* Choriocarcinoma is a rapidly invasive, widely metastatic human chorionic gonadotropin (HCG)-producing neoplasm, usually intrauterine and gestational. Primary gastric choriocarcinoma is very rare, and its pathogenesis is still uncertain. We report a case of primary gastric choriocarcinoma associated with adenocarcinoma in a 36-year-old woman. The patient presented with gastrointestinal bleeding and a gastric mass clinically suspicious of gastric adenocarcinoma. Histopathologic evaluation proved the tumor to be a choriocarcinoma, with a minor component of a poorly differentiated adenocarcinoma. The patient was treated with a standard nongestational choriocarcinoma chemotherapy regimen. An impressive initial response was evidenced by clinical reduction of the tumor volume and drop of the serum P-HCG levels after the first cycle. However, the tumor rapidly recurred in the abdomen and disseminated to the lungs, which were documented by new elevation of serum P-HCG levels and computed tomographic scans despite continuing with 3 more cycles of chemotherapy. The patient died 6 months after diagnosis. (Arch Pathol Lab Med. 2001;125:1601-1604)
Choriocarcinoma is a rapidly invasive, widely metastatic human chorionic gonadotropin (HCG)-producing neoplasm, usually intrauterine and gestational. Almost all remaining choriocarcinomas arise in ectopic pregnancies, the gonads, or midline locations (mediastinum, retroperitoneum, and pineal gland) as a teratoma.1 Only rarely have the neoplasms been reported in parenchymal organs, such as the prostate, liver, lung, urinary bladder, nose, and gastrointestinal tract.2 Primary gastric choriocarcinoma is very rare, and its pathogenesis is still uncertain.
We report a case of primary gastric choriocarcinoma associated with adenocarcinoma in a 36-year-old women and review the literature published on the clinicopathologic findings and pathogenesis of this neoplasm.
REPORT OF A CASE
A 36-year-old Latin American woman presented to Texas Tech University Medical Center, Lubbock, Tex, with chief complaints of abdominal, chest, and back pain for 2 weeks, decreased appetite, weakness, and severe fatigue. Her initial evaluation demonstrated melena and extremely low hemoglobin and hematocrit levels (3.8 g/dL and 11.4%, respectively). The patient was initially admitted to the medical intensive care unit, where she had a full workup and was found to have a gastric mass. Esophagogastroduodenoscopy revealed a large, fungating, noncircumferential mass with necrotic areas and stigmata of recent bleeding in the anterior wall of the gastric body. Endoscopic biopsy specimens from the tumor mass were obtained. Subsequent computed tomographic (CT) scan of the pelvis and abdomen revealed that the mass was arising from the stomach antrum and extended to the lesser sac and also involved the transverse colon. On her initial evaluation, the patient also had an enlarged uterus, and although she had undergone bilateral tubal ligation about 6 years ago, a vaginal ultrasound was performed to rule out intrauterine pregnancy. No evidence of such a condition was identified. Serum beta-HCG levels, however, were positive, with a quantitative value of 68 mIU/mL. The patient had been previously healthy with a medical history unremarkable for any significant medical illness. Her 3 full-term pregnancies were followed by normal deliveries, and she had no history of abortuses. She denies alcohol or tobacco abuse.
The patient underwent a transabdominal CT-guided true-cut needle biopsy of the intraabdominal mass, which extended from the stomach wall to the abdominal wall. A CT scan of her head and chest were negative for metastatic disease. The remainder of her workup revealed slightly elevated serum carcinoembryonic antigen and normal a-fetoprotein levels. The patient was evaluated by the surgical oncologist who considered the mass to be unresectable. Chemotherapy was then initiated consisting of cisplatin, etoposide, and bleomycin. The patient responded well to the first cycle of therapy evidenced by the shrinkage of the tumor mass and decreased P-HCG level. Despite an impressive initial clinical response, after 3 chemotherapy cycles, CT scans of the chest, abdomen, and pelvis were performed, which showed progression of disease and spread to the colon, stomach, and lungs. The patient was then given one cycle of salvage chemotherapy consisting of vinblastine, ifosfamide, and cisplatin without any response. It was explained to the patient and family that further chemotherapy would probably be ineffective and that other alternative regimens of chemotherapy would be most likely unsuccessful. It was decided not to proceed with further chemotherapy because of progressive disease of tumor unresponsive to treatment. The patient died of tumor progression at home, and an autopsy was not performed.
Histologic evaluation of the minute, endoscopically obtained gastric biopsy specimens demonstrated almost complete replacement by a malignant neoplasm, characterized by solid tumor nests and trabeculae formed by large polyhedral tumor cells with abundant foamy basophilic cytoplasm and large, round hyperchromatic nuclei, some exhibiting prominent single nucleoli (cytotrophoblasts). Some of the cells exhibit intensely eosinophilic, keratinous-like cytoplasm. Scattered around and frequently surrounding the tumor cell nests were large, multinucleated, pleomorphic tumor cells (syncytiotrophoblasts) (Figure 1, a and b). Numerous typical and atypical mitotic figures were identified. The tumor exhibits prominent vascular invasion with frequent tumor thrombi and tumor cells lining vascular spaces. Extensive tumor necrosis, hemorrhage, and vascular thrombosis were also seen. Only occasional poorly formed glandular structures were focally identified. Histologic examination of the transabdominal true-cut needle biopsy specimen revealed similar features.
Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue sections from both tumor biopsy specimens. The tumor cells exhibited strong positive reaction with pan-cytokeratin AEl and AE3 and polyclonal carcinoembryonic antigen antibodies (Cell Marque, Austin, Tex) (Figure 2, a and b). Equally strong but focally positive reaction of tumor cells was seen with B72.3 and epithelial membrane antigen antibodies (Cell Marque). Some tumor cells, especially around tumor nests, exhibited a strong positive reaction with antibodies to beta-- HCG (BioGenex, San Ramon, Calif). Much stronger and more diffuse immunostaining of tumor cells with beta-HCG antibodies was demonstrated in the tissue obtained by the transabdominal true-cut needle biopsy specimens (Figure 3, a) compared with the endoscopically obtained gastric biopsy specimens. Rare periodic acid-Schiff, postdiastase digestion periodic acid-Schiff, and mucicarmine-positive intracytoplasmic material (Figure 3, b) was demonstrated in some tumor cells, which suggested glandular differentiation.
The histologic, immunohistochemical, and histochemical features of this malignant neoplasm, along with the elevated serum levels of beta-HCG, were consistent with a diagnosis of choriocarcinoma. The failure to identify an intrauterine or extrauterine gestational trophoblastic tumor or a nongestational gonadal or extragonadal germ cell tumor excluded the possibility of metastatic disease in the stomach. Only rare focal areas of the tumor exhibited evidence of glandular differentiation, and although the biopsy specimen may not be representative of the entire tumor, it appeared that the major component of this tumor was in fact choriocarcinoma. It was concluded that the tumor represented a primary gastric choriocarcinoma with a small component of poorly differentiated adenocarcinoma.
Primary gastric choriocarcinomas are rare. They can present in pure form, accompany adenocarcinoma, or be associated with nontrophoblastic gonadal tissue.3,4 These tumors may contain an undifferentiated component or show a transition between adenocarcinoma and choriocarcinoma. In the study by Jindrak et al,1 the average age of the patients with gastric choriocarcinoma was 52.6 years in men and 60.9 years in women. The younger age and numerical preponderance of men (17:10) may simply reflect reluctance on the part of pathologists to accept (and consequently report) a primary extragenital choriocarcinoma in women of childbearing years.1
The clinical presentation of gastric choriocarcinoma is similar to that of gastric adenocarcinoma and includes abdominal pain, anorexia, weight loss, nausea, and vomiting; however, it is more frequently a cause of gastrointestinal bleeding and may have some hormonal effects, such as gynecomastia, precocious puberty, and vomiting resembling that seen with pregnancy. Both radiologic and endoscopic evaluation demonstrates a bulky, intraluminal lesion that resembles gastric adenocarcinoma. Pathologically, the endoscopic biopsy specimen usually reveals the malignant nature of the tumor, although precise histologic characterization of the neoplasm may require large tissue samples, which can only be obtained by surgery.5
Primary gastric choriocarcinoma is a rapidly growing neoplasm, and untreated patients have an average survival of only several months.5 A treatment of choice has not been established, because few experiences have been reported. Current treatment methods include surgical intervention with combined chemotherapy. Radiotherapy has not been shown to improve the prognosis for this diseases
Regarding the pathogenesis of primary gastric choriocarcinoma, several theories have been proposed, including development from an underlying gastric teratoma, delayed metastasis from an intrauterine primary lesion, and emergence from putative displaced gonadal anlage. The most plausible explanation for the pathogenesis of gastric choriocarcinoma was proposed by Pick in 1926. Based on the observation that many cases of primary gastric choriocarcinoma were found in coexistence with an adenocarcinoma, in some of which a transition from adenocarcinoma to choriocarcinoma had been demonstrated, he proposed that the trophoblastic elements found in primary gastric choriocarcinoma developed from dedifferentiation of a poorly differentiated adenocarcinoma. A pure choriocarcinoma would then arise by overgrowth and elimination of the original adenocarcinoma.5 The possibility that the normal gastric mucosa undergoes trophoblastic metaplasia preceding neoplastic transformation must also be considered. Thus, not only do gastric choriocarcinomas show similarity to gastric adenocarcinomas in age and sex distribution and increased frequency in Japan,6 but also choriocarcinomas arising in other organs such as bladder7 and lung display adjacent carcinoma peculiar to the involved organ.
Although many investigators accepted the dedifferentiation theory, many puzzling questions remain, such as the role of HCG-producing cells normally present in the gastric mucosa.8 It is possible that some pure choriocarcinomas originate de novo in HCG-producing cells of the normal gastric mucosa without a preceding adenocarcinoma. Yakeishi et al8 reported immunohistochemical evidence of HCG-positive cells in the normal gastric mucosa and in adenocarcinomas and choriocarcinomas in various proportions and intensities. Because somatic cells remain the entire genome for an organism, with differentiation depending on repression or expression of various groups of genes, it is conceivable that, under the profound changes that occur during carcinogenesis, the gastric mucosal cells directly develop the morphologic and functional characteristics of a choriocarcinoma.9
It is therefore conceivable that choriocarcinomas occur primarily in the stomach most commonly as a result of a dedifferentiation mechanism from an underlying, poorly differentiated adenocarcinoma, in a manner similar to what has been demonstrated to occur in other mesenchymal and epithelial tumors from different organs. The more uncommon pure choriocarcinomas may be explained by overgrowth of the adenocarcinoma by the choriocarcinoma and alternatively by de novo choriocarcinomas arising in HCG-producing cells normally present in the stomach.
The significance of elevated serum beta-HCG levels and/ or immunoreactivity of beta-HCG antibodies in tumor cells is still controversial. It has been reported that patients with gastric adenocarcinoma and high levels of HCG in the serum or a high density of HCG-positive cells in the tumor tissue had a poorer prognosis or a shorter survival time.10 However, other studies proposed that the existence of beta-HCG-positive cells in gastric adenocarcinomas has no prognostic significance.8
It appears from these and other studies that the presence of an elevated serum beta-HCG level and/or the presence of beta-HCG immunoreactive tumor cells, independent of intensity or density, in an otherwise routine gastric adenocarcinoma is a common finding and does not have any diagnostic or prognostic significance, since these adenocarcinomas behave according to their grade, stage, and histologic type in a similar fashion to their contra part without beta-HCG-producing tumor cells. These tumors are adenocarcinomas and in no way should be interpreted as adenocarcinomas with choriocarcinoma differentiation. Follow-up with evaluation of serum beta-HCG levels, however, may be helpful in evaluating response to treatment and/or recurrent disease.
Gastric choriocarcinomas, on the other hand, are rare tumors that are characterized by the presence of a double cell population with cytologic, histologic, architectural, and immunohistochemical features similar to those seen in gestational choriocarcinomas, whether presenting in its pure form or mixed with an adenocarcinoma component. Most reported gastric choriocarcinomas, including our own case, exhibited a component of poorly differentiated adenocarcinoma. This component may be almost completely overgrown by the choriocarcinoma or in rare cases be more easily recognized. Therefore, the diagnosis of choriocarcinoma should not be made merely on the basis of the presence of beta-HCG immunoreactive cells, but these cells need to be present in the background of a tumor that is cytologically, histologically, and biologically consistent with the better known gestational choriocarcinoma.
Although the number of cases of well-documented gastric choriocarcinomas reported to date is small, it appears that these tumors behave more like gestational or germ cell choriocarcinomas with rapid and extensive hematogenous dissemination as opposed to the preferred lymphatic way of adenocarcinomas. Metastatic disease frequently contains pure choriocarcinoma, although mixed chorioadenocarcinoma metastases have also been seen. Mortality is high and survival short, with most patients dying of disease within 6 months. Little is known about specific treatment modalities for gastric choriocarcinoma. Although chemotherapy seems to be the treatment of choice, chemotherapy regimens used and proved successful for gestational choriocarcinoma had not been effective in gastric choriocarcinoma, in a way similar to nongestational choriocarcinomas of either gonadal or extragonadal origin.
Our case fits the clinical, cytologic, histologic, and immunohistochemical criteria for a diagnosis of primary gastric choriocarcinoma. The patient was young and presented with gastrointestinal bleeding and a gastric mass clinically suggestive of gastric adenocarcinoma. Histopathologic evaluation proved the tumor to be a choriocarcinoma with a minor component of a poorly differentiated adenocarcinoma consistent with the dedifferentiation theory of histogenesis. The patient was treated with 4 cycles of a standard nongestational choriocarcinoma chemotherapy regimen with an impressive initial response evidenced by clinical reduction of the tumor volume and drop of the serum beta-HCG levels from 131 mIU/mL at the beginning of chemotherapy to an all time low of 9 mIU/mL after her first cycle. However, the tumor rapidly progressed and disseminated in a hematogenous pattern of metastatic disease despite continuing with 3 more cycles of chemotherapy. Metastatic disease to the lungs and colon was documented by new elevation of serum beta-HCG levels and CT scans. Chemotherapy was then stopped, and the patient died at home 6 months after initial diagnosis. Unfortunately, an autopsy was not performed, so the final tumor extent and histologic features could not be evaluated.
The report of this case of primary gastric choriocarcinoma is important to add data to the literature regarding this rare condition, to better understand its histopatho-- genesis, to help others in its diagnosis and management, and eventually to improve patient treatment and prognosis.
1. Jindrak K, Bochetto JF, Alpert Lt. Primary gastric choriocarcinoma: case report with review of world literature. Hum Pathol. 1976;7:595-604.
2. Wurzel J, Brooks JJ. Primary gastric choriocarcinoma: immunohistochemistry, postmortem documentation, and hormonal effects in a postmenopausal female. Cancer. 1981;48:2756-2761.
3. Saigo PF, Brigati DJ, Sternberg SS, Rosen PP, Turnbull AD. Primary gastric choriocarcinoma: an immunohistological study. Am) Surg Pathol. 1981;5:333342.
4. Imai Y, Kawabe, Takahashi M, et al. A case of primary gastric choriocarcinoma and a review of the Japanese literature. J Gastroenterol. 1994;29:642-646.
5. Krulewski T, Cohen LB. Choriocarcinoma of the stomach: pathogenesis and clinical characteristics. Am j Gastroenterol. 1988;83:1172-1175.
6. Connolly C, Gillan J, Maguire R, Hitchcock H. Primary choriocarcinoma of the mediastinum. Ir Med Sci. 1979;148:20-22.
7. Kawmura J, Rhinsho K, Taki Y, et al. Choriocarcinoma and undifferentiated cell carcinoma of the bladder with gonadotropin secretion. J Urol. 1979;121: 684-686.
8. Yakeishi Y, Mori M, Enjoji M. Distribution of beta-human chorionic gonadotropin-positive cells in noncancerous gastric mucosa and in malignant gastric tumors. Cancer. 1990;66:695-701.
9. Garcia RL, Ghali VS. Gastric choriocarcinoma and yolk sac tumor in a man: observations about its possible origin. Hum Pathol. 1985;16:955-958.
10. Tomita K, Kuwajima M. Chorionic gonadotropin in gastric cancer tissue, especially its relation to the patient's prognosis. jpn J Cancer Clin. 1981;27:12811282.
Zhi Liu, MD, PhD; Jose L. Mira, MD; Jose C. Cruz-Caudillo, MD
Accepted for publication June 1, 2001.
From the Departments of Pathology (Drs Liu and Mira) and Internal Medicine (Dr Cruz-Caudillo), Texas Tech University, Health Science Center, Lubbock, Tex.
Reprints: Jose L. Mira, MD, Department of Pathology and Laboratory Medicine, Texas Tech University Health Sciences Center, 3601 Fourth St, Lubbock, TX 79430 (e-mail: email@example.com).
Copyright College of American Pathologists Dec 2001
Provided by ProQuest Information and Learning Company. All rights Reserved