A Rare Case of Recurrent Alphafetoprotein-producing. without Re-elevation of Serum AFP

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1 The Journal of International Medical Research 2006; 34: A Rare Case of Recurrent Alphafetoprotein-producing Gastric Cancer without Re-elevation of Serum AFP K TOMIYAMA 1, M TAKAHASHI 2, T FUJII 2, H KUNISUE 2, Y KANAYA 2, S MARUYAMA 2, N YOKOYAMA 2, N SHIMIZU 1 AND M SODA 2 1 Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; 2 Department of Surgery, Himeji St Mary Hospital, Himeji, Japan We report an extremely rare case of recurrent alpha-fetoprotein (AFP)-producing gastric cancer without re-elevation of serum AFP. The patient was a 78-year-old woman with AFP-producing gastric cancer, a rare type of gastric adenocarcinoma. A Borrmann III gastric tumour was surgically resected and AFP-producing gastric cancer was diagnosed based on high levels of serum AFP ( ng/ml) and immunohistochemical examination of the tumour. The serum AFP level decreased to the normal range after resection without any sign of recurrence by imaging, but the patient developed local recurrence of the cancer and died 13 months after surgery. No re-elevation of serum AFP levels was observed after recurrence. Although serum AFP levels are believed to be useful for follow-up in the post-operative period, the possibility that serum AFP levels do not always correlate with the extent of the cancer should be kept in mind. KEY WORDS: ALPHA-FETOPROTEIN-PRODUCING GASTRIC CANCER; SERUM ALPHA-FETOPROTEIN LEVEL; LOCAL RECURRENCE Introduction Alpha-fetoprotein (AFP)-producing gastric cancer is a rare condition with a high incidence of liver metastasis and a poor prognosis 1 4 that accounts for only % of malignant gastric tumours. 5,6 Serum AFP levels are generally understood to elevate in association with recurrence. 4,7 Measures of serum AFP levels have therefore been used as markers during the postoperative follow-up period. Herein we report a rare case of recurrent AFP-producing gastric cancer. Serum AFP levels in this patient were strikingly high prior to tumour resection, and decreased after surgery. Levels did not rebound despite the recurrence and expansion of the tumour, however. Case report A 78-year-old woman was admitted to our hospital with upper abdominal pain. No significant family or past medical history was identified. On physical examination she looked pale but not icteric. Superficial lymph nodes, including the axilla and 109

2 supraclavicular area, were not swollen. An elastic, hard, movable mass approximately 5.5 cm in diameter was palpable in the left, upper abdomen. Gastroendoscopy revealed a large Borrmann III tumour from the anterior to the posterior abdominal wall along the greater curvature of the gastric antrum. Histopathological examination of a specimen taken from the tumour showed a poorly differentiated adenocarcinoma. Blood analysis demonstrated the presence of anaemia (red blood cell count /l, haemoglobin 7.3 g/dl, platelet count /l). Routine blood chemistry findings were within normal limits except for elevated values of C-reactive protein (1.69 mg/dl) and lactate dehydrogenase (253 IU/l). The serum AFP level was significantly elevated at ng/ml (< 10 ng/ml is considered to be the normal range). However, the levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were within normal ranges. Abdominal computed tomography (CT) showed a thickening of the gastric wall extending from the antrum to the angle along the greater curvature, with extensive involvement of the lymph nodes. No space-occupying lesion indicative of a metastatic tumour was seen in the liver. Surgery was proposed, based on a diagnosis of AFP-producing gastric cancer with regional lymph node metastasis. During surgery it was noted that metastatic lymph nodes had invaded the mesentery of the transverse colon. Collateral vessels developed from the primary tumour and some venous tumour emboli were also found. The patient underwent a distal gastrectomy with D1 lymphadenectomy, and the invasion of the transverse mesocolon was resected along with the primary tumour. The surgical stage was IIIA: T3, N1, H0, P0, according to the classification proposed by the Japanese Gastric Cancer Association. 8 The resected stomach contained an cm Borrmann III cancer in the antrum, and multiple venous tumour emboli were found around the primary tumour. Microscopically, the primary tumour penetrated the muscle coat and invaded the subserosal layer. For the most part, the primary tumour was composed of a poorly differentiated adenocarcinoma. Focally, the tumour cells formed a glandular structure and had the characteristics of a moderately differentiated adenocarcinoma. Immunohistochemical staining showed AFP-positive tumour cells in the compartment of a poorly differentiated adenocarcinoma (Fig. 1). Vascular and lymphatic permeations were noted in the primary tumour (v3, ly3). 8 Perigastric lymph nodes along the greater curvature (regional lymph nodes 1, 3, 6) 8 contained metastatic tumour cells. The post-surgical course was uneventful and the serum AFP level decreased to 1.99 ng/ml within 5 months of the operation. At the follow-up examination 5 months after surgery, abdominal CT revealed a tumour 5 cm in diameter with invasion located on the dorsal side of the pancreas (Fig. 2). Although local recurrence was highly suspected, the serum AFP level remained within normal range (1.54 ng/ml). The patient complained of tarry stools and upper gastrointestinal endoscopy demonstrated oesophageal varices. Abdominal CT scans also showed tumour emboli expanding from the superior mesenteric vein to the second branches of the portal vein, massive ascites and multiple intraperitoneal nodules. These findings indicated that carcinomatous peritonitis and portal hypertension induced by tumour emboli were the likely cause of the oesophageal varices. The patient died 13 months after surgery because of hepatic failure associated with the recurrence of gastric cancer. The serum AFP level never 110

3 A B FIGURE 1: Haematoxylin and eosin staining (A) and immunohistochemical staining (B) for alpha-fetoprotein (AFP) (magnification 200). The primary tumour shows focal AFP-positive cells in a poorly differentiated component FIGURE 2: Abdominal computed tomography scan 5 months after surgery to remove an alpha-fetoprotein-producing gastric cancer (Borrmann III gastric tumour) in a 78-year-old woman. The scan shows a tumour 5 cm in diameter adjacent to the dorsal side of the pancreas. It is believed that this represents a local recurrence of the tumour 111

4 elevated at any stage during the postoperative course (Fig. 3). Discussion Since Bourreille et al. 1 first reported a case of AFP-secreting gastric cancer, many of these gastric cancers have been reported, particularly in Japan. AFP-producing tumours represent % of all gastric cancers, 5,6 and the main features of these cancers are a high incidence of advanced stage, a high frequency of hepatic metastases and a poor prognosis. Recently, a new clinicopathological entity, hepatoid adenocarcinoma, has been described. 2 Although the concept of an AFP-producing gastric cancer is well established, there are no definite diagnostic criteria. The criteria most commonly reported are: (i) preoperative high serum AFP levels; and (ii) detection of AFP in tumour cells by immunohistochemical staining. 9,10 We diagnosed AFP-producing gastric cancer in this patient on the basis that both these criteria were met. Since we could not obtain informed consent to perform an autopsy, we were unable to acquire histological evidence that the intraperitoneal nodules were a recurrence of the primary tumour. We do, however, consider these metastatic lesions to be a recurrence of the primary gastric cancer: although it is possible that the recurrent tumour adjacent to the pancreas arose from the pancreas, it is unlikely that a primary pancreatic tumour would develop extensively outward as it did in this case. In addition, the clinical course is compatible with the recurrence of a primary cancer. Serum AFP levels decreased to the normal range post-surgically and never increased again, despite tumour recurrence and expansion. There are a number of theories that could explain why the serum AFP level did not rise on the recurrence of the cancer. One is that the character of the metastatic lesion may have changed from that of the primary tumour. Murata et al. 11 reported a case where the histological features of the metastatic focus were different from that of AFP (ng/ml) Operation Months FIGURE 3: Serial changes in serum alpha-fetoprotein (AFP) concentrations in a 78-year-old woman with recurrent AFP-producing gastric cancer during the entire 13-month post-operative course up to her death 112

5 the primary lesion, suggesting that the productivity of AFP might decline or disappear in metastatic lesions in such a case. Conversely, there are some cases of hidden AFPproducing gastric cancers in which the preoperative serum-afp levels are within normal ranges, but are high at the terminal stage. 12 Such cases suggest that AFP-producing gastric cancers can have a high differential potency, and support our hypothesis. Another explanation is that only the AFPnegative component of the primary tumour metastasized. It is common for different types of histological features to coexist in the tumour tissue of AFP-producing gastric cancers. Kang and Kim 3 reported an AFPproducing gastric cancer in which the preoperative serum AFP level was high and AFP-positive cells were found only in metastatic lymph nodes. This report suggests that only some components in the tumour tissue might have the ability to metastasize. In our case, AFP was positive only in the poorly differentiated area of the primary tumour. It is possible that the metastatic lesions could have originated from some component other than the poorly differentiated area of the tumour. The form of recurrence is also interesting in this case. A solitary intraperitoneal metastasis and carcinomatous peritonitis are rare forms of recurrence in cases of AFPproducing gastric cancers, which usually develop hepatic metastases. 4 Conclusion To the best of our knowledge, this report describes the first case where AFP-serum levels did not accompany the recurrence and progress of an AFP-producing gastric cancer. It is generally considered that the serum AFP level is important for early detection of recurrence and evaluation of therapeutic efficacy. 5 The present case suggests that clinicians need to pay attention in the postoperative course follow-up of AFP-producing gastric cancer, as tumour progression is not always accompanied by elevation of serum AFP levels. It is therefore essential not only to use tumour markers, but also to use imaging techniques in post-operative follow-up procedures. Conflicts of interest No conflicts of interest were declared in relation to this article. Received for publication 6 July 2005 Accepted subject to revision 18 July 2005 Revised accepted 8 September 2005 Copyright 2006 Cambridge Medical Publications References 1 Bourreille J, Metayer P, Sauger F, Matray F, Fondimare A: Existence of alpha-fetoprotein during gastric-origin secondary cancer of the liver. Presse Med 1970; 78: Ishikura H, Kirimoto K, Shamoto M, Miyamoto Y, Yamagiwa H, Itoh T, et al: Hepatoid adenocarcinomas of the stomach. An analysis of seven cases. Cancer 1986; 58: Kang GH, Kim YI: Alpha-fetoprotein-producing gastric carcinoma presenting focal hepatoid differentiation in metastatic lymph nodes. Virchows Arch 1998; 432: Wakasugi T, Akamo Y, Takeyama H, Hasegawa M, Teranishi F, Manabe T: Solitary intraperitoneal recurrence of alpha-fetoproteinproducing gastric carcinoma: report of a case. Surg Today 2002; 32: Yamanaka H, Nakane Y, Tanaka K, Imabayashi N, Nishi M, Hioki K, et al: AFPproducing gastric cancer analysis of 17 cases. Gan No Rinsho 1986; 32: Takahashi Y, Mai M, Ogino T, Ueda H, Sawaguchi K, Ueno M: Clinicopathological study of AFP producing gastric cancer significance of AFP in gastric cancer. Nippon Geka Gakkai Zasshi 1987; 88: Uefuji K, Ichikura T, Tamakuma S: Roles of histological findings and serum AFP levels in the prognosis of AFP-producing gastric cancers. 113

6 Jpn J Clin Oncol 1994; 24: Japanese Research Society for Gastric Cancer: The General Rules for Gastric Cancer Study, 12th edn (in Japanese). Tokyo: Kanehara, Umekawa Y, Watanabe M, Ikeda S, Fukumoto S, Hirakawa H, Shimada Y: Alpha-fetoproteinproducing early gastric cancer accompanying liver cirrhosis: a case report. J Gastroenterol 1994; 29: Murakami Y, Ohhigashi S, Kohno N: A case of AFP-producing gastric cancer in Japan. J Hiroshima Med Assn 1985; 38: Murata M, Ohta T, Oda K, Shibata K, Matsuda Y, Ohsawa M, et al: A case of AFP producing gastric cancer with different histological feature in the primary and the metastatic lesions. J Jpn Surg Assoc 1998; 59: Kodama T, Kameya T, Hirota T, Shimosato Y, Ohkura H, Mukojima T, et al: Production of alpha fetoprotein, normal serum protein, and human chorionic gonadotropin in stomach cancer: histologic and immunohistochemical analysis of 35 cases. Cancer 1981; 48: Address for correspondence Dr K Tomiyama Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, Shikata-cho Okayama 700, Japan. tomiyam33@taupe.plala.or.jp 114