Hepatoid adenocarcinoma of the stomach: Nine case reports and treatment outcomes

  • Authors:
    • Cheng Xiao
    • Fusheng Wu
    • Han Jiang
    • Lisong Teng
    • Fang Song
    • Qiangfeng Wang
    • Huanxia Yang
  • View Affiliations

  • Published online on: June 29, 2015     https://doi.org/10.3892/ol.2015.3430
  • Pages: 1605-1609
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Hepatoid adenocarcinoma (HAC), an extrahepatic tumor, has notable morphological similarities to hepatocellular carcinoma, which has been reported in gastrointestinal tract organs, including the rectum, gallbladder, lung, ovary and urinary bladder. HAC of the stomach (GHAC) is a rare variant of gastric cancer, characterized by aggressive behavior and extremely poor prognosis. Correct diagnosis depends on clinicopathological and immunohistochemical studies. In the present study, we reported nine cases of GHAC who were treated in the First Affiliated Hospital of Zhejiang University, China, from January 2009 to December 2013. All patients underwent radical gastrectomy; among them, one patient had stage I, one had stage II and seven had stage III. Elevated serum α‑fetoprotein was observed in eight cases. Until now, only one patient has succumbed, four patients have liver metastases, one has lung metastasis and four remain disease‑free. Relatively longer survival requires accurate diagnosis at an earlier stage and active multimodality treatment, including radical gastrectomy and adjuvant chemotherapy.

Introduction

Hepatoid adenocarcinomas (HACs) have been reported in gastrointestinal tract organs, including the gallbladder (4%), pancreas (4%), uterus (4%), lung (5%) and ovary (10%); however, the stomach (63%) is the most common origin of tumors according to a study of 261 HAC cases (1). This is due to the fact that the gastric system and liver were derived from the primitive foregut of the embryo (2). Bourreille et al firstly reported a case of α-fetoprotein-producing gastric carcinoma (AFPPGC) with liver metastasis in 1970 (3), and Ishikura et al termed this type of gastric cancer ‘hepatoid adenocarcinoma of the stomach (GHAC)’ (4). The majority of patients with GHAC demonstrate an elevated serum AFP level; however, 46% of GHAC tissues were negatively stained with AFP (2). GHAC is a rare type of gastric adenocarcinoma, with an incidence of only 0.38–1% among all gastric cancers (5,6). In view of the high incidence of liver metastasis, GHAC has a relatively poorer prognosis than common gastric cancer. It is difficult to distinguish GHAC with liver masses from primary hepatocellular carcinoma (HCC). To present the clinicopathological features, and to evaluate the therapeutic regimen and outcomes for patients with GHAC, we retrospectively analyzed nine cases which were treated in the First Affiliated Hospital of Zhejiang University, China, from January 2009 to December 2013.

Case report

Clinical data

Relevant clinical data are provided in Table I. Eight patients were male and one was female (median age, 63 years; range, 47–72 years). Eight patients had epigastric discomfort that had persisted for a certain time. Case 5 had an elevated serum AFP level that had persisted for two years; ultrasonographic and computed tomography (CT) scans had detected multiple hepatic nodules, so the patient was initially misdiagnosed as having primary HCC. Then hepatic artery digital subtraction angiography and transcatheter arterial chemoembolization (TACE) were performed, followed by a gastric biopsy which revealed gastric carcinoma. The hepatic nodes in this case were confirmed as angioma. Gastroscopy and biopsy revealed that gastric adenocarcinoma was present in all patients. The tumors of six cases were located in the antrum, two in the cardia and one in the corpus. All patients were serologically negative for hepatitis B surface antigen and hepatitis C antibody, and they did not reveal any imaging signs of cirrhosis. Cases 2 and 7 had a history of alcohol abuse, and the others did not. The laboratory investigation revealed that the serum AFP levels of eight patients were notably elevated, with a median level of 916.8 ng/ml (range, 4.4–8455.9 ng/ml; Table I).

Table I.

Preoperative clinical features in nine cases of hepatoid adenocarcinoma.

Table I.

Preoperative clinical features in nine cases of hepatoid adenocarcinoma.

CaseGender/ageSite/size (cm)Pre-/postoperative AFP (ng/ml)Liver/lung metastasesClinical presentationEndoscopic Borrmann type
1M/47Stomach, gastric body/1.5×1.34.4/7.7NoEpigastric discomfort II
2M/63Antrum/5.0×3.0916.8/441.9NoEpigastric tenderness  III
3F/76 Cardia/7.0×5.0×3.0448.6/63.0NoUpper abdominal pain II
4M/61Antrum/6.5×4.03633.9/3.3NoEpigastric discomfortI
5M/69Antrum/3.0×2.55333.2/58.2NoElevated serum AFP II
6M/57Antrum/3.0×4.042.3/5.1NoUpper abdominal pain II
7M/67Cardia/4.0×3.2270.0/32.9NoEpigastric discomfort II
8M/58Antrum/4.5×4.08455.9/471.1NoUpper abdominal pain II
9M/72Antrum/4.0×6.01079.3/n.a.NoEpigastric tenderness II

[i] AFP, α-fetoprotein; M, male; F, female; n.a., not assessed.

Treatment procedures and prognosis

A CT scan revealed that three patients (cases 2, 4 and 6) had multiple retroperitoneal area and perigastric lymph node enlargement, so the three cases received neo-adjuvant chemotherapy. None of these patients developed liver or lung metastases. Due to the notably elevated serum AFP level, case 5 was misdiagnosed as HCC and received TACE treatment at first admission until gastric endoscopy identified gastric adenocarcinoma. All patients received radical gastrectomy, among whom seven received subtotal gastrectomy, and two (cases 1 and 7) received total gastrectomy. According to the American Joint Committee on Cancer (2010AJCC) pathological tumor-node-metastasis (pTNM) staging classification for carcinoma of the stomach, stages I and II were observed in one patient, respectively, and stage III was observed in seven patients. These patients recovered following surgery without any notable postoperative complications. Seven patients underwent adjuvant postoperative chemotherapy. In case 5, after four cycles of chemotherapy regimen with S-1 and oxaliplatin, the serum AFP increased from 58.2 to 1449.0 ng/ml, and a magnetic resonance imaging scan revealed multiple hepatic metastases 6 months after surgery. Case 9 demonstrated multiple hepatic metastases one month after surgery and succumbed 5 months after surgery. Case 2 demonstrated a partial response following six cycles of chemotherapy with FOLFOX regimen, but was observed to have multiple liver metastases, so the patient was administered TS-1 as chemotherapy as well as liver radiofrequency ablation (RFA). Case 4 was observed to have a liver metastasis 18 months after surgery, following four cycles of chemotherapy with a combination of capecitabine plus paclitaxel; this case underwent liver tumor resection. Case 8 had lung metastasis 22 months after surgery and received paclitaxel plus carboplatin as the chemotherapy regimen, demonstrating a partial response. Until present, only one patient has succumbed, four patients have liver metastases, one has lung metastasis and four remain disease-free. Relevant treatment procedures and prognosis data are shown in Table II. Written informed consent was obtained from the patient's family and this study was approved by the ethics committee of First Affiliated Hospital of Zhejiang University, Hangzhou, China.

Table II.

Treatment and prognosis of nine cases of hepatoid adenocarcinoma.

Table II.

Treatment and prognosis of nine cases of hepatoid adenocarcinoma.

CaseNeo/adjuvant chemotherapySurgery/R0+D2StatusDFS (months)OS (months)
1No/SOXx6YesDisease-free77 (censored)
2 (FOLFOXx2)/(FOLFOXx4), TS-1YesLiver metastases47 (censored)
3NoYesDisease-free66 (censored)
4(SOXx2)/(SOXx4), capecitabine plus paclitaxelYesLiver metastases1828 (censored)
5No/(SOXx4)YesLiver metastases1115 (censored)
6(SOXx2)/(SOXx4)YesDisease-free3234 (censored)
7No/(SOXx6)YesDisease-free3636 (censored)
8No/(SOXx6), paclitaxel plus carboplatinYesLung metastases2243 (censored)
9NoYesLiver metastases1  5

[i] Censored, survival or lost to follow-up; R0, curative resection; D2, D2 lymphadenectomy; DFS, disease-free survival; OS, overall survival; Neo, neo-adjuvant chemotherapy; FOLFOX, oxaliplatin + folinic + fluorouracil; SOX, oxaliplatin + TS-1.

Pathological and immunohistochemical features

The pathological diagnostic criteria of GHAC was that tumor cells histologically demonstrate features resembling HCC. There was no particular quantity requirement for histological hepatoid differentiation, and patients with focal hepatoid or intermingled with sarcoma were also diagnosed with GHAC. Of the nine GHAC cases, six were confirmed to be HAC with complete hepatocyte-like regions; HAC intermingled with signet-ring cell components was observed in one case, with sarcoma cell components in one case and with tubular adenocarcinoma components in one case, respectively. Most of the patients (8/9) had poorly differentiated tumors. Eight patients had lymph node metastasis. Six had endovascular tumor emboli. Tumor cells were arranged in a trabecular pattern and resembled HCC, with abundant blood sinus. Polygonal cells with eosinophilic cytoplasm and hyperchromatic nucleoli indicated hepatoid differentiation. Immunohistochemistry revealed that the neoplastic cells in hepatoid areas of primary tumors and metastases demonstrated positivity for AFP, with the exception of cases 1 and 9. Specifically, the tumors in two cases were stained positively for synaptophysin and chromogranin A, which indicated neuroendocrine differentiation. The histopathological and immunohistochemical features of the nine cases are shown in Table III. Immunohistochemical features of hepatoid adenocarcinoma of the stomach are showed in Fig. 1

Table III.

Histopathological and immunohistochemical features in nine cases of hepatoid adenocarcinoma.

Table III.

Histopathological and immunohistochemical features in nine cases of hepatoid adenocarcinoma.

Case Histopathlogy/differentiationAFPCKCgASYNVascular invasionpTNM stage/pstage
1Hepatoid with signet-ring cell carcinoma/PCK2+n.a.n.a.+pT2N3aM0/IIIA
2Hepatoid/P+CK2++++pT4aN3bM0/IIIC
3Carcinosarcoma+n.a.n.a.n.a.n.a.pT1bN0M0/IA
4Hepatoid/P+CK7+CK19+CK20-n.a.n.a.pT4aN2M0/IIIB
5Hepatoid/P+CK20+++pT3N1M0/IIB
6Hepatoid/M-P+CK20-+pT4aN3M0/IIIC
7Hepatoid with tubular adenocarcinoma/P+CK19++pT4aN3M0/IIIC
8Hepatoid/M-P+CK7-CK19+CK20++pT4aN2M0/IIIB
9Hepatoid/PCK14-CK20++PT4aN2M0/IIIB

[i] AFP, α-fetoprotein; CK, cytokeratin; CgA, chromogranin A; SYN, synaptophysin; pTNM, pathological tumor-node-metastasis; P, poorly differentiated; M, moderately differentiated; n.a., not assessed.

Discussion

The GHAC cases in our study were characterized histologically by hepatoid differentiation and shared clinical features, including elevated serum AFP, predilection for elderly male patients and location in the antrum, aggressive behavior, and preferential metastases to the lymph nodes and liver, which is similar to the results of previous studies (69). GHAC patients usually have an elevated serum AFP level, so it is often misdiagnosed as primary HCC, particularly in GHAC patients with simultaneously occurring liver-occupying lesions. Generally, neighboring cirrhotic lesions are frequently observed in primary HCC, while they seldom occur in GHAC with liver metastases. Although metastatic lesions in the liver demonstrate a histological appearance similar to that of HCC, the clinical background and immunohistochemical examination still aid the differential diagnosis, since HCC often develops from liver cirrhosis to HCC, frequently accompanied by positive HepPar1 (10). The clinicopathological entity of GHAC is a tumor composed of polygonal cells arranged in a solid or trabecular manner that resembles HCC; hence, the pathological diagnostic criteria of GHAC is that tumor cells histologically demonstrate hepatoid features (11,12). Although two tumor cases in our study did not express AFP, the morphology and immunophenotype were consistent with GHAC. Immunohistochemical staining is conducive to distinguishing HCC from GHAC with liver metastases; however, its success has been limited by the lack of a reliable positive marker for hepatocellular differentiation. GHAC is frequently positive for AFP (91%), cytokeratin (CK)18/CK19 (100%), CK20 (25%), pancytokeratin (AE1/AE3) (92.3%) and α1-antitrypsin (91%) (13), and glypican-3 has been reported to be useful in the differential diagnosis between GHAC and HCC (1). In addition to these markers, palate, lung and nasal epithelium carcinoma-associated protein represents a promising marker in distinguishing HAC from HCC, since it is detected in liver metastases of GHAC, but not in HCC (14). However, none of these markers are sensitive or specific enough. The serum AFP level was not associated with the dimension, size, stage or prognosis of GHAC (15); however, patients with AFP-positive gastric cancer have a significantly higher tendency to develop liver metastasis and have a shorter long-term survival than patients with AFP-negative gastric cancers (16), since AFP's ability to suppress lymphocyte DNA synthesis inhibits lymphocyte transformation (17). Koide et al reported that AFP-producing gastric cancers have high malignant potential (high proliferative activity, weak apoptosis and rich neovascularization) compared with that of AFP-negative gastric cancers (18). Patients with normal AFP levels may represent a subtype of GHAC, with a more positive biological behavior (19). The measurement of the serum AFP level is also helpful during the follow-up period, as it usually falls sharply following adequate surgical treatment, while persistence of AFP elevation following active multimodality treatment including tumor resection may indicate regional or distant metastasis. Kumashiro et al reported that the histogenesis of HAC was strongly associated with the intestinal phenotype, and its hepatoid component was in some way associated with reduced CDX2 expression. High levels of CD10 and low levels of CDX2 expression may be associated with the aggressive biological behavior of GHAC (5).

Although there is no standard therapy protocol for GHAC, the diseases primary treatment modality can be based on that of common gastric adenocarcinoma. The majority of patients (6/9) in our study received first-line postoperative adjuvant chemotherapy. The liver metastases should undergo tumor resection if metastatic tumors are resectable; certain patients gain a survival benefit from this (case 4). Additionally, RFA is a safe and effective alternative for the partly unresectable liver metastases (case 2). TACE with doxorubicin transiently arrests the progression of recurrent liver metastases (20). Systemic chemotherapy demonstrated good effects in our cases.

The poor prognosis is associated with tendency of venous invasion, lymphatic permeation, lymph node metastasis, and synchronous and metachronous metastasis of the liver or other organs. One study reveals that a higher expression of c-Met may be associated with the poor prognosis of AFP-producing gastric cancer (21). Survival is closely associated with the pTNM stage. Baek et al reported that the median overall survival of patients with stages I–III and stage IV was 28.0 and 8.2 months, respectively (9). Relatively longer survival requires accurate diagnosis at an earlier stage as well as active multimodality treatment, including radical gastrectomy and adjuvant chemotherapy.

In conclusion, GHAC usually occurs with an elevated serum AFP level, and has unique pathological and immunohistochemical characteristics with notable morphological similarities to primary HCC. GHAC is associated with liver and lymph node metastases, indicating that the prognosis is poorer than with ordinary gastric cancer. It is essential to differentiate metastatic liver lesions of GHAC from primary HCC.

References

1 

Metzgeroth G, Strobel P, Baumbusch T, Reiter A and Hastka J: Hepatoid adenocarcinoma - review of the literature illustrated by a rare case originating in the peritoneal cavity. Onkologie. 33:263–269. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Nagai E, Ueyama T, Yao T and Tsuneyoshi M: Hepatoid adenocarcinoma of the stomach. A clinicopathologic and immunohistochemical analysis. Cancer. 72:1827–1835. 1993. View Article : Google Scholar : PubMed/NCBI

3 

Bourreille J, Metayer P, Sauger F, Matray F and Fondimare A: Existence of alpha feto protein during gastric-origin secondary cancer of the liver. Presse Med. 78:1277–1278. 1970.(in French). PubMed/NCBI

4 

Ishikura H, Fukasawa Y, Ogasawara K, Natori T, Tsukada Y and Aizawa M: An AFP-producing gastric carcinoma with features of hepatic differentiation. A case report. Cancer. 56:840–848. 1985. View Article : Google Scholar : PubMed/NCBI

5 

Kumashiro Y, Yao T, Aishima S, et al: Hepatoid adenocarcinoma of the stomach: histogenesis and progression in association with intestinal phenotype. Hum Pathol. 38:857–863. 2007. View Article : Google Scholar : PubMed/NCBI

6 

Liu X, Cheng Y, Sheng W, et al: Analysis of clinicopathologic features and prognostic factors in hepatoid adenocarcinoma of the stomach. Am J Surg Pathol. 34:1465–1471. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Gao YB, Zhang DF, Jin XL and Xiao JC: Preliminary study on the clinical and pathological relevance of gastric hepatoid adenocarcinoma. J Dig Dis. 8:23–28. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Zhang JF, Shi SS, Shao YF and Zhang HZ: Clinicopathological and prognostic features of hepatoid adenocarcinoma of the stomach. Chin Med J (Engl). 124:1470–1476. 2011.PubMed/NCBI

9 

Baek SK, Han SW, Oh DY, Im SA, Kim TY and Bang YJ: Clinicopathologic characteristics and treatment outcomes of hepatoid adenocarcinoma of the stomach, a rare but unique subtype of gastric cancer. BMC Gastroenterol. 11:562011. View Article : Google Scholar : PubMed/NCBI

10 

Maitra A, Murakata LA and Albores-Saavedra J: Immunoreactivity for hepatocyte paraffin 1 antibody in hepatoid adenocarcinomas of the gastrointestinal tract. Am J Clin Pathol. 115:689–694. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Ishikura H, Kanda M, Ito M, Nosaka K and Mizuno K: Hepatoid adenocarcinoma: a distinctive histological subtype of alpha-fetoprotein-producing lung carcinoma. Virchows Arch A Pathol Anat Histopathol. 417:73–80. 1990. View Article : Google Scholar : PubMed/NCBI

12 

Galvez-Munoz E, Gallego-Plazas J, Gonzalez-Orozco V, Menarguez-Pina F, Ruiz-Macia JA and Morcillo MA: Hepatoid adenocarcinoma of the stomach - a different histology for not so different gastric adenocarcinoma: a case report. Int Semin Surg Oncol. 6:132009. View Article : Google Scholar : PubMed/NCBI

13 

Su JS, Chen YT, Wang RC, Wu CY, Lee SW and Lee TY: Clinicopathological characteristics in the differential diagnosis of hepatoid adenocarcinoma: a literature review. World J Gastroenterol. 19:321–327. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Sentani K, Oue N, Sakamoto N, et al: Gene expression profiling with microarray and SAGE identifies PLUNC as a marker for hepatoid adenocarcinoma of the stomach. Mod Pathol. 21:464–475. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Inoue M, Sano T, Kuchiba A, Taniguchi H, Fukagawa T and Katai H: Long-term results of gastrectomy for alpha-fetoprotein-producing gastric cancer. Br J Surg. 97:1056–1061. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Chang YC, Nagasue N, Abe S, Taniura H, Kumar DD and Nakamura T: Comparison between the clinicopathologic features of AFP-positive and AFP-negative gastric cancers. Am J Gastroenterol. 87:321–325. 1992.PubMed/NCBI

17 

Yachnin S: The immunosuppressive properties of alpha-fetoprotein: a brief overview. Ann N Y Acad Sci. 417:105–107. 1983. View Article : Google Scholar : PubMed/NCBI

18 

Koide N, Nishio A, Igarashi J, Kajikawa S, Adachi W and Amano J: Alpha-fetoprotein-producing gastric cancer: histochemical analysis of cell proliferation, apoptosis and angiogenesis. Am J Gastroenterol. 94:1658–1663. 1999. View Article : Google Scholar : PubMed/NCBI

19 

Papatsimpas G, Kamposioras K, Goula K, et al: Hepatoid pancoast tumor. A case report and review of the literature. Lung Cancer. 77:239–245. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Lu CC, De-Chuan C, Lee HS and Chu HC: Pure hepatoid adenocarcinoma of the stomach with spleen and lymph-node metastases. Am J Surg. 199:e42–e44. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Amemiya H, Kono K, Mori Y, et al: High frequency of c-Met expression in gastric cancers producing alpha-fetoprotein. Oncology. 59:145–151. 2000. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September-2015
Volume 10 Issue 3

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Xiao C, Wu F, Jiang H, Teng L, Song F, Wang Q and Yang H: Hepatoid adenocarcinoma of the stomach: Nine case reports and treatment outcomes. Oncol Lett 10: 1605-1609, 2015
APA
Xiao, C., Wu, F., Jiang, H., Teng, L., Song, F., Wang, Q., & Yang, H. (2015). Hepatoid adenocarcinoma of the stomach: Nine case reports and treatment outcomes. Oncology Letters, 10, 1605-1609. https://doi.org/10.3892/ol.2015.3430
MLA
Xiao, C., Wu, F., Jiang, H., Teng, L., Song, F., Wang, Q., Yang, H."Hepatoid adenocarcinoma of the stomach: Nine case reports and treatment outcomes". Oncology Letters 10.3 (2015): 1605-1609.
Chicago
Xiao, C., Wu, F., Jiang, H., Teng, L., Song, F., Wang, Q., Yang, H."Hepatoid adenocarcinoma of the stomach: Nine case reports and treatment outcomes". Oncology Letters 10, no. 3 (2015): 1605-1609. https://doi.org/10.3892/ol.2015.3430