å¡ CASE REPORT å¡
Ovarian and Hepatic Metastases of Gastric Carcinoma Associated with High Serum Levels of Human Chorionic Gonadotropin (hCG), Alpha-Fetoprotein (AFP), and Carcinoembryonic Antigen (CEA): A Case Report Masataka Sano, Yukio Inamoto, Danjiro Nagamine, Haruo Yamada, Masao Ogiwara, Shoichi Sekino*, Yoshiaki Hirama*, Masahiro Aoki*, Hiroshi Hano**, Tadakazu Shimoda*** and Muneo Kawamura**** A 45-year-old woman who underwent gastrectomy for gastric carcinoma which had metastasized to the liver and ovaries, showed high serum levels of hCG, AFP and CEA. To locate the source, an immunohistochemical technique was utilized. HCG-producing cells were detected in poorly differentiated adenocarcinoma of a primary tumor and an ovarian metastatic site, and AFP-producing cells in poorly differentiated adenocarcinoma forming a medullary pattern of primary site and metastatic foci. CEA-producing cells were found diffused in primary tumor and metastatic foci. From the viewpoint of oncodevelopmental gene expression (Cancer Res 36:3423, 1976), it is interesting that the serum levels of these three tumor markers (Internal (hCG, AFP, Medicine CEA) 31: were 260-264, elevated1992) simultaneously. Key words: immunohistochemical study, tumor marker
Introduction Human chorionic gonadotropin (hCG) , a glycoprotein secreted from the placetal chorionic villi, is important in the diagnosis of pregnancy and as a marker for chorionic tumors. Some non-trophoblastic tumors have recently been shown to secrete the hormone (1-3). In gastric carcinoma, production of hCG has been reported (4-6), and detection of the hCG producing cells by immuno histochemical methods has been attempted to investigate Here, we report aofpatient with gastric carcinoma the significance the cell production. which metastasized to the ovaries and liver with marked elevatiopn of serum hCG level as well as serum AFP and CEA levels. The materials obtained were investigated by the immunohistochemical method. Case Report A 45-year-old woman, who had received partial From Departments of Internal
Medicine,
^Obstetrics
gastrectomy due to cancer in 1988, visited a clinic com plaining of menstrual disorder on April 28, 1989 and was suspected of being pregnant. Since vaginal bleeding was noted on May 26, she visited our hospital the following dayadmission and was immediately On her physical admitted. examination revealed slightly anemic palpebral conjunctivae. Superficial lymph nodes were not palpable and abdominal findings were normal. Laboratory tests showed no abnormalities in the urinalysis, complete blood count, and coagulation studies. Biochemical tests disclosed hypoproteinemia (5.8g/dl) with elevations of alkaline phosphatase and lactic acid dehydrogenase. C-reactive protein was 4+ (9.4 mg/dl) , and the erythrocyte sedimentation rate was 47mm/h. Pregnancy test was positive by 2,000 fold (hCG: 2,000 IU/1). Various tumor markers were at high levels: 4,700ng/ml for AFP, 2,000ng/ml for CEA, and 6,400 mlU/ml for hCG. hCG/3 also showed a high serum level of 90ng/ml and the same level in the urine. CA19 9 and TPA levels were also elevated, at 89 and 880U/ml,
and Gynecology,
^Pathology, Fuji Central Hospital, Fuji, ***Department of Pathology, The Jikei University School of Medicine, Tokyo and ****Kawamura Hospital, Fuji Received for publication July 2, 1990; Accepted for publication July 10, 1991 Reprint requests should be addressed to Masataka Sano, MD, Department of Internal Medicine, Fuji Central Hospital, 50 Takashima-cho 417,Japan 260
Internal
Medicine
Vol. 31, No. 2 (February
1992)
hCG-producing respectively. Endocrinological examination showed that LH and FSH levels were low, and that progesterone was not elevated to the level usually seen in pregnancy. Gynecological examination showed no gestational sac in the uterus, and therefore ectopic pregnancy or incomplete abortion were suspected. Dilation and curet tage were performed on May 30. The endometrium obtained showed only a decidual change. Afterwards, there was no fall in the hCG titer, and imaging technique (ultrasonography, computed tomography) revealed no abnormal findings in the pelvis. On July 5, a slightly enlarged left ovary (the right one was normal in size) was detected by exploratory laparotomy and was removed. The histological diagnosis was a Krukenberg tumor. Systemic imaging investigations demonstrated mul tiple metastatic foci in the liver. Gastroendoscopy, however, did not disclose any abnormal findings. Thus, the final diagnosis was of recurring gastric cancer in the ovary and liver, and thereafter combination chemotherapy with cisplatin (CDDP), adriamycin (ADR), 5-fluorouracil (5-FU) and mitomycin C (MMC) was started from August 9. After four courses of treat ment the tumor did not reduce in size. Although the patient was temporarily discharged, the hepatic metas Accordingly, she waswith admitted again onascites January 4, 1990. tatic foci progressed jaundice, and appeared. Despite one course of combination chemotherapy with CDDP, etoposide, and ADR, there was no response. She died on March 5. An autopsy was performed 90min after her death, and showed metastases to the liver, right ovary, and a
Gastric
Carcinoma Table 1.
Date
hCG(mIU/ml 14,
Change is Tumor Markers /3hCG(ng/ml)
AFP(ng/ml)
CEA(ng/ml)
1989
23,
90
6,
4 ,700 7 ,000 5 ,600 7 ,600 7,200 7,700 4,600 6 ,000 13 ,000 13,000 17,000 7.200
2 ,000 2,500 2 ,400 4, 3,700 28, 4 ,900 18, 7,100 5, 6,000 23, 6,300 28, ll ,000 27, 20 ,000 23 3.0 Jan 17, 1990 27 ,000 .3 6, eb 28.000 hCG: human chorionic gonadotropin, AFP: alpha-fetoprotein, CEA: carcino-embryonic antigen ll,
250 320 640
24,
F
2
1
retroperitoneal lymph node. The altered levels of the tumor markers (hCG, AFP, CEA) are listed in Table 1; the serum hCG level reached a maximum of 43,000 mlU/ml in August 1989, and there after declined continuously to a low of 1.3 mlU/ml at the time of death. The AFP level went up to 17,000ng/ml, but fell to 7,200 ng/ml at the time of death. The CEA level remained high along with the tumor progression from the time of recurrence, and finally reached 28,000 ng/ml. Histopathological Findings Samples under investigation included the primary focus in the stomach at the time of partial gastrectomy
Fig. 1. Primary lesion in the stomach, a) A depressive type of advanced cancer measuring 40 x 30mm is located on the posterior wall and lesser curvature of the antrum (arrow heads), b) Papillo-tubular adenocarcinoma (left upper quadrant) is formed with poorly differentiated adenocarcinoma (right upper quadrant) (HE, x25). (inset) PAP staining for hCG: HCG-positive cells are found in the region of the poorly differentiated adenocarcinoma with a medullary pattern(x25). Internal Medicine Vol. 31, No. 2 (February 1992)
261
Sano et al (July 8, 1988), the left ovarian metastatic foci at the time of the exploratory laparotomy (July 5, 1989), and the metastatic foci in the right ovary and liver at the time of autopsy (March 6, 1990). The peroxidase antiperoxidase (PAP) stainings for hCG, AFP, and CEA were per formed on paraffin The gastric cancer, sections. measuring 40x 30mm, was a recessed type of advanced cancer located on the posterior
wall and lesser curvature of the antrum (Fig. la). The histologic appearance of the primary focus, shown in Fig. lb, was papillo-tubular adenocarcinoma, with poorly differentiated adenocarcinoma being particularly pronounced in the infiltrating regions. There were also areas of signet ring cell carcinoma. Infiltration extending to the serosa was observed, and invasion of tumor cells into lymphatics and vessels was notable. Metastasis
Fig. 2. Metastatic foci to the ovary, a) Poorly differentiated adenocarcinoma with number of cells possessing large bizarre nuclei are found in this field (HE, x50). b) PAP staining for AFP: Positive cells are identified in the region of poorly differentiated adenocarcinoma (arrows) (xlOO). c) PAP staining for CEA: Almost all cells are positive for CEA (xlOO).
Fig. 3. Metastatic foci to the liver, a) The photo shows medullary proliferation in papillary adenocarcinoma. There are some PAS-positive intracytoplasmic hyaline globules (HGs) (arrow) (HE, x50). b) PAP staining for AFP: Positive cells are mainly detected in the region of the medullary structure (arrows) (xlOO). c) PAP staining for CEA: Positive cells are diffusely detected (X lOO). 262
Internal
Medicine
Vol. 31, No. 2 (February
1992)
hCG-producing was noted in one out of 17 resected lymph nodes. PAP staining showed hCG-positive cells in the region of poorly differentiated adenocarcinoma with a medullary pattern adjacent to the papillo-tubular adenocarcinoma (Fig. lb inset). Anti-AFP staining showed some positive cells scattered in the same area as hCG-positive cells. Positive cellshistologic for CEA were diffusely distributed. The appearance of the metastatic foci of the ovary was mainly composed of poorly differentiated adenocarcinoma, or signet ring cell carcinoma. In ad dition, cells with large bizarre nuclei were seen in certain areas (Fig. 2a). A few hCG-positive cells were identified in the region of poorly differentiated adenocarcinoma. Small AFP-positive cell foci were observed in the same area as hCG-positive cells (Fig. 2b). Almost all cells were positive for CEA (Fig. 2c). HE staining of the liver metastatic foci is shown in Fig. 3a. The tumor was essentially papillary adeno carcinoma with areas partly medullary in pattern. There were some PAS-positive intracytoplasmic hyaline glo bules (HGs), and infiltration into veins was also notable. PAP-staining showed no positive hCG cells. AFP-positive cells were mainly detected in the medullary structure region, and intracytoplasmic HGs were also positive (Fig. 3b). Anti-CEA staining showed diffuse positivity of tumor cells (Fig. 3c). Discussion We suspected that this 45-year-old woman with late menstruation might at first have had a gynecological disease such as choriocarcinoma because the hCG level was markedly elevated. Further examination, however, revealed the recurrence of gastric cancer with metastatic foci to the ovaries and liver tumor which produced hCG, AFP, and CEA. The reported incidence of hCG ectopic production by gastric cancer, as measured in plasma, varies from 9 to 52% (1-4), the level being 50mIU/ml or less in most cases (1). Endocrinological symptoms due to hCG are usually not prominent in nontrophoblastic tumors (5). It was difficult to diagnose this particular case partlyhCG-producing because of the high level (6,400mlU/ml) Regarding tumors, Okano (5) reported and emmeniopathy. that the characteristics of hCG immunostaining are dependent on the histological type of the tumor rather than on their origin, and that the cells producing hCG are bizarre giant cells resembling choriocarcinoma. In contrast, Itoh and Tahara (6) reported that hCG producing cells are detected more frequently in poorly differentiated or undifferentiated areas than in well differentiated areas, and that giant cells resembling syncytial trophoblasts are not found. In the present case, hCG-positive cells were noted in poorly differentiated areas of both the primary and the ovarian metastatic foci. Syncytio-trophoblast-like cells were not observed. Internal Medicine Vol. 31, No. 2 (February 1992)
Gastric
Carcinoma
Concerning AFP-producing gastric cancer, Kodama et al (7) reported that there are two histological types: the medullary type, and the well differentiated papillary or tubular type. Koyama et al (8) reported that in cases with high serum AFP levels, AFP-producing cells are observed in poorly differentiated areas, especially with medullary arrangements. In the present patient, AFP positive cells were also noted in the regions of medullary pattern in poorly differentiated adenocarcinoma of both primary and metastatic foci. These cells had some histologic features similar to those of hepatoid adeno Generally, CEA-producing cells are said to be com carcinoma as defined by Ishikura et al (9). mon in well differentiated adenocarcinoma (10). Koyama et al (8) have reported that in AFP-producing gastric carcinoma also, CEA is strongly stained in well dif ferentiated adenocarcinoma tissues in the glandular epithelium or in areas of medullary-type carcinoma invasion. In the present patient, CEA-positive cells were diffusely distributed everywhere despite the degree Kokura et al (ll) reported a case of gastric carcinoma of differentiation. with high simultaneous hCG, CEA, and AFP serum levels. Similar to the present case, metastases to the liver and ovaries were also detected. Further, Honda et al (12) reported a case of gastric carcinoma with high hCG, CEA, and AFP serum levels which metastasized to neither liver nor ovaries. In the latter case, serum levels of the three tumor markers were lower than in the former case or in the present case, and after gastrectomy these serum levels declined. Accordingly, serum levels of these tumor markers seem to rise along with tumor progression. In the present case, the hCG level fell markedly after the initiation of chemotherapy, but the AFP and CEA levels were continuously elevated, and hCG-producing cells were not found in the metastatic foci in the liver at the time of autopsy. This might have indicated that the hCG-producing cells were more sensitive to therapy than the AFP- and CEA-producing cells. Otherwise, considering tumor progression, it might also be con ceivable that a change in phenotypic expression had The prognosis when the hCG level is high occurred with is thepoor cancer progression. (13), and also when AFP is produced by tumor cells, because the tumor tends to metastasize to the liver (14). Furthermore, a report (15) on the relationship between the productive patterns of these three tumor markers (hCG, AFP, and CEA) and the prognosis showed that the prognosis was poorer with the increase of the number of tumor markers showing abnormal serum levels. In the present case, the survival after gastrectomy was only 20 months. Miyayama and Miyayama (16) reported, in patients with gastric cancer, that the production of hCG (which is a placental hormone) indicates dysdifferentiation and 263
Sano et al that the production of AFP and CEA (which exist in the fetal gastrointestinal mucosa) signifies dedifferentiation. In the present case, the production of all these tumor markers may suggest the multipotentiality of tumor cells developing in various directions. The changes in the tumor marker levels during therapy were different with respect to each other, which may suggest certain changes in the phenotypic expression of the cancer cells along with the cancer progression! From the viewpoint of oncodevelopmental gene expression (17), it is very interesting that these three tumor markers showed high serum levels simultaneously and different changes with respect to each other. References 1) Papapetrou PD, Sakarelou NP, Braouzi H, et al. Ectopic pro duction of human chorionic gonadotropin (hCG) by neoplasmas. Cancer 45: 2583, 1980. 2) Braunstein GD, Vaitukaitis JL, Cabrone PP, et al. Ectopic production of human chorionic gonadotropin by neoplasmas. Ann Intern Med 78: 39, 1973. 3) Hattori M, Fukase M, Yoshimi H, et al. Ectopic production of human chorionic gonadotropin in malignant tumors. Cancer 42: 2328, 1978. 4) Birkenfeld S, Noiman G, Krispin M, Schwartz S, Zakut H. The incidence and significance of serum hCG and CEA in patients with gastrointestinal malignant tumors. Eur J Surg Oncol 15: 103, 1989. 5) Okano T. Immunohistochemical and clinical study of hCG producing tumors. Jpn J Clin Oncol 9: 215, 1979. 6) Itoh H, Tahara E. Human chorionic gonadotropin in human gastric carcinoma: A retrospective immunochemical study. Acta Pathol Jpn 33: 287, 1983.
264
Kodama T, Kameya T, Hirota T, et al. Production of alphafeto protein, normal serum proteins, and human chorionic gonado tropin in stomach cancer. Histologic and immunohistochemical analysis of 35 cases. Cancer 48: 1647, 1981. Koyama S, Ebihara T, Osuga T. Histologic and immunohisto chemical studies of alpha-fetoprotein (AFP) producing gastric carcinoma. Gastroenterol Jpn 22: 419, 1987. Ishikura H, Kirimoto K, Shamoto M, et al. Hepatoid adeno-^ carcinoma of the stomach: An analysis of seven cases. Cancer 58: 119, 1986. Naieroska-Guttmejer A, Szawlowski AW. Immunohistochemical detection of carcinoembryonic antigen (CEA) in noncancerous and cancerous gastric mucosa. Int J Biol Markers 4: 8, 1989. Kokura S, Morita Y, Ueda S, et al. A case of gastric carcinoma showing high serum levels of CA19-9, AFP, CEA and HCG. Nippon Shokakibyo Gakkai Zasshi 84: 2456, 1987 (in Japanese). Honda T, Katsuma S, Tokuda Y, et al. Carcinoembryonic anti gen, alpha-fetoprotein and human chorionic gonadotropin producing gastric cancer. Nippon Naika Gakkai Zasshi 73: 521, 1984 (in Japanese). Tomita K, Kuwajima M. Chorionic gonadotropin in gastric cancer tissue, especially its relation to the patients prognosis. Jpn J Cancer Clin 27: 1281, 1981 (in Japanese). Ohta D, Kajiwara Y, Harada E, et al. Alpha-fetoprotein pro ducing gastric cancer: Clinical and pathological analysis. Nippon Shokakigeka Gakkai Zasshi 18: 43, 1985 (in Japanese). Yonemura Y, Hashimoto T, Sawa T, et al. The significance of measurement of serum CEA, AFP and hCG in gastric cancer patients. Nippon Rinsho Gekai Gakkai Zasshi 48: 174, 1987 (in Japanese). Miyayama H, Miyayama Y. Immunohistochemical study of AFP, CEA, hCG and placental Al-P expressed in human gas trointestinal cancers in comparison to embryo-fetal gastrointestinal mucosa. Pathol Clin Med 3: 905, 1985 (in Japanese). Fishman WH. Activation of developmental genes in neoplastic transformation. Cancer Res 36: 3423, 1976.
Internal
Medicine
Vol. 31, No. 2 (February
1992)
Ovarian and Hepatic Metastases of Gastric Carcinoma Associated with High Serum Levels of Human Chorionic Gonadotropin (hCG), Alpha-Fetoprotein (AFP), and Carcinoembryonic Antigen (CEA): A Case Report Masataka Sano, Yukio Inamoto, Danjiro Nagamine, Haruo Yamada, Masao Ogiwara, Shoichi Sekino*, Yoshiaki Hirama*, Masahiro Aoki*, Hiroshi Hano**, Tadakazu Shimoda*** and Muneo Kawamura**** A 45-year-old woman who underwent gastrectomy for gastric carcinoma which had metastasized to the liver and ovaries, showed high serum levels of hCG, AFP and CEA. To locate the source, an immunohistochemical technique was utilized. HCG-producing cells were detected in poorly differentiated adenocarcinoma of a primary tumor and an ovarian metastatic site, and AFP-producing cells in poorly differentiated adenocarcinoma forming a medullary pattern of primary site and metastatic foci. CEA-producing cells were found diffused in primary tumor and metastatic foci. From the viewpoint of oncodevelopmental gene expression (Cancer Res 36:3423, 1976), it is interesting that the serum levels of these three tumor markers (Internal (hCG, AFP, Medicine CEA) 31: were 260-264, elevated1992) simultaneously. Key words: immunohistochemical study, tumor marker
Introduction Human chorionic gonadotropin (hCG) , a glycoprotein secreted from the placetal chorionic villi, is important in the diagnosis of pregnancy and as a marker for chorionic tumors. Some non-trophoblastic tumors have recently been shown to secrete the hormone (1-3). In gastric carcinoma, production of hCG has been reported (4-6), and detection of the hCG producing cells by immuno histochemical methods has been attempted to investigate Here, we report aofpatient with gastric carcinoma the significance the cell production. which metastasized to the ovaries and liver with marked elevatiopn of serum hCG level as well as serum AFP and CEA levels. The materials obtained were investigated by the immunohistochemical method. Case Report A 45-year-old woman, who had received partial From Departments of Internal
Medicine,
^Obstetrics
gastrectomy due to cancer in 1988, visited a clinic com plaining of menstrual disorder on April 28, 1989 and was suspected of being pregnant. Since vaginal bleeding was noted on May 26, she visited our hospital the following dayadmission and was immediately On her physical admitted. examination revealed slightly anemic palpebral conjunctivae. Superficial lymph nodes were not palpable and abdominal findings were normal. Laboratory tests showed no abnormalities in the urinalysis, complete blood count, and coagulation studies. Biochemical tests disclosed hypoproteinemia (5.8g/dl) with elevations of alkaline phosphatase and lactic acid dehydrogenase. C-reactive protein was 4+ (9.4 mg/dl) , and the erythrocyte sedimentation rate was 47mm/h. Pregnancy test was positive by 2,000 fold (hCG: 2,000 IU/1). Various tumor markers were at high levels: 4,700ng/ml for AFP, 2,000ng/ml for CEA, and 6,400 mlU/ml for hCG. hCG/3 also showed a high serum level of 90ng/ml and the same level in the urine. CA19 9 and TPA levels were also elevated, at 89 and 880U/ml,
and Gynecology,
^Pathology, Fuji Central Hospital, Fuji, ***Department of Pathology, The Jikei University School of Medicine, Tokyo and ****Kawamura Hospital, Fuji Received for publication July 2, 1990; Accepted for publication July 10, 1991 Reprint requests should be addressed to Masataka Sano, MD, Department of Internal Medicine, Fuji Central Hospital, 50 Takashima-cho 417,Japan 260
Internal
Medicine
Vol. 31, No. 2 (February
1992)
hCG-producing respectively. Endocrinological examination showed that LH and FSH levels were low, and that progesterone was not elevated to the level usually seen in pregnancy. Gynecological examination showed no gestational sac in the uterus, and therefore ectopic pregnancy or incomplete abortion were suspected. Dilation and curet tage were performed on May 30. The endometrium obtained showed only a decidual change. Afterwards, there was no fall in the hCG titer, and imaging technique (ultrasonography, computed tomography) revealed no abnormal findings in the pelvis. On July 5, a slightly enlarged left ovary (the right one was normal in size) was detected by exploratory laparotomy and was removed. The histological diagnosis was a Krukenberg tumor. Systemic imaging investigations demonstrated mul tiple metastatic foci in the liver. Gastroendoscopy, however, did not disclose any abnormal findings. Thus, the final diagnosis was of recurring gastric cancer in the ovary and liver, and thereafter combination chemotherapy with cisplatin (CDDP), adriamycin (ADR), 5-fluorouracil (5-FU) and mitomycin C (MMC) was started from August 9. After four courses of treat ment the tumor did not reduce in size. Although the patient was temporarily discharged, the hepatic metas Accordingly, she waswith admitted again onascites January 4, 1990. tatic foci progressed jaundice, and appeared. Despite one course of combination chemotherapy with CDDP, etoposide, and ADR, there was no response. She died on March 5. An autopsy was performed 90min after her death, and showed metastases to the liver, right ovary, and a
Gastric
Carcinoma Table 1.
Date
hCG(mIU/ml 14,
Change is Tumor Markers /3hCG(ng/ml)
AFP(ng/ml)
CEA(ng/ml)
1989
23,
90
6,
4 ,700 7 ,000 5 ,600 7 ,600 7,200 7,700 4,600 6 ,000 13 ,000 13,000 17,000 7.200
2 ,000 2,500 2 ,400 4, 3,700 28, 4 ,900 18, 7,100 5, 6,000 23, 6,300 28, ll ,000 27, 20 ,000 23 3.0 Jan 17, 1990 27 ,000 .3 6, eb 28.000 hCG: human chorionic gonadotropin, AFP: alpha-fetoprotein, CEA: carcino-embryonic antigen ll,
250 320 640
24,
F
2
1
retroperitoneal lymph node. The altered levels of the tumor markers (hCG, AFP, CEA) are listed in Table 1; the serum hCG level reached a maximum of 43,000 mlU/ml in August 1989, and there after declined continuously to a low of 1.3 mlU/ml at the time of death. The AFP level went up to 17,000ng/ml, but fell to 7,200 ng/ml at the time of death. The CEA level remained high along with the tumor progression from the time of recurrence, and finally reached 28,000 ng/ml. Histopathological Findings Samples under investigation included the primary focus in the stomach at the time of partial gastrectomy
Fig. 1. Primary lesion in the stomach, a) A depressive type of advanced cancer measuring 40 x 30mm is located on the posterior wall and lesser curvature of the antrum (arrow heads), b) Papillo-tubular adenocarcinoma (left upper quadrant) is formed with poorly differentiated adenocarcinoma (right upper quadrant) (HE, x25). (inset) PAP staining for hCG: HCG-positive cells are found in the region of the poorly differentiated adenocarcinoma with a medullary pattern(x25). Internal Medicine Vol. 31, No. 2 (February 1992)
261
Sano et al (July 8, 1988), the left ovarian metastatic foci at the time of the exploratory laparotomy (July 5, 1989), and the metastatic foci in the right ovary and liver at the time of autopsy (March 6, 1990). The peroxidase antiperoxidase (PAP) stainings for hCG, AFP, and CEA were per formed on paraffin The gastric cancer, sections. measuring 40x 30mm, was a recessed type of advanced cancer located on the posterior
wall and lesser curvature of the antrum (Fig. la). The histologic appearance of the primary focus, shown in Fig. lb, was papillo-tubular adenocarcinoma, with poorly differentiated adenocarcinoma being particularly pronounced in the infiltrating regions. There were also areas of signet ring cell carcinoma. Infiltration extending to the serosa was observed, and invasion of tumor cells into lymphatics and vessels was notable. Metastasis
Fig. 2. Metastatic foci to the ovary, a) Poorly differentiated adenocarcinoma with number of cells possessing large bizarre nuclei are found in this field (HE, x50). b) PAP staining for AFP: Positive cells are identified in the region of poorly differentiated adenocarcinoma (arrows) (xlOO). c) PAP staining for CEA: Almost all cells are positive for CEA (xlOO).
Fig. 3. Metastatic foci to the liver, a) The photo shows medullary proliferation in papillary adenocarcinoma. There are some PAS-positive intracytoplasmic hyaline globules (HGs) (arrow) (HE, x50). b) PAP staining for AFP: Positive cells are mainly detected in the region of the medullary structure (arrows) (xlOO). c) PAP staining for CEA: Positive cells are diffusely detected (X lOO). 262
Internal
Medicine
Vol. 31, No. 2 (February
1992)
hCG-producing was noted in one out of 17 resected lymph nodes. PAP staining showed hCG-positive cells in the region of poorly differentiated adenocarcinoma with a medullary pattern adjacent to the papillo-tubular adenocarcinoma (Fig. lb inset). Anti-AFP staining showed some positive cells scattered in the same area as hCG-positive cells. Positive cellshistologic for CEA were diffusely distributed. The appearance of the metastatic foci of the ovary was mainly composed of poorly differentiated adenocarcinoma, or signet ring cell carcinoma. In ad dition, cells with large bizarre nuclei were seen in certain areas (Fig. 2a). A few hCG-positive cells were identified in the region of poorly differentiated adenocarcinoma. Small AFP-positive cell foci were observed in the same area as hCG-positive cells (Fig. 2b). Almost all cells were positive for CEA (Fig. 2c). HE staining of the liver metastatic foci is shown in Fig. 3a. The tumor was essentially papillary adeno carcinoma with areas partly medullary in pattern. There were some PAS-positive intracytoplasmic hyaline glo bules (HGs), and infiltration into veins was also notable. PAP-staining showed no positive hCG cells. AFP-positive cells were mainly detected in the medullary structure region, and intracytoplasmic HGs were also positive (Fig. 3b). Anti-CEA staining showed diffuse positivity of tumor cells (Fig. 3c). Discussion We suspected that this 45-year-old woman with late menstruation might at first have had a gynecological disease such as choriocarcinoma because the hCG level was markedly elevated. Further examination, however, revealed the recurrence of gastric cancer with metastatic foci to the ovaries and liver tumor which produced hCG, AFP, and CEA. The reported incidence of hCG ectopic production by gastric cancer, as measured in plasma, varies from 9 to 52% (1-4), the level being 50mIU/ml or less in most cases (1). Endocrinological symptoms due to hCG are usually not prominent in nontrophoblastic tumors (5). It was difficult to diagnose this particular case partlyhCG-producing because of the high level (6,400mlU/ml) Regarding tumors, Okano (5) reported and emmeniopathy. that the characteristics of hCG immunostaining are dependent on the histological type of the tumor rather than on their origin, and that the cells producing hCG are bizarre giant cells resembling choriocarcinoma. In contrast, Itoh and Tahara (6) reported that hCG producing cells are detected more frequently in poorly differentiated or undifferentiated areas than in well differentiated areas, and that giant cells resembling syncytial trophoblasts are not found. In the present case, hCG-positive cells were noted in poorly differentiated areas of both the primary and the ovarian metastatic foci. Syncytio-trophoblast-like cells were not observed. Internal Medicine Vol. 31, No. 2 (February 1992)
Gastric
Carcinoma
Concerning AFP-producing gastric cancer, Kodama et al (7) reported that there are two histological types: the medullary type, and the well differentiated papillary or tubular type. Koyama et al (8) reported that in cases with high serum AFP levels, AFP-producing cells are observed in poorly differentiated areas, especially with medullary arrangements. In the present patient, AFP positive cells were also noted in the regions of medullary pattern in poorly differentiated adenocarcinoma of both primary and metastatic foci. These cells had some histologic features similar to those of hepatoid adeno Generally, CEA-producing cells are said to be com carcinoma as defined by Ishikura et al (9). mon in well differentiated adenocarcinoma (10). Koyama et al (8) have reported that in AFP-producing gastric carcinoma also, CEA is strongly stained in well dif ferentiated adenocarcinoma tissues in the glandular epithelium or in areas of medullary-type carcinoma invasion. In the present patient, CEA-positive cells were diffusely distributed everywhere despite the degree Kokura et al (ll) reported a case of gastric carcinoma of differentiation. with high simultaneous hCG, CEA, and AFP serum levels. Similar to the present case, metastases to the liver and ovaries were also detected. Further, Honda et al (12) reported a case of gastric carcinoma with high hCG, CEA, and AFP serum levels which metastasized to neither liver nor ovaries. In the latter case, serum levels of the three tumor markers were lower than in the former case or in the present case, and after gastrectomy these serum levels declined. Accordingly, serum levels of these tumor markers seem to rise along with tumor progression. In the present case, the hCG level fell markedly after the initiation of chemotherapy, but the AFP and CEA levels were continuously elevated, and hCG-producing cells were not found in the metastatic foci in the liver at the time of autopsy. This might have indicated that the hCG-producing cells were more sensitive to therapy than the AFP- and CEA-producing cells. Otherwise, considering tumor progression, it might also be con ceivable that a change in phenotypic expression had The prognosis when the hCG level is high occurred with is thepoor cancer progression. (13), and also when AFP is produced by tumor cells, because the tumor tends to metastasize to the liver (14). Furthermore, a report (15) on the relationship between the productive patterns of these three tumor markers (hCG, AFP, and CEA) and the prognosis showed that the prognosis was poorer with the increase of the number of tumor markers showing abnormal serum levels. In the present case, the survival after gastrectomy was only 20 months. Miyayama and Miyayama (16) reported, in patients with gastric cancer, that the production of hCG (which is a placental hormone) indicates dysdifferentiation and 263
Sano et al that the production of AFP and CEA (which exist in the fetal gastrointestinal mucosa) signifies dedifferentiation. In the present case, the production of all these tumor markers may suggest the multipotentiality of tumor cells developing in various directions. The changes in the tumor marker levels during therapy were different with respect to each other, which may suggest certain changes in the phenotypic expression of the cancer cells along with the cancer progression! From the viewpoint of oncodevelopmental gene expression (17), it is very interesting that these three tumor markers showed high serum levels simultaneously and different changes with respect to each other. References 1) Papapetrou PD, Sakarelou NP, Braouzi H, et al. Ectopic pro duction of human chorionic gonadotropin (hCG) by neoplasmas. Cancer 45: 2583, 1980. 2) Braunstein GD, Vaitukaitis JL, Cabrone PP, et al. Ectopic production of human chorionic gonadotropin by neoplasmas. Ann Intern Med 78: 39, 1973. 3) Hattori M, Fukase M, Yoshimi H, et al. Ectopic production of human chorionic gonadotropin in malignant tumors. Cancer 42: 2328, 1978. 4) Birkenfeld S, Noiman G, Krispin M, Schwartz S, Zakut H. The incidence and significance of serum hCG and CEA in patients with gastrointestinal malignant tumors. Eur J Surg Oncol 15: 103, 1989. 5) Okano T. Immunohistochemical and clinical study of hCG producing tumors. Jpn J Clin Oncol 9: 215, 1979. 6) Itoh H, Tahara E. Human chorionic gonadotropin in human gastric carcinoma: A retrospective immunochemical study. Acta Pathol Jpn 33: 287, 1983.
264
Kodama T, Kameya T, Hirota T, et al. Production of alphafeto protein, normal serum proteins, and human chorionic gonado tropin in stomach cancer. Histologic and immunohistochemical analysis of 35 cases. Cancer 48: 1647, 1981. Koyama S, Ebihara T, Osuga T. Histologic and immunohisto chemical studies of alpha-fetoprotein (AFP) producing gastric carcinoma. Gastroenterol Jpn 22: 419, 1987. Ishikura H, Kirimoto K, Shamoto M, et al. Hepatoid adeno-^ carcinoma of the stomach: An analysis of seven cases. Cancer 58: 119, 1986. Naieroska-Guttmejer A, Szawlowski AW. Immunohistochemical detection of carcinoembryonic antigen (CEA) in noncancerous and cancerous gastric mucosa. Int J Biol Markers 4: 8, 1989. Kokura S, Morita Y, Ueda S, et al. A case of gastric carcinoma showing high serum levels of CA19-9, AFP, CEA and HCG. Nippon Shokakibyo Gakkai Zasshi 84: 2456, 1987 (in Japanese). Honda T, Katsuma S, Tokuda Y, et al. Carcinoembryonic anti gen, alpha-fetoprotein and human chorionic gonadotropin producing gastric cancer. Nippon Naika Gakkai Zasshi 73: 521, 1984 (in Japanese). Tomita K, Kuwajima M. Chorionic gonadotropin in gastric cancer tissue, especially its relation to the patients prognosis. Jpn J Cancer Clin 27: 1281, 1981 (in Japanese). Ohta D, Kajiwara Y, Harada E, et al. Alpha-fetoprotein pro ducing gastric cancer: Clinical and pathological analysis. Nippon Shokakigeka Gakkai Zasshi 18: 43, 1985 (in Japanese). Yonemura Y, Hashimoto T, Sawa T, et al. The significance of measurement of serum CEA, AFP and hCG in gastric cancer patients. Nippon Rinsho Gekai Gakkai Zasshi 48: 174, 1987 (in Japanese). Miyayama H, Miyayama Y. Immunohistochemical study of AFP, CEA, hCG and placental Al-P expressed in human gas trointestinal cancers in comparison to embryo-fetal gastrointestinal mucosa. Pathol Clin Med 3: 905, 1985 (in Japanese). Fishman WH. Activation of developmental genes in neoplastic transformation. Cancer Res 36: 3423, 1976.
Internal
Medicine
Vol. 31, No. 2 (February
1992)
