Clinicopathological Characteristics and Prognosis of Alpha-fetoprotein Producing Gastric Cancer

Dong Hoon Lew; Woon Tae Jung; Hong Jun Kim; Hyun Ju Min; Chang Yoon Ha; Hyun Jin Kim; Tae Hyo Kim; Gyung Hyuck Ko

doi:10.4166/kjg.2013.62.6.327

Journal List > Korean J Gastroenterol > v.62(6) > 1007169

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Lew, Jung, Kim, Min, Ha, Kim, Kim, and Ko: Clinicopathological Characteristics and Prognosis of Alpha-fetoprotein Producing Gastric Cancer

Original Article

Korean J Gastroenterol 2013;62(6):327-335.

Published online: 4 October 2013

DOI: https://doi.org/10.4166/kjg.2013.62.6.327

Clinicopathological Characteristics and Prognosis of Alpha-fetoprotein Producing Gastric Cancer

Dong Hoon Lew^1,³, Woon Tae Jung^1,³, Hong Jun Kim^1,³, Hyun Ju Min^1,³, Chang Yoon Ha^1,³, Hyun Jin Kim^1,³, Tae Hyo Kim^1,³, Gyung Hyuck Ko^2,³

¹Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang Institute of Health Sciences, Jinju, Korea

²Department of Pathology, Gyeongsang National University School of Medicine, Gyeongsang, Korea

³Institute of Health Sciences, Gyeongsang National University, Jinju, Korea

Correspondence to: Woon Tae Jung, Department of Internal Medicine, Gyeongsang National University School of Medicine, 79 Gangnam-ro, Jinju 660-702, Korea. Tel: +82-55-750-8617, Fax: +82-55-758-9122, E-mail: wtjung@gnu.ac.kr

Received 19 August 2013 Revised 1 November 2013 Accepted 1 November 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

Several studies reported a subgroup of gastric cancer patients showing elevated serum alpha-fetoprotein (AFP) at the time of diagnosis. We investigated the clinicopathological characteristics and prognostic factors of AFP producing gastric cancer (AFPPGC) by comparing with AFP non-producing gastric cancer (AFPNPGC).

Methods

A total of 909 patients were diagnosed with gastric cancer from January 2005 to March 2013 at Gyeongsang National University Hospital and their AFP levels were measured at the time of diagnosis. After excluding 138 patients with underlying liver diseases, 34 patients with elevated serum AFP level over 10 mg/mL were assigned to AFPPGC group and the remaining 737 patients with serum level of AFP below 10 ng/mL were assigned to AFPNPGC group.

Results

The median survival length was shorter in AFPPGC group than AFPNPGC group (18.3±25.5 months vs. 30.0±22.0 months, p=0.004). The incidence of liver metastasis (47.1% vs. 3.3%, p＜0.001) and lymph node metastasis (91.2% vs. 31.6%, p＜0.001) was significantly higher in AFPPGC group. The probability of encountering metachronous liver metastasis after the operation was higher in AFPPGC group (44.4% vs. 2.0%, p＜0.001). Multivariate analysis revealed that patients in the AFPPGC group who received chemotherapy (p=0.037) or underwent operation (p=0.001) had a better survival rate.

Conclusions

AFPPGC behaves more aggressively and shows a worse prognosis. Therefore, serum AFP level should be routinely checked in all patients diagnosed with gastric cancer.

Keywords: Alpha-Fetoproteins, Stomach neoplasms, Prognosis

References

1. Harper ME, Dugaiczyk A. Linkage of the evolutionarily-related serum albumin and alpha-fetoprotein genes within q11–22 of human chromosome 4. Am J Hum Genet. 1983; 35:565–572.

2. Fujii H, Ichikawa K, Takagaki T, et al. Genetic evolution of alpha fetoprotein producing gastric cancer. J Clin Pathol. 2003; 56:942–949.

3. Bourreille J, Metayer P, Sauger F, Matray F, Fondimare A. Existence of alpha feto protein during gastric-origin secondary cancer of the liver. Presse Med. 1970; 78:1277–1278.

4. Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005; 42:1208–1236.

5. Karayiannakis AJ, Kakolyris S, Giatromanolaki A, et al. Hepatoid Adenocarcinoma of the Gallbladder: Case Report and Literature Review. J Gastrointest Cancer. 2011. [Epub ahead of print].

6. Liu Q, Bannan M, Melamed J, Witkin GB, Nonaka D. Two cases of hepatoid adenocarcinoma of the intestine in association with inflammatory bowel disease. Histopathology. 2007; 51:123–125.

7. Mokrim M, Belbaraka R, Allaoui M, et al. Hepatoid adenocarcinoma of the lung: a case report and literature review. J Gastrointest Cancer. 2011. [Epub ahead of print].

8. Liu X, Cheng Y, Sheng W, et al. Clinicopathologic features and prognostic factors in alpha-fetoprotein-producing gastric cancers: analysis of 104 cases. J Surg Oncol. 2010; 102:249–255.

9. Koide N, Nishio A, Igarashi J, Kajikawa S, Adachi W, Amano J. Alpha-fetoprotein-producing gastric cancer: histochemical analysis of cell proliferation, apoptosis, and angiogenesis. Am J Gastroenterol. 1999; 94:1658–1663.

10. Joo YH, Jung HY, Kang GH, et al. ClinicoPathologic Characteristics of the Alpha-fetoprotein Producing Gastric Carcinoma. Korean J Gastroenterol. 2000; 36:54–60.

11. Ishikura H, Fukasawa Y, Ogasawara K, Natori T, Tsukada Y, Aizawa M. An AFP-producing gastric carcinoma with features of hepatic differentiation. A case report. Cancer. 1985; 56:840–848.

12. Liu X, Sheng W, Wang Y. An analysis of clinicopathological features and prognosis by comparing hepatoid adenocarcinoma of the stomach with AFP-producing gastric cancer. J Surg Oncol. 2012; 106:299–303.

13. Chun H, Kwon SJ. Clinicopathological characteristics of alpha-fetoprotein-producing gastric cancer. J Gastric Cancer. 2011; 11:23–30.

14. Ramsey WH, Wu GY. Hepatocellular carcinoma: update on diagnosis and treatment. Dig Dis. 1995; 13:81–91.

15. Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer. 1996; 77:2217–2222.

16. Christiansen M, Høgdall CK, Andersen JR, Nørgaard-Pedersen B. Alpha-fetoprotein in plasma and serum of healthy adults: pre-analytical, analytical and biological sources of variation and con-struction of age-dependent reference intervals. Scand J Clin Lab Invest. 2001; 61:205–215.

17. Uefuji K, Ichikura T, Tamakuma S. Roles of histological findings and serum AFP levels in the prognosis of AFP-producing gastric cancers. Jpn J Clin Oncol. 1994; 24:135–140.

18. Motoyama T, Aizawa K, Watanabe H, Fukase M, Saito K. Alpha-fe-toprotein producing gastric carcinomas: a comparative study of three different subtypes. Acta Pathol Jpn. 1993; 43:654–661.

19. Chang YC, Nagasue N, Kohno H, et al. Clinicopathologic features and long-term results of alpha-fetoprotein-producing gastric cancer. Am J Gastroenterol. 1990; 85:1480–1485.

20. McIntire KR, Waldmann TA, Moertel CG, Go VL. Serum alpha-fe-toprotein in patients with neoplasms of the gastrointestinal tract. Cancer Res. 1975; 35:991–996.

21. Su JS, Chen YT, Wang RC, Wu CY, Lee SW, Lee TY. Clinicopathological characteristics in the differential diagnosis of hepatoid adenocarcinoma: a literature review. World J Gastroenterol. 2013; 19:321–327.

22. Kumashiro Y, Yao T, Aishima S, et al. Hepatoid adenocarcinoma of the stomach: histogenesis and progression in association with intestinal phenotype. Hum Pathol. 2007; 38:857–863.

23. Kaji M, Yonemura Y, Harada S, Liu X, Terada I, Yamamoto H. Participation of c-met in the progression of human gastric cancers: anti-c-met oligonucleotides inhibit proliferation or invasiveness of gastric cancer cells. Cancer Gene Ther. 1996; 3:393–404.

24. Kataoka H, Miura Y, Joh T, et al. Alpha-fetoprotein producing gastric cancer lacks transcription factor ATBF1. Oncogene. 2001; 20:869–873.

25. Jeong SH, Shim HJ, Hwang JE, et al. A case of gastric hepatoid adenocarcinoma misdiagnosed as an extragonadal germ cell tumor. Korean J Med. 2007; 73:107–111.

26. Kang GH, Kim YI. Hepatoid adenocarcinoma of the stomach: a pathologic analysis of 14 cases. Korean J Pathol. 1994; 28:620–628.

27. Yong KJ, Gao C, Lim JS, et al. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N Engl J Med. 2013; 368:2266–2276.

28. Ikeda H, Sato Y, Yoneda N, et al. α-Fetoprotein-producing gastric carcinoma and combined hepatocellular and cholangiocarcinoma show similar morphology but different histogenesis with respect to SALL4 expression. Hum Pathol. 2012; 43:1955–1963.

29. Zhang JF, Shi SS, Shao YF, Zhang HZ. Clinicopathological and prognostic features of hepatoid adenocarcinoma of the stomach. Chin Med J (Engl). 2011; 124:1470–1476.

30. Usuba T, Toyama Y, Watanabe K, Kashiwagi H, Yanaga K. Combination chemotherapy using TS-1, Paclitaxel and cisplatin for multiple lung metastases from AFP-producing gastric cancer: a case report. Hepatogastroenterology. 2007; 54:1302–1304.

31. Inamoto O, Maki A, Araki H, et al. A case of long-term surviving AFP-producing gastric cancer with liver metastases treated by three liver resections. Jpn J Gastroenterol Surg. 2013; 46:7–15.

Fig. 1.

Patient selection.

Fig. 2.

(A) Immunohistochemical staining in AFP-producing gastric cancer. Gastric adenocarcinoma cells express AFP in the cytoplasm of some tumor cells and in the glandular lumina (AFP, ×100). (B) Immunohistochemical staining in AFP non-producing gastric cancer. Gastric adenocarcinoma in this case is negative for AFP (×100).

Fig. 3.

Survival of gastric cancer patients compared with those of the same stage according to AFP production. Survival of AFPPGC is shorter than that of AFPNPGC with same stage. AFPPGC, AFP producing gastric cancer; AFPNPGC, AFP non-producing gastric cancer.

Table 1.

Case Series of Patients with Alpha-fetoprotein-producing Gastric Cancer

No.	Sex	Age (yr)	Serum AFP (ng/mL)	Stage		Metastasis	Treatment	Recurrence after operation (duration, mo)	Survival (mo)
1	M	50	215,444.0	IV	M1	Liver	CTx	−	12
2	M	74	60,500.0	IV	T2N2M1	Liver	CTx	−	2
3	F	73	60,500.0	IV	T2N1M1	Liver	−	−	2
4	M	63	60,500.0	IV	M1	Liver	CTx	−	17
5	F	79	3,587.0	IV	T2N1M1	Liver	CTx	−	5
6	M	53	2,420.0	IV	M1	Liver	CTx	−	21 (alive)
7	M	54	1,064.0	II	T2N1M0	−	OP	Liver, pancreas, jejunum, peritoneum (48)	50
8	M	69	663.2	IV	T4N1M1	Liver, pancreas	CTx	−	11
9	M	59	604.0	IV	M1	Liver	−	−	1
10	M	75	501.0	IV	M1	Liver	−	−	6
11	M	63	298.0	IIIa	−	−	CTx	−	6
12	M	60	149.6	IIIa	T3N1M0	−	OP+CTx	Liver (15)	24
13	M	68	107.1	IIIa	T3N1M0	−	OP+CTx	−	18 (f/u loss)
14	M	76	100.4	IV	T4N1M1	Liver, pancreas	CTx	−	6
15	M	63	88.0	IIIa	T2N2M0	−	OP+CTx	Liver (29)	30
16	F	78	80.5	IV	M1	Liver	CTx	−	7 (alive)
17	M	56	80.0	IV	M1	Liver	−	−	5
18	M	59	78.3	IV	T3N2M1	Liver	CTx	−	11
19	F	67	73.0	IV	M1	−	−	−	3
20	M	51	71.0	IV	M1	−	CTx	−	2
21	M	72	66.1	II	T3N0M0	−	OP+CTx		74 (alive)
22	M	56	62.9	II	T2N1M0	−	OP+CTx	Liver (13)	22
23	F	71	56.4	Ia	T1N0M0	−	OP	−	123 (alive)
24	F	59	46.6	IV	M1	−	CTx	−	22 (alive)
25	M	46	40.6	IV	M1	−	CTx	−	4
26	M	60	38.7	IIIa	−	−	OP+CTx	−	13
27	M	61	34.4	IV	M1	Liver	CTx	−	19
28	M	64	30.2	IIIa	−	−	OP+CTx	−	13
29	M	53	27.1	IV	M1	−	CTx	−	7
30	M	51	21.3	Ia	T1N0M0	−	OP	−	70
31	M	72	20.5	IV	M1	Liver	−	−	2
32	M	53	17.9	IV	M1	Liver	CTx	−	10
33	M	55	17.4	IV	M1	−	CTx	−	6
34	M	80	14.7	IV	M1	−	CTx	−	2
Average			64	11,982.4					18.3

M, male; F, female; CTx, chemotherapy; OP, operation; f/u, follow up.

Table 2.

Comparison between AFP-producing Gastric Cancer Patients and AFP Non-producing Gastric Cancer

	AFPPGC (n=34)	AFPNPGC (n=737)	p-value
Age (yr)	64.0±10.3	61.6±11.7	0.244
Sex (Male： female)	3.25: 1	2.19: 1	0.360
Location of tumor			0.002
Cardia	0	48 (6.6)
Body	10 (29.4)	277 (38.3)
Antrum	13 (38.2)	330 (45.6)
Antrum to body	8 (23.5)	56 (7.7)
Antrum to cardia	2 (5.9)	6 (0.8)
Cardia to body	1 (2.9)	7 (1.0)
Advanced gastric carcinoma	32 (94.1)	323 (43.8)	＜0.001
Early gastric carcinoma	2 (5.9)	414 (56.2)
Metastasis to lymph nodes	31 (91.2)	229 (31.6)	＜0.001
Stage
Ia	2 (5.9)	392 (54.1)
Ib	1 (2.9)	80 (11.0)
II	7 (20.6)	114 (15.7)
IIIa	5 (14.7)	33 (4.6)
IIIb		19 (2.6)
IIIc		21 (2.9)
IV	19 (55.9)	65 (9.0)
Operation	9 (26.5)	648 (89.6)	＜0.001
Survival length (mo)	18.3±25.5	30.0±22.0	0.004
Liver metastasis
Pre operation	16 (47.1)	24 (3.3)	＜0.001
Post operation	4 (44.4)	13 (2.0)	＜0.001
Metastasis to other organs
Pre operation	21 (61.8)	73 (9.9)	＜0.001
Post operation	2 (5.9)	22 (3.0)	0.286
Time to recurrence after
operation (mo)
Liver	22.0±16.9	14.2±9.7	0.373
Other organs	32.5±11.6	26.7±4.0	0.771
Pathologic finding			＜0.001
Well-differentiated	0	223 (30.3)
Moderately-differentiated	14 (41.2)	176 (23.9)
Poorly-differentiated	17 (50.0)	196 (26.6)
Signet ring cell carcinoma	3 (8.8)	142 (19.3)
Patients who underwent resection	n=9	n=648
Tumor size (cm)			0.006
＜1	0 (0)	100 (15.4)
≥1, ＜5	2 (22.2)	385 (59.4)
≥5, ＜10	7 (77.8)	141 (21.7)
≥10	0 (0)	22 (3.3)
Lymphatic invasion	6 (66.7)	44 (6.7)	＜0.001
Vessel invasion	1 (11.1)	3 (0.5)	0.053
Neural invasion	4 (44.4)	44 (6.7)	＜0.001

Values are presented as mean±SD or n (%).

AFPPGC, AFP-producing gastric cancer (serum AFP ≥10 ng/mL); AFPNPGC, AFP non-producing gastric cancer (serum AFP ＜10 ng/mL).

Table 3.

Univariate Survival Analysis of All Gastric Cancer Patients according to Clinical Factors

Variable	Cases (n)	5-year survival rate (%)	p-value
Sex			0.919
Male	528	74
Female	230	80
Smoking			0.037
Smoker	234	71
Non smoker	524	79
Location			<0.001
Cardia	48	62
Body	287	78
Antrum	343	79
Antrum to body	64	71
Antrum to cardia	8	0
Cardia to body	8	0
Stage			<0.001
Ia	394	95
Ib	81	89
II	121	66
IIIa	38	48
IIIb	19	85
IIIc	21	90
IV	84	0
Age (yr)			0.012
30–39	31	62
40–49	103	83
50–59	159	76
60–69	251	78
70–79	185	82
80-	29	0
Pathologic finding			<0.001
Well-differentiated		98
Moderately-differentiated		88
Poorly-differentiated		86
Signet ring cell carcinoma		89
AFP (ng/mL)			<0.001
≥10		18
＜10		79

Table 4.

Independent Prognostic Factors in Multivariate Analysis by Cox Proportional Hazard Model in All Patients with Gastric Cancer

	Hazard ratio	95% CI	p-value
AFP	1.773	1.074–2.927	0.025
Smoking	1.646	1.111–2.437	0.013
Stage
Ia
Ib	1.292	0.353–4.726	0.442
II	5.382	2.427–11.934	＜0.001
IIIa	17.327	7.358–40.801	＜0.001
IIIb	2.348	0.295–18.704	0.420
IIIc	2.636	0.330–21.050	0.361
IV	76.464	36.677–159.414	＜0.001

Table 5.

Univariate Analysis of Factors Affecting Survival in Patients with AFP-producing Gastric Cancer

Factor	Case (n)	Survival (mo)	p-value
Smoker	18	32.1	0.096
Non-smoker	16	23.6
Alcohol drinker	23	15.9	0.579
Non-drinker	11	33.3
Location			0.686
Body	10	22.6
Antrum	13	22.1
Cardia	8	46.1
Antrum to cardia	2	2.0
Body to cardia	1	22.0
AGC or EGC			0.193
AGC	32	13.5
EGC	2	96.5
Chemotherapy			0.377
Yes	22	13.0
No	12	44.5
Operation			＜0.001
Yes	9	69.9
No	25	9.4
Lymph node metastasis			0.044
Yes		19.3
No		90.0
Stage			−
Ia	2	96.5
Ib	1	24.0
II	7	27.9
IIIa	5	8.0
IIIb	0	−
IIIc	0	−
IV	19	8.9

AGC, advanced gastric cancer; EGC, early gastric cancer.

Table 6.

Survival of Gastric Cancer Patients with Liver Metastasis according to AFP Production

	AFPPGC	AFPNPGC	p-value
Age (yr)	67.8±10.9	67.3±10.3	0.901
Sex (male： female)	3：1	5.25：1	0.689
Pathologic finding			0.245
Well-differentiated	0	4 (16)
Moderately-differentiated	8 (50)	13 (52)
Poorly-differentiated	8 (50)	8 (32)
Signet ring cell carcinom	a 0	0
Survival length (mo)	8.7	14.6	0.080

Values are presented as mean±SD, n (%), or number only. AFPPGC, AFP-producing gastric cancer (serum AFP ≥10 ng/mL); AFPNPGC, AFP non-producing gastric cancer (serum AFP ＜10 ng/mL).

TOOLS

Similar articles