Elevated
-foetoprotein and hepatic metastasesits not always what it seems!
G. M. Marx+,
A. Boyce and
D. Goldstein
Prince of Wales Hospital, Randwick, Sydney, Australia
Received 20 April 2001; revised and accepted 8 August 2001.
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Abstract
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Gastric cancers that secrete
-foetoprotein (AFP) are a rare but well defined entity. These tumours tend to be aggressive with a poor prognosis. Recognition and identification of this group of patients is important in influencing prognosis, treatment options and further clinical research into this entity. We report three cases of gastric cancers associated with elevated AFP. This entity should be considered in patients with hepatic lesions and an elevated AFP without risk factors for hepatocellular carcinoma or in patients with associated gastric symptoms.
Key words:
-foetoprotein (AFP), cancer, gastric, hepatoid
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Introduction
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Tumour markers are useful in the diagnosis and management of certain tumours. The elevation of serum
-foetoprotein (AFP) in conjunction with hepatic lesions may be associated with hepatocellular carcinoma or germ-cell tumours. This marker can, however, be elevated in other circumstances, including AFP-secreting gastric tumours. Gastric cancers that secrete AFP are a rare but well defined entity. The majority of reports are from the Japanese literature, with only few reports in non-Japanese patients. This tumour tends to be aggressive with a poor prognosis. Identification of this group of patients and differentiation from AFP-negative gastric tumours and hepatocellular carcinoma is important in influencing prognosis, treatment options and further research into this entity. This paper describes three cases of patients with hepatic lesions and elevated serum AFP who were subsequently found to be secondary to an AFP-producing gastric cancer.
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Case 1
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A 77-year-old Greek man presented with bloating and an episode of per rectal blood loss. He also complained of anorexia and malaise. He was an in-patient in a tertiary referral hospital with acute urinary retention secondary to benign prostatic hypertrophy. He had a computed tomography (CT) scan that confirmed multiple hepatic metastases. A biopsy of one of these lesions demonstrated a poorly differentiated adenocarcinoma that stained strongly for AFP. A gastroscopy showed a proliferative lesion on the anterior wall of the gastric antrum. This was biopsied and revealed a poorly differentiated gastric cancer. His baseline AFP was 32 000.
The patient was commenced on palliative continuous infusion of 5-fluorouracil (5-FU), which he had for 7 weeks. Treatment was ceased due to a clinical deterioration in the patients condition with a deterioration in performance status and worsening of symptoms. This was associated with a worsening of his tumour markers. The patient died of progressive disease 5 months after diagnosis (Figure 1).
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Case 2
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A 49-year-old Russian man presented with a 12-month history of weight loss (14 kg), right upper quadrant pain, night sweats and dyspepsia. He had multiple hepatic metastases seen on an abdominal ultrasound. This was biopsied and demonstrated moderately differentiated adenocarcinoma of unknown primary. An endoscopy was performed because of his gastric symptoms. This revealed a 25-cm malignant ulcer on the greater curvature, which was shown to be an ulcerated, infiltrating, moderately differentiated adenocarcinoma. It stained negatively for AFP.
The patients baseline markers were as follows: carcinoembryonic antigen (CEA) 168, CA19.9 281, lactate dehydrogenase (LDH) 980 and AFP 30 450. He was commenced on palliative epirubicin, cisplatin, continuous-infusion fluorouracil (ECF) chemotherapy, which was complicated after cycle 2 with a thrombosed Port-A-Cath requiring its removal and cessation of infusional 5-FU. This was changed to oral uraciltegafur (UFT). After two cycles of this combination he had progressive disease with an increase in the size and number of hepatic metastases, an increase in AFP and a deterioration of symptoms with an increase in night sweats.
The patient was commenced on a phase II trial of irinotecan, 5-FU, leucovorin combination therapy and completed two cycles. He had an initial response to therapy with a reduction in his night sweats and tumour markers. His CT scan at that stage showed stable disease. This response was of very short duration with progressive disease, both symptomatically and with markers, after 1 month. He required second daily paracentesis for rapidly re-accumulating ascites. Despite two lines of chemotherapy the patient was insistent on having further active therapy. He was given weekly paclitaxel for 3 weeks. At that stage therapy was ceased due to a further deterioration in the patients condition. He died comfortably 8 months after diagnosis (Figure 2).
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Case 3
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A 73-year-old man with a background of chronic bronchitis and a myocardial infarction presented with a 2-month history of weight loss (7 kg), anorexia and fatigue. He had mild symptoms of dyspepsia and reflux. He had no history of hepatitis or cirrhosis. A CT scan confirmed that he had multiple hepatic metastases and a biopsy of one of these lesions demonstrated a poorly differentiated adenocarcinoma with columnar malignant cells arranged in glandular islands. There was apical mucin and the tumour was AFP negative. The baseline markers showed elevated CEA 304, CA19.9 56940 and AFP 4023.
In view of his mild gastric symptoms this patient underwent a gastroscopy, which confirmed a 58 cm polypoid adenocarcinoma involving the gastric fundus. This man was commenced on palliative ECF chemotherapy and after two cycles of therapy had a significant improvement in symptoms with an improvement in appetite, energy levels and weight gain. Nausea, vomiting and pain control also showed improvement. A reduction in his AFP as well as a marked reduction in the number and size of hepatic metastases on CT scanning paralleled this (Figure 3).
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Discussion
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AFP was first identified in fetal cord blood. It is a protein with a molecular weight of 70 000 and has a half life of 57 days. It is produced by the fetal liver and yolk sac. Its actual role has not been defined clearly. It is not synthesised by the normal adult liver but can be elevated in hepatoma, germ-cell tumours, benign hepatocellular disease (including cirrhosis, active hepatitis and partial hepatectomy), ataxia-telangiectasia syndrome, WiscottAldrich syndrome and pregnancy. AFP is elevated in 90% of patients from the Orient with hepatoma and only 60% to 70% of patients from the USA or Europe with hepatoma.
Gastric cancers that secrete AFP are a rare but distinct entity. The first case was described in 1970 by Bourille et al. [1]. They described a gastric adenocarcinoma with a high serum AFP level and synchronous hepatic metastases. It has subsequently become clear that there are two distinct histologic subtypes: a medullary type and a papillary or tubular type. The medullary type tends to stain more strongly for AFP and morphologically resembles a hepatic carcinoma [2].
It has been proposed that these AFP-producing gastric carcinomas with features of hepatic differentiation are a distinct clinicopathological entity and should be termed hepatoid adenocarcinoma of the stomach [3, 4]. The main features are a hepatoid morphologic pattern, a very high AFP, bile production and a poor prognosis [2]. Hepatoid carcinomas of the stomach can be differentiated from other AFP-producing gastric carcinomas morphologically: AFP-producing gastric carcinomas have a more classical histologic appearance, tend to be well differentiated and have a similar outcome to typical gastric cancer [2].
AFP-secreting gastric cancers occur with a frequency of 2% to 6% [2]. A Japanese study demonstrated an incidence of 3.9%. Fifteen of 387 patients had elevated serum AFP levels, and these were associated with AFP positivity on immunohistochemistry in the primary tumour [5]. Pre-operative measurement of AFP is not performed routinely. In one study the AFP was only elevated in 2% of patients [6]. These authors felt that routine measurement of AFP was not of value in the staging and management of patients with gastric cancer.
The prognosis of this tumour tends to be poor with a high frequency of hepatic metastases at presentation. Liver metastases have been reported to occur in 70% to 80% of cases and approximately half are metachronous [5, 7]. Yoshinabo et al. [7] describe a case of a man with a solitary hepatic metastasis which was completely excised and the patient was alive at 12 months post-surgery at the time of the report with no evidence of disease.
Despite the well documented poor prognosis of this tumour there are only limited data as to the cellular or molecular mechanisms involved. The c-met proto-oncogene is known to regulate cell migration and proliferation and to encode the c-Met receptor. Hepatocyte growth factor (HGF) is a ligand for the c-Met receptor. The regulation of gastric cancer cell lines by HGF/c-Met has been described recently [8]. HGF is strongly associated with the progression of cancer cells to invasive phenotypes and the development of distant metastases [8]. In one study of stage matched gastric cancers, a higher incidence of c-Met overexpression was found in AFP-secreting tumours, and a higher expression in poorly differentiated tumours in the AFP-positive group than in tumours that were AFP negative [8]. These authors concluded that c-Met overexpression might be one explanation for the poorer prognosis in this patient group. Another study has shown, using immunohistochemistry studies, that AFP-positive tumours have a higher malignant potential with high proliferative activity (using Ki-67), weak apoptosis and rich neovascularisation (using VEGF levels and microvessel density) [9]. These results indicate that this tumour behaves biologically as a high-grade malignancy, and this correlates with its poor prognosis clinically.
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Conclusion
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AFP-secreting gastric cancer is a well-defined entity that is associated with a poor prognosis. This entity should be considered in patients with liver lesions and an elevated AFP without risk factors for hepatocellular carcinoma or in patients with associated gastric symptoms. Defining this entity is important due to the implications on prognosis, treatment options and patient enrolment in future trials.
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Footnotes
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+ Correspondence to: Medical Oncology Department, Guys Hospital, St Thomas Street, London SE1 9RT, UK. Tel: +44-20-7955-5000; Fax: +44-20-7955-4939; E-mail: gavin.marx@kcl.ac.uk 
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