HEH is an extremely rare hepatic tumor with varying biological behavior. Currently, there is no effective indicator to predict the malignancy. For most HEH patients, the tumor progresses slowly with no severe clinical symptoms. Due to the rarity of the disease, HEH patients were commonly misdiagnosed as metastatic carcinoma. Although several studies have reported the radiological characteristics of HEH [16–19], confirmed diagnosis still rely on the pathological examination.
No standard treatment has been established for HEH patients yet. Liver transplantation was reported to be an effective treatment with acceptable long-term outcomes [4, 7, 20, 21]. However, the scarcity of organ donation limits the accessibility of liver transplantation for HEH patients. Surgical resection was another treatment option, but the long-term results were not well [22–24]. Moreover, curative surgery is implausible for most HEH patients because of the multicentricity of the tumor. Studies regarding to chemotherapy, targeted therapy or immunotherapy have been reported, but the results were undetermined [10, 25–32]. Thalidomide as anti-angiogenic therapy has also been reported to control tumor progression, but tumor response has seldom been achieved [8, 33–36].
IFN-a 2b as an immunotherapy has been used for the treatment of hematological malignancies . IFN-a therapy for EH has also been proposed for tumor reduction and metastasis prevention [9, 13, 14]. Kayler et al reported that IFN-α was used for treatment of metastatic HEH after liver transplantation . IFN-a has also been reported to have antiproliferative activity through cancer cell growth inhibition, activation of immune cells, inhibition of vascularization, and induction of cytokines [12, 38].
Since 2014, a total of 42 HEH patients with progressed disease have received the treatment of IFN-a 2b. In this study, PR and CR were observed in 22 patients with an ORR of 52.4%. SD was observed in 12 patients and the DCR was 81.0%. Based on our knowledge, this is the most effective medicine ever reported for HEH patients. Moreover, comparing to previous studies of liver transplantation which reported the 5-year survival rate of 70–83% [4, 7], the HEH patients in this study achieved a 5-year survival rate of 97.2%. Although the median follow-up time was only 33 months in this study, the tendency of better long-term survival could be speculated. Moreover, the safety of long-term treatment with IFN-a 2b was fully verified. The median duration of IFN-a 2b was 19 months and no severe (grade ≥ 3) AE was recorded. Considering the risk of hypothyroidism, serum level of thyroxin should be monitored regularly. The anti-tumor mechanism of IFN-a 2b is not fully investigated or understood, but the encouraging result of this study will provide evidence-based treatment suggestion for HEH patients. Since EH also happens in other organs such as lung and bone, further clinical study could be designed to verify the effect of IFN-a 2b for other EH patients. However, due to the scarcity of EH, inclusion of patients would be a hard long-period work.
There are two major limitations about this study. First, the disease is so rare that the group of HEH patients live across the whole country. For some patients who are very far from our center, they prefer to perform regular blood tests and radiological examination in local medical institution, and send us the images and results, which could lead to the potential inaccuracy of radiological comparison. Second, the IFN-a 2b that the HEH patients used were not from the same pharmaceutical company. They purchased the IFN-a 2b which local medical institution could provide and the dosage was the same. Although there are the limitations we mentioned above, the results of this study still provide valuable clinical evidence for the treatment of HEH.