Reappraisal of Hepatocellular Adenoma from Federal Health System, Rio de Janeiro, Brazil

Background: Hepatocellular adenoma is a rare liver tumor that may require surgical treatment in cases of hemorrhage or suspicion of malignant lesions. Aim: To analyze data from patients who underwent hepatectomy for hepatocellular adenoma (HCA) in Rio de Janeiro, Brazil. Methods: From January 2005 to March 2019, sixty-nine patients with HCA underwent hepatectomy at centers in Rio de Janeiro. They were included in the analysis patients undergoing hepatectomy with pathological diagnosis of hepatocellular adenoma and excluded patients with hepatectomy with anatomopathological diagnosis other than hepatocellular adenoma, mainly nodular focal hyperplasia. Data related to patients, tumor and surgery were analyzed retrospectively. Results: Sixty patients (87%) were female and nine were male. Among women, 83% had a history of contraceptive use;among men, only one had an androgen intake history. Overall mean age was 36.4 years (15 - 49), with men older than women (33.9 ± 8.14 years vs. 40.4 ± 6.27 years;P = 0.02). Forty one patients reported abdominal pain, associated or not to other symptoms;32% had an episode of hemorrhage;28 were asymptomatic with an incidental radiological finding. In total, 45 patients presented only one lesion and overall mean size was 8.1 cm (2 - 31);tumors were larger among men (mean size 12.9 ± 9.86 cm vs. 7.7 ± 4.58 cm;P = 0.009). Twenty one surgeries were laparoscopic. Hepatocellular carcinoma (HCC) was identified in three specimens and the incidence was higher among men (22.2% vs. 1.6%;P = 0.042) and in tumors larger than 20 cm (66.6% vs. 0.02%). There was no perioperative mortality. Two of the three patients with HCC died with extrahepatic recurrence;the remaining patient is well after 36 months. Overall mean follow-up time was 14.2 months (2 - 76). Conclusion: Male patients with HCA were older and had larger tumors when compared to females. Incidence of HCC was higher among men and in lesions larger than 20 cm. Male patients with HCA should be treated more aggressively than females.

HPV18 Utilizes Two Alternative Branch Sites for E6*I Splicing to Produce E7 Protein

Human papillomavirus 18(HPV18) E6 and E7 oncogenes are transcribed as a single bicistronic E6 E7 pre-mRNA. The E6 ORF region in the bicistronic E6 E7 pre-mRNA contains an intron. Splicing of this intron disrupts the E6 ORF integrity and produces a spliced E6*I RNA for efficient E7 translation. Here we report that the E6 intron has two overlapped branch point sequences(BPS) upstream of its 30 splice site, with an identical heptamer AACUAAC, for E6*I splicing. One heptamer has a branch site adenosine(underlined) at nt 384 and the other at nt 388. E6*I splicing efficiency correlates to the expression level of E6 and E7 proteins and depends on the selection of which branch site. In general, E6*I splicing prefers the 30 ss-proximal branch site at nt 388 over the distal branch site at nt 384. Inactivation of the nt 388 branch site was found to activate a cryptic acceptor site at nt 636 for aberrant RNA splicing. Together, these data suggest that HPV18 modulates its production ratio of E6 and E7 proteins by alternative selection of the two mapped branch sites for the E6*I splicing, which could be beneficial in its productive or oncogenic infection according to the host cell environment.