Androgen-Induced, β-Catenin-Activated Hepatocellular Adenomatosis with Spontaneous External Rupture

Abstract

Androgens have long been recognized as oncogenic agents. They can induce both benign and malignant hepatocellular neoplasms, including hepatocellular adenoma (HCA) and hepatocellular carcinoma, though the underlying mechanisms remain unclear. Androgen-induced liver tumors are most often solitary and clinically silent. Herein, we reported an androgen-induced HCA complicated by spontaneous rupture. The patient was a 24-year-old male presenting with fatigue, diminished libido, radiology-diagnosed hepatocellular adenomatosis for 3 years, and sudden-onset, severe, sharp, constant abdominal pain for one day. He used Aveed (testosterone undecanoate injection) from age 17 and completely stopped one year before his presentation. A physical exam showed touch pain and voluntary guarding in the right upper quadrant of the abdomen. An abdominal CT angiogram demonstrated multiple probable HCAs, with active hemorrhage of the largest one (6.6 × 6.2 × 5.1 cm) accompanied by large-volume hemoperitoneum. After being stabilized by a massive transfusion protocol and interventional embolization, he underwent a percutaneous liver core biopsy. The biopsy specimen displayed atypical hepatocytes forming dense cords and pseudoglands. The lesional cells diffusely stained β-catenin in nuclei and glutamine synthetase in cytoplasm. Compared to normal hepatocytes from control tissue, the tumor cells were positive for nuclear AR (androgen receptor) expression but had no increased EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit) protein expression. The case indicated that androgen-induced hepatocellular neoplasms should be included in the differential diagnosis of acute abdomen.

Keywords: EZH2; androgen; hepatocellualr adenomatosis; liver rupture; β-catenin.

Figure 1

Axial abdominal contrast-enhanced CTT showing the largest hepatocellular adenoma that ruptured with active bleeding.

Figure 2

Histologic changes of the lesions on H&E stain. Lesions on segments 3 (A) and 4B (B) were both composed of uniform hepatocytes with mild cytologic atypia, growing in dense cords with occasional foci of pseudoglandular architecture. Hemosiderin, giant cell reaction, hyalinization, and necrosis in tissue from segment 4B suggested prior embolization therapy (C).

Figure 3

The lesional tissue from segments 3 and 4B shared similar immunophenotypes. The β-catenin immunostains showed diffuse nuclear staining in lesional cells (A), while glutamine synthetase was strongly and diffusely positive (B). Lesional cells were stained negative for glypican-3 (C). Although reticulin stains highlighted patchy foci of disruption and loss (D), CD34 immunostain displayed a patchy sinusoidal pattern of staining (E). C-reactive protein immunostains were negative (F).

Figure 4

Androgen pathway activation in the lesions. AR and EZH2 expression was examined with immunohistochemistry in the lesions ((A) AR, (C) EZH2, respectively) and normal liver tissue ((B) AR, (D) EZH2, respectively). The rare positive signal was distributed in sinusoidal cells in (C). Insets for higher resolution of nuclear staining.