Marked elevation of alpha fetoprotein caused by hepatoid adenocarcinoma of stomach: A case report

Abstract

BACKGROUND

Alpha-fetoprotein (AFP) is primarily used as a tumour marker for hepatocellular carcinoma and germ cell tumours. Hepatoid adenocarcinoma of stomach (HAS) is a rare and aggressive subtype of gastric cancer with hepatocyte differentiation. We report a case of extremely high AFP levels caused by HAS.

CASE SUMMARY

A 75-year-old man was admitted with abdominal pain and weight loss. Tumour markers showed an unusually high AFP of 889200 ng/mL. Computed tomography showed an exophytic mass in the stomach with extensive portal vein thrombosis. Gastroscopy showed a 5 cm ulcerated mass on the lesser curve of the stomach. Histology confirmed hepatoid adenocarcinoma, which mimics hepatocellular carcinoma. The immunohistochemistry was positive for cytokeratin AE1AE3, caudal type homeobox 2, hepatocyte paraffin 1 and AFP. He was treated with fluorouracil leucovorin oxaliplatin and nivolumab. However, he died due to progressive disease.

CONCLUSION

Markedly high AFP levels should prompt physicians to evaluate for uncommon causes including HAS.

Key Words: Gastric cancer; Alpha-fetoprotein; Hepatoid adenocarcinoma; Gastroscopy; Chemotherapy; Case report

Core Tip: We report a rare case of hepatoid adenocarcinoma (HAC). Markedly elevated alpha-fetoprotein levels should prompt physicians to evaluate for uncommon causes including HAC of stomach. Histology and immunohistochemistry are integral to establishing the diagnosis. Gastroscopy is also a crucial diagnostic step. There is currently no established treatment protocol for HAC of stomach; however, treatment for metastatic gastric cancer has been used. A low serum alpha-fetoprotein level is generally associated with better survival, but long-term studies are required to confirm this.

INTRODUCTION

Alpha-fetoprotein (AFP) is a serum glycoprotein that is produced from embryogenesis and foetal liver[1]. Many tissues develop the ability to synthesise this oncofetal protein during malignant transformation. It is thus used as a tumour marker for hepatocellular carcinoma (HCC) and germ cell tumour[2]. Hepatoid adenocarcinoma (HAC) of stomach (HAS) is a rare type of malignancy that causes high AFP levels[3]. HAS is an aggressive subtype of gastric cancer, accounting for only 0.3% of all gastric adenocarcinoma[4]. Other organs like lungs, colon and pancreas can also be involved with HAC[5]. Due to the rarity of this condition, there is currently no established guideline for HAS[6]. We report a case of HAS causing extremely high AFP levels.

CASE PRESENTATION

Chief complaints

A 75-year-old Caucasian man presented with abdominal pain, unintentional weight loss and functional decline.

History of present illness

The patient presented with a 4-week history of abdominal pain, 7 kg of unintentional weight loss and functional decline.

History of past illness

The patient’s only past medical history was chronic obstructive pulmonary disease.

Personal and family history

The patient denied any significant family history.

Physical examination

On physical examination, the patient had normal vital signs. He had a soft abdomen with mild tenderness in the lower abdomen. The examination was otherwise unremarkable.

Laboratory examinations

Blood tests arranged by his general practitioner showed a mildly raised C-reactive protein of 56 mg/L, a cholestatic pattern of liver function tests (bilirubin 10 μmol/L, alkaline phosphatase 448 U/L, gamma-glutamyl transferase 234 U/L) and an unusually elevated AFP level of 263700 ng/mL.

Imaging examinations

Subsequent computed tomography abdomen with quad phase showed an exophytic mass in the stomach with extensive portal vein thrombosis. The liver surface, particularly the left lobe, appeared nodular with a segment II hypo-enhancing lesion (Figure 1). In view of the nodular liver, extensive portal vein thrombosis and markedly elevated AFP levels, HCC was initially suspected. On magnetic resonance imaging, this lesion did not have the typical vascular characteristics of HCC and was not amenable to targeted biopsy. It also confirmed the presence of a nodular liver, likely due to liver cirrhosis with portal vein thrombosis extending from the main portal and splenic veins into both the right and left portal veins. However, there was no evidence of HCC (Figure 2). He was commenced on therapeutic enoxaparin to treat the portal vein thrombosis. The repeat AFP level increased to 412300 ng/mL.

Figure 1 Portal venous phase of computed tomography liver quad phase. A: Portal vein thrombosis with splenic vein thrombosis; B: Nodularity on the liver surface with segment II liver lesion.

Figure 2 Magnetic resonance imaging liver. A: Portal vein thrombosis; B: Gastric mass. There is no evidence of hepatocellular carcinoma.

FINAL DIAGNOSIS

The presence of portal vein thrombosis without evidence of HCC prompted further investigations for an underlying malignancy causing a hypercoagulable state. Hence, a gastroscopy was done which showed a 5 cm ulcerated friable mass on the lesser curve of the stomach. In addition, there were no varices or portal hypertensive gastropathy changes (Figure 3). The histology confirmed HAC, which can mimic HCC (Figure 4). The immunohistochemistry was positive for cytokeratin AE1AE3 (AE1AE3), caudal type homeobox 2 (CDX2), hepatocyte paraffin 1 (HepPar-1), and AFP (Figure 5).

Figure 3 Endoscopic photos of the gastric tumour detected during gastroscopy.

Figure 4 Histopathological findings. Hematoxylin and eosin staining of gastric biopsy demonstrating hepatoid adenocarcinoma of the gastrointestinal tract. Tumour shows pleomorphic nests and trabecular pattern mimicking that of hepatocellular carcinoma. A: 200 × magnification; B: 400 × magnification.

Figure 5 Immunohistochemistry findings. All images shown at 200 × magnification. A: Cytokeratin AE1AE3 stain strong positive; B: Caudal type homeobox 2 stain positive; C: Hepatocyte paraffin 1 stain positive; D: Alpha-fetoprotein stain positive.

TREATMENT

After multidisciplinary team discussion, he was started on a combination of chemoimmunotherapy with fluorouracil leucovorin oxaliplatin and nivolumab. The chemotherapy was commenced at a half the dose due to his frailty.

OUTCOME AND FOLLOW-UP

He had an AFP level of 889200 ng/mL prior to the commencement of treatment. However, he died after one cycle of chemoimmunotherapy.

DISCUSSION

HAC is an extrahepatic adenocarcinoma with hepatocyte differentiation, consisting of large polygonal eosinophilic hepatocytes. HAC can occur in different organs including lungs, stomach, colon, ovaries and pancreas. It is referred to as HAS when HAC occurs in the stomach[4]. HAS is a rare subtype of gastric cancer resembling the morphology and immunohistochemistry of HCC[7]. Compared with gastric adenocarcinoma, which is the most common form of gastric cancer, HAS is associated with elevated AFP levels, whereas AFP levels are typically normal in gastric adenocarcinoma. The exact mechanism of elevated AFP levels in HAS remains unclear[8]. It was postulated that cancers arising from the gastrointestinal tract may undergo dedifferentiation towards primitive embryonic hepatocyte, leading to the development of HAC[9].

Our case was unique in that the gastric tumour was associated with radiological cirrhosis with nodular liver surface and extensive portal vein thrombosis, raising the suspicion of HCC. The diagnosis of a gastric tumour is challenging in the presence of concomitant radiological cirrhosis and elevated AFP levels, particularly in the absence of specific gastrointestinal symptoms. Hence, histology and immunohistochemistry are integral to establishing the diagnosis.

Histologically differentiating HAC from HCC based on morphology can be challenging given both tumours have a hepatoid appearance, and immunohistochemically both express liver markers, AFP and HepPar-1, which both stained positive in the specimen[10]. A diagnosis of HAC can be more straightforward when the specimen has conventional adenocarcinoma adjacent to the hepatoid appearing tumour. However, in the context of small biopsies that only show hepatoid tumour cells, as we had, using an immunohistochemical panel is important in distinguishing HAC from HCC. Our immunohistochemical panel including AFP, HepPar-1 and a broad-spectrum cytokeratin, AE1AE3, which showed strong positive staining, supported the diagnosis of HAC, as certain cytokeratins including AE1AE3 have been shown to have up to 92.3% frequency in positivity in HAC, compared to HCC, which has a low frequency of positivity[11]. We additionally used CDX2, which was positive, an intestinal marker for adenocarcinoma commonly positive in HAC, and less than 5% expressed in HCC[12].

Given the platelet count was normal with no varices on gastroscopy, the patient likely had early cirrhosis with no clinically significant portal hypertension. In the view of this aggressive gastric cancer, it is possible that portal vein thrombus may be due to HAS rather than early cirrhosis. Based on our literature review, only one other case of HAS was also associated with portal vein thrombosis. The mortality of gastric cancer increases significantly with associated portal vein thrombosis[13,14].

Gastroscopy was a crucial diagnostic step in this case. The gastroscopy showed a large and ulcerated mass on the lesser curvature of the stomach. Based on the literature review, we found eight case reports and one cohort study describing the endoscopic appearance of gastric HAS. Majority of them showed a mass with ulceration (three cases) or infiltrative lesion (two cases) (Table 1).

Table 1 Summary of reported cases on hepatoid adenocarcinoma with their alpha-fetoprotein levels before and after treatment.

Ref.	Age, sex	Gastroscopy findings	AFP pre-treatment (ng/mL)	AFP post-treatment (ng/mL)	Pres-ence of PVT	Treatment	Prognosis (months)
Mahajan et al[19], 2014	60 male	Ulcerated mass - antrum	6590	125	-	Chemotherapy	12
Shen et al[20], 2016	70 male	Mass - antrum	14399	10	-	Chemotherapy, surgery	7
Quino-Florentin et al[21], 2021	44 female	Infiltrative mass - cardia	49800	-	-	Chemotherapy	0
Sun et al[23], 2022	60 male	Mass - body	1210	0	-	Chemotherapy	8
Zhang et al[14], 2022	57 male	Mass - antrum	6998	Normal	Yes	Chemotherapy	12
Bathobakae et al[24], 2024	49 female	Ulcerated mass - body	1252	-	-	Chemotherapy	6
Zhu et al[22], 2024	80 male	Infiltrative mass - body	22195	-	-	Chemotherapy	0.5
Zhong et al[25], 2026	68 male	Mass - antrum	919	8.2	-	Chemotherapy, surgery	14
Li et al[16], 2024	64 male	Mass - cardia	52951	9	-	Chemotherapy, immunotherapy, surgery	6
This case	75 male	Ulcerated mass - body	889200	-	Yes	Chemotherapy, immunotherapy	0.5

AFP: Alpha fetoprotein; PVT: Portal vein thrombosis.

Currently there is no established treatment protocol for HAS[15]. Previous studies used radical resection and platinum-based chemotherapy[15,16] Our patient received fluorouracil leucovorin oxaliplatin, which is also a platinum-based chemotherapy. Our treatment was based on first-line treatment for metastatic gastric cancer with platinum-fluoropyrimidine doublet[17]. Oxaliplatin is the most used platinum drug. Nivolumab was added as part of the immunotherapy regimen. The patient had a low HER2 status, so HER2-targeted therapy (trastuzumab) was not used. Unfortunately, the patient did not tolerate the treatment despite dose reduction due to frailty.

Most cases of gastric HAC were reported from China, Japan and Korea. To our knowledge, this is the only case report of HAS from Australia. In 2022, there were two cases of metastatic HAC of unknown primary origin reported from Australia with unremarkable endoscopic findings[18].

In many reported cases, serum AFP has been used as a marker not only to aid diagnosis but also for monitoring treatment response (Table 2). Reduction in AFP levels following treatment was documented in six out of nine cases[19,20]. Markedly elevated AFP levels also appeared to be associated with a poorer prognosis. However, this requires further validation in larger cohort studies. Consistent with reports from Peru and China, our patient had a markedly elevated AFP level of 889200 ng/mL, and all of them died shortly after commencing treatment[21,22]. According to Yang et al[3], a high preoperative serum AFP level is an independent risk factor for overall survival. Based on our review of previous cases, a low serum AFP level is generally associated with better survival. However, this requires confirmation in long-term studies.

Table 2 Serum alpha-fetoprotein levels and treatment response.

Ref.	Initial AFP levels	Treatment and duration	Post-treatment AFP levels
Mahajan et al[19], 2014	6590	Radical gastrectomy, 6 months of chemotherapy: 5-fluorourcil and cisplatin	125
Shen et al[20], 2016	14399	Neoadjuvant therapy with 2 cycles of chemotherapy: Oxaliplatin and capecitabine, followed by gastrectomy and resection of left lobe of liver	10
Yoshizawa et al[26], 2017	1214	Emergency laparotomy with distal gastrectomy, cholecystectomy and reconstruction using Billroth II, followed by chemotherapy with S-1 (tegafur/gimeracil/oteracil)	Normalised (author didn’t specify the value)
Zhang et al[14], 2022	6998	6 cycles of docetaxel, oxaliplatin, tegafur gimeracil, followed by 3 cycles of oteracil potassium capecitabine	Normalised (author didn’t specify the value)
Sun et al[23], 2022	1210	One cycle of chemotherapy: Oxaliplatin and S-1. 11 cycles of sintilimab	0
Zhong et al[25], 2026	919	Billroth II gastrectomy, right hemihepatectomy, adjuvant chemoradiotherapy (capecitabine)	14
Li et al[16], 2024	52951	Neoadjuvant therapy with chemo-immunotherapy: Oxaliplatin, S-1, sintilimab and laparoscopic total gastrectomy with lymph node dissection	9

AFP: Alpha-fetoprotein.

Strengths and limitations

The strength of this case lies in its rarity and educational value, highlighting the need for clinicians to consider HAS as a differential diagnosis in addition to HCC when evaluating patients with very high AFP levels. The case is limited by its single-patient nature and the limited evidence regarding treatment efficacy due to the short follow-up duration.

CONCLUSION

Markedly elevated AFP levels should prompt physicians to evaluate for uncommon causes including HAS. Gastroscopy is a crucial diagnostic step. A low serum AFP level is generally associated with better survival, but long-term studies are required to confirm this.