N+), absent (N-) or could not be assessed (Nx). The reasons why lymph node dissection was not performed were liver dysfunction (n = 5), misdiagnosis of the tumors as hepatocellular carcinoma (n = 5), extended hepatic lobectomy due to extensive spread in the liver (n = 7) and general poor condition associated with cholangitis (n = 1) or respiratory disease (n = 1). Lymph node metastasis was also noted and confirmed histopathologically. The sites of lymph nodes, lymph node groups (Table 1) and macroscopic features of the tumors were also classified as proposed by the Liver Cancer Study Group of Japan (5).

Table 1. .Lymph node groups by tumor location (Liver Cancer Study Group of Japan)

Tumor location	Groups of regional lymph nodes
	N1	N2	N3
Right lobe	hepatoduodenal ligament	along left gastric artery	distant lymph nodes*
		along common hepatic artery
		along celiac artery
		posterior surface of pancreas head
Left lobe	right cardiac region	along left gastric artery	distant lymph nodes*
	lesser curvature of stomach	along common hepatic artery
	hepatoduodenal ligament	along celiac artery
		posterior surface of pancreas head

*For example, abdominal aorta, root of the mesentery

Table 2. Patient characteristics and surgical procedures

Characteristics/surgical procedure		N+(n = 23)	N-(n = 28)	Nx(n = 19)	Total(n = 70)
Sex	Male	13	18	12	43
	Female	10	10	7	27
Mean age (years)		59.5	60.9	60.6	59.9
(range)		(37-74)	(32-79)	(30-73)	(30-79)
Liver cirrhosis		0	0	4	4
Hepatolithiasis		4	2	1	7
Liver metastasis		3	4	3	10
Portal tumor thrombus		2	0	5	7
Hepatic lobectomy		21	26	10	57
Resection of the biliary confluence		20	20	4	44
Curative resection		4*	19	12	35

N+, lymph node metastasis is present; N-, lymph node metastasis is not present, Nx, lymph node metastasis cannot be assessed.
*P = 0.0003 vs N-; P = 0.0024 vs Nx.

Lymph node dissection was performed in the N1 and N2 regions (Table 1). The patients with tumors in the left hepatic lobe underwent lymph node dissection along the lesser curvature of the stomach and in the right cardiac region. Enlarged lymph nodes in other regions, e.g. around the abdominal aorta, were sampled.

Cumulative survival rates of all patients were calculated with the Kaplan-Meier method; survival rates were compared using the log-rank test. The duration of survival was defined as the time from the first liver surgery to the date of death or last contact. For comparisons between the subgroups, the [chi]² test was used. Mutivariate analysis using Cox's proportional hazards model was performed with the following factors as covariables: macroscopic type, lymph node metastasis, liver metastasis, portal tumor thrombus, histopathological type and curative resection. The significance level was set at P < 0.05.

RESULTS

Characteristics of Patients and Surgical Procedures

Of the 70 patients in this study, 43 were men and 27 were women with a mean age of 59.9 years (range 30-79 years). Sex, age, and the presence of liver cirrhosis, hepatolithiasis, liver metastasis and portal tumor thrombus did not differ significantly among patients in different subgroups (Table 2). The rate of accompanying liver cirrhosis was higher in patients with Nx disease than in those with N+ or N- disease. Hepatic lobectomy was performed in 57 of the 70 patients, and resection of the biliary confluence was performed in 44. These resection rates were lower in patients with Nx disease than in those with N+ or N- disease. Curative resection was performed in 35 patients (50%). The curative resection rate was significantly lower in patients with N+ disease than in those with N- or Nx disease (P = 0.0003, P = 0.0024) (Table 2).

Table 3. Macroscopic types, histopathological types and location of tumors

Macroscopic types/histopathological types/location of tumor	N+(n = 23)	N-(n = 28)	Nx(n = 19)	Total(n = 70)
Mass-forming type	6	8	14*	28
Periductal-infiltrating type	4	8	2	14
Intraductal growth type	2	8	0	10
Mass-forming + periductal-infiltrating type	11**	4	3	18
Papillary adenocarcinoma	2	8***	1	11
Well-differentiated tubular adenocarcinoma	0	2	4****	6
Moderately differentiated tubular adenocarcinoma	17	16	10	43
Poorly differentiated adenocarcinoma	3	1	4	8
Others	1	1	0	2
Left side	12	20	12	44
Right side	11	8	7	26

N+, lymph node metastasis is present; N-, lymph node metastasis is not present; Nx, lymph node metastasis cannot be assessed.
*P = 0.0021 vs N+; P = 0.0024 vs N-.
**P = 0.0089 vs N-; P = 0.0284 vs Nx.
***P = 0.0462 vs Nx.
****P = 0.0207 vs N+.

Table 4. Groups of regional lymph node, location of tumors and metastatic sites

Sites of lymph node	Groups of regional lymph node			Location of tumors
	N1 (n = 10)	N2 (n = 9)	N3 (n = 4)	Right (n = 11)	Left (n = 12)	Total (n = 23)
Hepatoduodenal ligament	9	7	3	10	9	19
Right cardiac region lesser curvature of stomach	2	1	0	-	3	3
Along common hepatic artery	0	9	1	7	3	10
Posterior surface of pancreas head	0	5	3	4	4	8
Distant lymph nodes*	0	0	4	1	3	4

*For example, abdominal aorta, root of the mesentery.

Macroscopic Features, Histopathological Types and Location of the Tumors

The rate of mass-forming tumors was significantly higher in patients with Nx disease than in those with N+ or N- disease (P = 0.0021, P = 0.0024). Mass-forming plus periductal-infiltrating tumors were more frequent in patients with N+ disease than in those with N- or Nx disease (P = 0.0089, P = 0.0284) (Table 2). The rate of papillary adenocarcinoma was significantly higher in patients with N- disease than in those with Nx disease (P = 0.0462). The rate of well-differentiated tubular adenocarcinoma was significantly higher in patients with Nx disease than in those with N+ disease (P = 0.0207). The location of the tumor was not correlated with the rate of lymph node metastasis (Table 3).

Figure 1. Cumulative survival curve after surgery for intrahepatic cholangiocarcinoma. The long-term survival after surgery in patients with N- disease (n = 28) (P < 0.0001) was significantly better than that of patients with N+ disease (n = 23).

Groups of Regional Lymph Nodes, Location of the Tumors and Metastatic Sites

Lymph node metastasis in the hepatoduodenal ligament was present in all groups with nodal metastasis regardless of tumor location. Each of the nine patients in the N2 group had metastatic nodes along the common hepatic artery. The four patients in the N3 group had metastatic nodes around the abdominal aorta, and one patient had metastatic nodes at the root of the mesentery. The three patients with tumors in the left hepatic lobe had lymph node metastasis along the lesser curvature of the stomach or in the right cardiac region (Table 4).

Long-term Survival After Surgery

The five-year survival rate (0%) of N+ patients was significantly lower (P < 0.0001) than that (51%) of N- patients (Fig. 1); however, survival rates did not differ between patients in the N1, N2 and N3 groups (Fig. 2). The five-year survival rate of Nx patients was 23%, which was not significantly different from that of N+ patients.

Figure 2. Cumulative survival curve after surgery for intrahepatic cholangiocarcinoma with lymph node metastasis. The long-term survival after surgery did not differ significantly between patients with metastasis to different nodal groups (N1, n = 10; N2, n = 9; N3, n = 4).

Multivariate analysis revealed that lymph node metastasis (P = 0.0059) and curative resection (P = 0.0040) were statistically significant independent risk factors; however, macroscopic type (P = 0.1821), liver metastasis (P = 0.1863), portal tumor thrombus (P = 0.9488) and histopathological type (P = 0.1395) were not.

Recurrence

Hepatic recurrence, lymph node recurrence, local recurrence at the hepatic hilus, peritoneal dissemination and remote organ metastasis were investigated among N+, N- and Nx patients. Recurrence rates at each site tended to be higher in N+ patients than in N- or Nx patients, but did not differ significantly (Table 5).

Table 5. Recurrence after surgery

Sites	N+(n = 23)	N-(n = 28)	Nx(n = 19)	Total(n = 70)
Hepatic recurrence	8	5	6	19
Lymph node metastasis	4	2	3	9
Local recurrence at hepatic hilus	7	4	4	15
Peritoneal dissemination	5	4	3	12
Remote organ metastasis	4	2	4	10

DISCUSSION

Lymph node metastasis is an important prognostic factor in ICC (2-4,6). The rate of metastasis to hilar lymph nodes in ICC is 50% (2-4); however, the rate of metastasis to other sites has not been reported. As a result, a systematic or standard lymph node dissection for ICC has not been established. The Liver Cancer Study Group of Japan (5) has proposed a classification of regional lymph nodes in liver cancer. Therefore, whether lymph node dissection according to the classification improves outcomes after surgery must be investigated before a standard lymph node dissection for ICC can be established.

The TMN classification for tumors of the liver (7) indicates that the hilar nodes (i.e. those in the hepatoduodenal ligament) are regional lymph nodes. The Liver Cancer Study Group of Japan (5) has proposed that these nodes belong to the N1 group. The present study also found that the hepatoduodenal ligament was the most common site of nodal metastasis in ICC. These lymph nodes may be sentinel nodes in ICC.

We found that metastasis to different groups of lymph node did not affect outcome after surgery. In the patients with lymph node metastasis, disease recurred in the liver, throughout the abdomen, and at remote sites as well as in lymph nodes. These findings suggest that extended lymph node dissection does not improve outcome in cases of ICC with lymph node metastasis. If ICC has metastasized to lymph nodes of the hepatoduodenal ligament, the patient should be treated with adjuvant chemotherapy rather than with extended lymph node dissection.

When metastasis to the lymph nodes of the hepatoduodenal ligament is not detected, where, and to what extent, should dissection be performed? Although the present findings cannot resolve this issue, we consider it significant that the five-year survival rate of patients with N- disease (51%) was better than that of patients with Nx disease (23%). Lymph node dissection in the N1 and N2 regions may improve outcome after surgery in patients with N- disease. Because metastasis can be diagnosed with dissection in the N1 and N2 regions, outcome after surgery for ICC can be predicted and the need for post-operative adjuvant chemotherapy can be determined. We conclude that lymph node dissection in the N1 and N2 regions should be performed in histopathologically confirmed cases of ICC.

Acknowledgment

This study was presented and awarded as excellent work at the 25th Japanese Society for Cancer and Lymph Node Research.

References

1. Lee YT, Geer DA. Primary liver cancer: pattern of metastasis. J Surg Oncol 1987;36:26-31. MEDLINE Abstract

2. Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, et al. Cholangiocarcinoma: A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996;224:463-75. MEDLINE Abstract

3. Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for cholangiocarcinoma. Arch Surg 1995;130:270-6. MEDLINE Abstract

4. Chou FF, Sheen-Chen SM, Chen CL, Chen YS, Chen MC. Prognostic factors of resectable intrahepatic cholangiocarcinoma. J Surg Oncol 1995;59:40-4. MEDLINE Abstract

5. Liver Cancer Study Group of Japan. Clinical and surgical findings. In: Liver Cancer Study Group of Japan, editors. Classification of Primary Liver Cancer. First English Edition. Tokyo: Kanehara Shuppan 1997;1-22.

6. Chu KM, Lai EC, Al-Hadeedi S, Arcilla CE Jr, Lo CM, Liu CL, et al. Intrahepatic cholangiocarcinoma. World J Surg 1997;21:301-5. MEDLINE Abstract

7. Ishak KG, Anthony PP, Sobin LH. TMN classification of tumours of the liver. In: Ishak KG, Anthony PP, Sobin LH, editors. Histological Typing of Tumours of the Liver. World Health Organization, Berlin: Springer-Verlag 1994;37-45.

---

Received August 26, 1998; accepted November 26, 1998
For reprints and all correspondence: Masakazu Yamamoto, Tokyo Metropolitan Ebara Hospital, 4-5-10, Higashi-Yukigaya Ohta-ku, Tokyo 145-0065, Japan

---

This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 19 Mar 1999
Copyright© 1999 Foundation for Promotion of Cancer Research.
CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				M. Yamamoto, K. Takasaki, T. Imaizumi, S. Ariizumi, N. Matsumura, and M. Nakano A Long-term Survivor of Intrahepatic Cholangiocarcinoma with Lymph Node Metastasis: a Case Report Jpn. J. Clin. Oncol., June 1, 2002; 32(6): 206 - 209. [Abstract] [Full Text] [PDF]

				J. Okami, K. Dohno, M. Sakon, K. Iwao, T. Yamada, H. Yamamoto, Y. Fujiwara, H. Nagano, K. Umeshita, N. Matsuura, et al. Genetic Detection for Micrometastasis in Lymph Node of Biliary Tract Carcinoma Clin. Cancer Res., June 1, 2000; 6(6): 2326 - 2332. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (15) Request Permissions Google Scholar Articles by Yamamoto, M Articles by Yoshikawa, T Search for Related Content PubMed PubMed Citation Articles by Yamamoto, M Articles by Yoshikawa, T Social Bookmarking          What's this?