Introduction

Gastric cancer (GC) is among the most lethal malignancies worldwide and represents a major global public health concern. According to recent data from the Global Cancer Observatory (GLOBOCAN), GC remained the fifth leading cause of cancer-related mortality in 2022¹. Projections for 2040 estimate more than 1,300,000 deaths and 1,800,000 new cases². Chronic infection with Helicobacter pylori is responsible for at least 80% of gastric cancers worldwide³, including approximately 90% of non-cardia (distal) tumors and 50% of cardia (proximal) tumors^4,5. GC can be classified as cardia or non-cardia, each exhibiting distinct epidemiological and clinical characteristics. Cardia GC is associated with genetic factors, the diffuse histotype, and reduced survival, reflecting more aggressive biological behavior and diagnosis at advanced stages. In contrast, non-cardia GC predominantly exhibits the intestinal histotype. It typically arises in the antropyloric region, is strongly associated with environmental factors, demonstrates improved prognosis when detected early, and shows higher prevalence of chronic H. pylori infection^6-9. According to the Lauren and Jarvi classification, GC is categorized as intestinal or diffuse based on clinical and epidemiological features.

The intestinal type is more frequent in men and older populations, predominantly involves the antropyloric region, and is strongly associated with environmental risk factors, including suboptimal public health conditions, water sanitation deficiencies, chronic H. pylori infection, and premalignant conditions described in Correa’s cascade^10,11. The diffuse histotype is more common in women and in younger individuals and is associated with mutations in the CDH1 gene, which encodes E-cadherin. These molecular alterations contribute to carcinogenesis in this tumor subtype. Diffuse-type GC shows limited association with environmental factors and H. pylori infection^10,11. According to the most recent World Health Organization (WHO) classification, the most common histological subtypes include tubular, papillary, poorly cohesive, mucinous, and mixed adenocarcinoma. Within this classification framework, hepatoid gastric adenocarcinoma (HGA) is described as a rare subtype included in the category of hepatoid adenocarcinoma and related entities^12-14. HGA is an uncommon entity, accounting for approximately 0.3%-1.0% of all gastric cancers, and exhibits morphological features highly similar to hepatocellular carcinoma (HCC). This subtype is characterized by high short-term mortality, as it is frequently diagnosed at advanced stages¹⁵.

This report presents the clinical case of a 68-year-old male patient diagnosed with hepatoid adenocarcinoma with adenosquamous overlap. The diagnosis represented a significant challenge and was ultimately clarified through immunohistochemistry. In addition to describing the fundamental features of this histopathological subtype, the present report highlights its low incidence and possible tumor histogenesis.

Case description

A 68-year-old male patient presented to the emergency department with progressive dysphagia initially affecting solid foods and later liquids, with long-standing progression. The patient also reported anorexia and severe weight loss of 20 kg over a three-month period. At the time of consultation, he presented with intermittent burning epigastric pain without radiation and three episodes of coffee-ground emesis occurring eight hours prior to admission. No relevant personal or family medical history was reported. Physical examination revealed a hemodynamically stable patient with marked wasting of adipose and muscle tissue, mucocutaneous flaccidity, anorexia, and kwashiorkor-type malnutrition. No additional abnormalities were identified on physical examination. Upper gastrointestinal endoscopy revealed a protruding and ulcerated lesion (Bormann type IV), from which biopsy samples were obtained.

Histopathological evaluation described a strongly eosinophilic tumor arranged in a rosette-like pattern, mimicking hepatoid, squamous, and neuroendocrine differentiation (Figure 1). Immunohistochemical analysis demonstrated strong positivity for HepPar-1 and moderate positivity for alpha-fetoprotein (AFP), CK7, and Ki-67, with negative expression for SALL-4 (sal-like protein 4), findings that confirmed hepatoid differentiation (Figure 2). Computed tomography (CT) scans of the abdomen and chest were performed as part of staging studies, revealing hepatic and retroperitoneal metastases as well as peritoneal carcinomatosis. Given the patient’s clinical condition, the multidisciplinary tumor board referred the patient for comprehensive management by Clinical Oncology, Nutrition, Psychology, and Palliative Care. After six months of multidisciplinary management, the patient died due to cardiorespiratory arrest.

Figure 1 Histopathological description of the tumor. A and B. The images show a strongly eosinophilic tumor arranged in a rosette-like pattern with cells resembling hepatocytes. Images obtained from the archives of the Department of Pathology, Fundación Hospital San Pedro. 

Figure 2 Tumor immunohistochemistry. A, B, C, and D. The slides show strong immunoreactivity for HepPar-1 and alpha-fetoprotein (AFP), confirming hepatoid differentiation. Immunohistochemical staining for cytokeratins (CK7) and Ki-67 was also performed. Images obtained from the archives of the Department of Pathology, Fundación Hospital San Pedro. 

Discussion

This case is noteworthy because this rare histological subtype may be confused with other uncommon tumor types within the WHO classification and may also overlap with metastatic hepatocellular carcinoma (HCC) due to its similar histopathological architecture. As in the present case, overlap with adenosquamous carcinoma may occur, representing a significant diagnostic challenge. Immunohistochemistry plays a crucial role in clarifying cellular lineage and establishing an accurate diagnosis, as conventional histopathological evaluation using hematoxylin and eosin staining may be insufficient to definitively determine tumor origin and biological nature. Diagnostic uncertainty may negatively affect diagnostic timing and prognosis due to the aggressive biological behavior of this tumor subtype.

The incidence of HGA ranges between 0.3% and 1.0% of all gastric tumors. Hepatic metastases and increased peritoneal dissemination occur in 46.3%-75.6% of patients with HGA^15-17. A recent systematic review by Ling et al.¹⁸ reported low three-year overall survival (hazard ratio [HR]: 3.21; 95% confidence interval [CI]: 1.54-6.67; p = 0.002). The most common clinical manifestations include abdominal pain, epigastric discomfort, hematemesis, and melena¹⁹. HGA demonstrates low incidence but high diagnostic complexity and aggressive biological behavior, with marked propensity for vascular invasion and early metastasis, particularly to the liver (97.3%) and peritoneum (35.3%)²⁰. Less frequent metastatic sites include the lungs, spleen, and brain¹⁸.

Given the inherent limitations of conventional hematoxylin and eosin histopathology, accurate diagnostic confirmation requires immunohistochemistry. Immunohistochemical characterization is the cornerstone of correct tumor identification, as macroscopically HGA resembles a Bormann type III-IV tumor with poor differentiation. Histopathological evaluation demonstrates morphology similar to hepatocellular carcinoma, characterized by large eosinophilic cells arranged in trabecular architecture or solid nested patterns separated by sinusoidal vascular channels^21,22. Immunohistochemical markers with the highest specificity include HepPar-1 for determining tumor lineage and cellular differentiation. Increased mismatch repair (mMR) protein proficiency has been reported. Positive expression of alpha-fetoprotein (AFP) and transcription factor SALL-4 (Spalt-like transcription factor 4) has also been described. Overexpression of HER2 and negative expression of EBER (Epstein-Barr virus-encoded small RNA) have been observed. The molecular profile of HGA is characterized by negative EBER expression and mMR status, whereas AFP and SALL-4 expression support definitive diagnosis²³. In the present case, immunohistochemistry showed positive expression for HepPar-1 and AFP.

Genetic mutations reported in this tumor subtype include DK12, MYC, OCT4-pg1, HUWE1, and MYCBP2²⁰. Functional MYC overactivation induces hepatoid differentiation through the influence of pluripotent stem cells, a mechanism that contributes to tumor clonality and poor prognosis¹⁸.

The therapeutic approach to HGA is based primarily on surgical management and comprehensive perioperative treatment; however, prognosis remains poor despite adherence to current therapies. These findings underscore the importance of early and accurate diagnosis to guide appropriate treatment strategies^20,24-26. Further research is required to characterize the molecular pathology of HGA, identify novel biomarkers for targeted therapy, and improve treatment strategies. Potential therapeutic targets such as ERBB2, FGFR2, MET, and HGF appear promising²⁷.

Conclusions

HGA is a rare and aggressive clinical entity that represents both a diagnostic and therapeutic challenge. Immunohistochemistry is essential for confirming the diagnosis using markers such as AFP (64%), HepPar-1, GPC3, and SALL4. HGA is typically diagnosed at advanced stages and demonstrates aggressive biological behavior, with high incidence of hepatic and peritoneal metastases.