Clinical manifestations in patients with alpha-fetoprotein – producing gastric cancer

Alpha-fetoprotein (afp) is a glycoprotein that is normally produced during gestation by the fetal liver and yolk sac1. Elevation of serum afp is considered to be abnormal in adults and is often used as a tumour marker in hepatocellular carcinoma and tumours of gonadal origin2. However, a variety of other malignancies also produce afp, of which gastric cancer is the most common3. Elevated serum afp can occur in patients without hepatocellular carcinoma but with chronic liver disease such as viral hepatitis or cirrhosis4,5. The influence of serum afp on the prognosis of patients with gastric cancer remains unclear. Alpha-fetoprotein–producing gastric cancer (afpgc) is rare, constituting only about 1%–6% of all gastric cancers6. Poor prognosis is usually associated with afpgc because of liver and lymph node metastasis3,7. Few studies to date have addressed the clinicopathologic features and long-term survival of patients with afpgc. Controversy exists about the clinical manifestations in these patients. Therefore, in this retrospective study, we reviewed clinicopathologic findings for 58 Chinese patients with afpgc and 1236 patients with normal serum afp attending a single centre. We also correlated survival time with serum afp concentration.


INTRODUCTION
Alpha-fetoprotein (afp) is a glycoprotein that is normally produced during gestation by the fetal liver and yolk sac 1 .Elevation of serum afp is considered to be abnormal in adults and is often used as a tumour marker in hepatocellular carcinoma and tumours of gonadal origin 2 .However, a variety of other malignancies also produce afp, of which gastric cancer is the most common 3 .Elevated serum afp can occur in patients without hepatocellular carcinoma but with chronic liver disease such as viral hepatitis or cirrhosis 4,5 .The influence of serum afp on the prognosis of patients with gastric cancer remains unclear.
Few studies to date have addressed the clinicopathologic features and long-term survival of patients with afpgc.Controversy exists about the clinical manifestations in these patients.Therefore, in this retrospective study, we reviewed clinicopathologic findings for 58 Chinese patients with afpgc and 1236 patients with normal serum afp attending a single centre.We also correlated survival time with serum afp concentration.

METHODS
We reviewed the medical records of 3172 consecutive patients with gastric adenocarcinoma who received surgical intervention at the Veterans General

Background
Patients with alpha-fetoprotein (afp)-producing gastric cancer have a high incidence of liver metastasis and poor prognosis.There is some controversy about clinical manifestations in these patients.

Methods
Our study enrolled patients who, before surgery, had gastric cancer with serum afp exceeding 20 ng/ mL [afp>20 (n = 58)] and with serum afp 20 ng/mL or less [afp≤20 (n = 1236)].Clinical manifestations were compared between the groups.
Hospital-Taipei between June 1988 and December 2011.Preoperative serum afp was assessed by radioimmunoassay (normal value: <20 ng/mL) in 1331 patients.The analysis excluded 37 patients with acute or chronic hepatitis, cirrhosis, or hepatocellular carcinoma.Surgical and pathologic findings for the remaining 1294 patients were recorded using the Japanese classification of gastric carcinoma and the Lauren classification 8,9 .Nodal status and disease stage were assessed using the tumour-node-metastasis (TNM) system of the Union for International Cancer Control 10 .Sex, age, tumour size (mucosal size of the tumour), peritoneal seeding, liver metastasis, lymph node metastasis, location of the main tumour, lymphatic and vascular invasion, clinical staging, curative surgery, cause of death, morphologic appearance and depth of cancer involvement, cancer cell differentiation, and survival time were recorded.
Statistical analysis was performed using the SPSS software application (SPSS for Windows, version 10.0: SPSS, Chicago, IL, U.S.A.).The chi-square test with Yates correction for continuity was used in comparisons of categorical data.The Fisher exact test was used when the numbers were less than 5. Survival curves were estimated by the Kaplan-Meier method, and differences were examined using the log-rank test.A multivariate analysis of prognostic factors was evaluated using the Cox proportional hazards model (forward stepwise method).Differences were considered significant when the p value was less than 0.05.
Table ii analyzes the depth of cancer involvement in the gastric wall.The afp>20 group included fewer cases of early gastric cancer (egc: 4% vs. 30.1%;p < 0.001) and more cases of advanced gastric cancer (96% vs. 69.9%,p < 0.001).In the 2 egc patients of the afp>20 group, cancer cells had involved the intramucosal and muscularis mucosa layers.In the afp≤20 group, 349 patients (30.1%) had egc, with cancer cells confined to the intramucosa in 97 cases (27.8%), to the muscularis mucosa in 94 cases (26.9%), and to the submucosal layer in 158 cases (45.3%).Cancer cells penetrated to serosal layer and beyond in more patients of the afp>20 group [40 patients (80%) vs. 628 patients (54.2%) in the afp≤20 group, p < 0.001].
In univariate analysis, serum afp greater than 20 ng/mL, male sex, age greater than 60, tumour size greater than 7 cm, peritoneal seeding, liver metastasis, lymph node metastasis, lymphatic and vascular invasion, tumour stage iv, no curative surgery, serosal invasion, and poorly differentiated and diffuse cell types were associated with survival (Table iv).
In multivariate analysis, the independent prognostic factors survival were serum afp, patient age, peritoneal seeding, liver metastasis, lymph node metastasis, vascular invasion, TNM stage, curative surgery, serosal invasion, and Lauren classification (Table v).

DISCUSSION
In our study, 58 patients with afpgc had a high percentage of lymph node and liver metastasis and a poor prognosis.The prevalence of afpgc is reported to be  0.17%-8.4% in patients with gastric cancer 3,6,[11][12][13][14] .Clinical manifestations in patients with afpgc have rarely been observed because of that small incidence 15 .Furthermore, controversy exists about those manifestations.We observed that 4.5% of gastric cancer patients (58 of 1294) had an abnormal serum afp reading (>20 ng/mL), a proportion that is comparable with those in other reports.To avoid confounding factors in patients with afpgc, we excluded 37 patients with liver disease (cirrhosis, hepatoma, acute hepatitis) from the analysis.
Liver metastasis (14.3%-75.6%) is one of the main features of afpgc or hepatoid adenocarcinoma of the stomach (has) [12][13][14]16 . In ur series, 16 patients (27.6%) in the afpgc group were found to have liver metastasis during follow-up.That group more frequently had liver metastasis than did patients with normal serum afp (n = 53, 4.4%, p < 0.001).However, the related literature describes some different observations.Nakajima et al. 17 reported that there was no correlation between preoperative afp values and histopathology, lymph node metastasis, vessel invasion, and liver metastasis.

Current OnCOlOgy-VOlume 21, number 3, June 2014
Copyright © 2014 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
The lower one third of the stomach is most common location for afpgc or has, in the range 40%-61.5% 3,6,[11][12][13]16 . Ourobservation was similar.In our series, the primary cancer was above the antrum in 29 patients with afpgc (50%) and in 646 patients (52.3%) with normal serum afp.
With respect to clinical staging, the literature reports a number of different observations.In one large series (270 patients), Adachi et al. 15 showed that most patients with afpgc had serosal invasion, lymph node metastasis, and liver metastasis; three quarters had stage iii or iv disease.Those authors found that the 5-year survival rate after gastrectomy was only 22%.The poor prognosis was attributable mostly to simultaneous metastases or early recurrence in the liver.However, Chun et al. 13 reported that 74% (n = 26) of their afpgc patients had stage i or ii disease.In our study, patients with normal serum afp were observed to have more stage i disease (25.2% vs. 3.3% in patients with afpgc) and less stage iv disease (27.1% vs. 58.6% in patients with afpgc, p < 0.001).
In our study, more patients died of gastric cancer in the afpgc group than in the afp≤20 group (58.6% vs. 27.1%,p < 0.001), an observation that might be explained by a low rate of curative surgery and greater rates of recurrent gastric cancer and liver metastasis in the patients with afpgc.[14]16,19 , with most publications reporting rates of less than 10% 6,12,14 .However, different observations have also been published.Chun et al. 13 found that 42.9% of their patients with afpgc (n = 15) had early-stage disease.In our series, egc was found in 4% of patients with afpgc (2 of 50), which is a rate lower than that seen in the patients with normal afp (349 of 1158, 30.1%, p < 0.001).Our finding is compatible with those in most other reports (0%-19.4%) 6,11,14, which found that advanced gastric cancer was present in most patients with has or afpgc 3,6,12,14 .In our study, patients with afpgc more often had advanced gastric cancer than did patients with normal serum afp (96% vs. 69.9%,p < 0.001).
Poorly differentiated cancer cells have been reported to predominate in patients with afpgc or has (48.6%-64.4%) 3,12,13,16; however, different findings have also been reported.In one large analysis of pooled data from Japan, Adachi et al. 15 found that well-differentiated cancers was predominated in patients with afpgc (n = 218, 87.2%).In our study, the incidence of poorly differentiated cancer cells (por 1, por 2, signet-ring cells, mucinous adenocarcinoma) was similar in both patient groups [50% in the afpgc group (n = 23) and 48.7% in the normal serum afp group (n = 558), p = 0.87].
Surgery is the currently the main therapy for gastric cancer.However, radical surgery was successful in only 6 patients of our afpgc group (10.3%).In contrast, radical surgery was much more successful in patients with normal serum afp (n = 468, 37.9%, p < 0.001).That difference might explain why the afpgc group had more liver metastasis and a worse prognosis than did patients with normal serum afp.
The 5-year survival rate in patients with afpgc has been reported to be 9%-66% 6,12,13,16 .However, there has been some controversy about the link between afp and survival duration.Survival duration after surgery has been found not to be linked to preoperative serum afp 6 .Inoue and colleagues observed that 1 patient with high serum afp (25,400 ng/mL) was still living 12 years after diagnosis of gastric cancer 6 .The large Japanese study using pooled data also showed similar results: Adachi et al. 15 found that 5-year survival rates were not different for patients with gastric cancer and a serum afp less than 1000 ng/mL (42.7%) or greater than 1000 ng/mL (39.4%).Nagai et al. 20 also reported that the 5-year survival rate was 40% in patients with lower afp and 38% in patients with higher afp.
Other authors found that patients with afpgc had a shorter survival duration.In one large series, Liu et al. 3 found that the 1-, 3-, and 5-year survival rates for patients with afpgc were 53%, 35%, and 28% respectively.Those authors also found that patients with afpgc or has had a poorer prognosis than did patients who had lower afp concentrations (p < 0.01) or non-has disease (p < 0.05) 3 .Chun et al. 13 found that the 5-year survival rate in patients with afp-producing disease was significantly poorer than that in non-afp-producing group (66% vs. 80%, p = 0.002); however, their reported 5-year survival rate was extremely high compared with that in other reports.In our study, we found that 1-, 3-, 5-, and 10-year survival rates for 20<afp≤300 patients were 46.7%, 28.9%, 17.8%, and 13.3% respectively.The 1-, 3-, and 5-year survival rates for afp>300 patients were 15.4%, 7.7%, and 0% respectively.Patients in the afp≤20 group had the best survival time, and patients in the 20<afp≤300 group had the poorest survival time (p < 0.001, Figure 1).

CONCLUSIONS
Patients with afp-producing gastric cancer had a low rate of successful surgery, a high rate of liver

table ii
Serum alpha-fetoprotein (afp) and depth of cancer involvement of the gastric wall a Data not available for 78 patients in the ≤20 ng/mL group, and 7 in the >20 ng/mL group.b By Fisher exact test.c By chi-square test.

table iv
Univariate analysis of all patients by the Kaplan-Meier method a Includes signet-ring cell carcinoma.Pts = patients.

table v
Independent prognostic factors by Cox modelling hr = hazard ratio; ci = confidence interval; afp = alpha-fetoprotein.