Spontaneous Regression of Hepatocellular Carcinoma after Eradication of HCV

Eric F. Martin1, Michael Huang2, Beatrice Madrazo3 and Cynthia Levy1* 1Division of Hepatology, University of Miami Miller School of Medicine, Miami, Florida, USA 2Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, Florida, USA 3Division of Radiology, University of Miami Miller School of Medicine, Miami, Florida, USA Journal of Gastroenterology, Pancreatology & Liver Disorders Open Access Case Report


Introduction
Hepatocellular Carcinoma (HCC) is the most common cause of primary liver cancer and the fifth most common cancer worldwide.Although early detection and development of therapies for HCC often improve prognosis, the prognosis of untreated, advanced HCC remains poor with a median survival of less than six months.Spontaneous regression of HCC is rare with a reported incidence rate of 1 in 140,000 cases of HCC [1].HCC regression is generally defined as the partial or complete regression of HCC in the absence of specific anti-neoplastic therapy, namely chemotherapy and/or locoregional therapy.The underlying mechanism of HCC regression, however, remains unknown.HCC regression following antiviral therapy for chronic HCV, specifically with sofosbuvir, has not been previously reported.Further understanding of this phenomenon could lead to novel strategies for HCC treatment.We report here one case in this patient before starting sofosbuvir and simeprevir (Figure 1A-C) and after finishing sofosbuvir and simeprevir (Figure 1D-F).Table 1 shows the trend of HCV RNA, AFP, and the size of the liver mass at initial visit, during HCV treatment, and at last visit.

Discussion
Spontaneous regression of HCC is a rare happening, yet the true incidence is difficult to accurately define.Upon reviewing 10 randomized controlled trials including 1640 patients with HCC, Oquiñena et al. [2] estimated the incidence of spontaneous regression of HCC to be 0.4%.The number of cases of spontaneous regression of HCC reported in the literature is higher in HCC than in other malignancies, which likely reflects a higher incidence of HCC compared to other malignancies.Although a large majority of the previously reported cases involves partial regression, few cases describe complete regression of HCC [3].There are even case reports of complete spontaneous regression of HCC with metastasis to the chest wall [4], portal vein tumor [5], and pulmonary metastases [6].In the event of the portal vein tumor thrombus and pulmonary metastases, both patients experienced chronic HCV.To our knowledge, no previous cases of HCC regression coinciding with anti-HCV therapy have been reported.
No evidence exists to support a correlation between the underlying etiology of liver disease and spontaneous regression of HCC.One of the largest and most recent reviews of the literature by Oquiñena et al. [7] included 59 clinical reports of spontaneous regression of HCC.The clinical profile and demographics varied widely in their cohort of patients.A plausible explanation for the pathogenic mechanism underlying HCC regression was offered in 27 of the 59 cases (46%).Of those identified, ischemia due to hemorrhagic shock or hepatic artery thrombosis was the most commonly detected cause, occurring in 10 of 59 cases (17%  is unknown [3,8].In a more recent systematic review of 75 patients with spontaneous remission of HCC, the cause of regression was attributed to tumor hypoxia in 21 (28%) and systemic inflammatory response in 25 (33%) patients while the cause of HCC regression of the remaining 29 (38%) patients were unknown [9].Recognized causes of tissue hypoxia include spontaneous hepatic artery thrombosis, an occlusive portal vein thrombosis, development of a large arterioportal shunt, angiospasm during angiography, and prolonged hypotension due to massive gastrointestinal bleeding.Tumor hypoxia as a mechanism for HCC regression seems intuitive as it is the basis of established treatment options for HCC, namely Transhepatic Arterial Chemoembolization (TACE) and the oral multiple kinase inhibitor sorafenib.TACE occludes the arterial supply to the tumor, which effectively reproduces the effect of HCC regression that has been reported after spontaneous arterial thrombosis [10][11][12].Likewise, sorafenib relies upon induction of tumor hypoxia due to its anti-angiogenesis effect.It is possible that the presence of an arterioportal shunt near the liver tumor may alter the dynamics of blood flow to the tumor, which is essential for tumor growth.Similar to TACE, tumor infarction due to disruption of the feeding vessel due to subintimal injury and tumor invasion could produce tumor hypoxia leading to tissue necrosis and regression of HCC.Rapid tumor growth, administration of vitamin K, abstinence from alcohol, consumption of herbal medicines, high fevers, and gastrointestinal bleeding have also been suggested as factors causing spontaneous regression of HCC [13].Of note, our patient had no radiographic evidence of an arterioportal shunt or spontaneous hepatic artery or portal vein thrombosis.
Perhaps most compelling are the immunological factors that have been implicated in the spontaneous regression of HCC.For over three decades, it has been proposed that the most important factor in spontaneous regression of cancer is stimulation of the immune process [14].It was previously shown that patients with HCC, particularly those with chronic HCV, had significant impairment in T-cell responses at baseline, which correlated with tumor burden and poor outcome [15].A previous report demonstrated that treatment with activated T-lymphocytes after surgery reduced the recurrence rates of HCC, suggesting that HCC regression may be associated with the host immune response [16].In a cohort of liver transplant recipients, those who achieved eradication of HCV after antiviral therapy achieved restoration of HCV-specific T-cell responses.On the other hand, patients with progressive HCV recurrence after liver transplant that failed antiviral therapy demonstrated declining frequencies of HCVspecific T-cells [17].Similarly, in a cohort of coinfected patients with HCV and HIV who were treated with Highly-Active Anti-Retroviral Therapy (HAART), HCV Ab-reactivity was associated with an inferior virologic response to HAART compared to HCV Ab-negative patients [18].It is possible that HCV lowers CD4+ T-cell recovery through direct pathogenic effect on the lymphocytes.It has also been hypothesized that CD4+ T-cell depletion results from ongoing cell activation and apoptosis drive by HCV [19].The studies present data that strongly support the theory of immune reconstitution following eradication of HCV, which may represent the immunologic trigger associated with spontaneous regression of HCC.

Conclusion
Spontaneous regression of HCC is rarely reported.Its coincidental course with anti-HCV therapy and HCV eradication, however, is new and yet unexplained.Further observational data and analysis of patients with spontaneous regression of HCC are required to build a clinical significance and potentially guide future growth of novel treatment strategies for HCC.

Figure 1 :
Figure 1: Representative images from triple phase CT scan of the liver before starting sofosbuvir and simeprevir (A-C) and after finishing sofosbuvir and simeprevir (D-F).1A.Arterial phase axial image demonstrates a 17mm x 23mm hyperenhancing lesion seen in segment VII (arrow) before starting sofosbuvir.1B.Portovenous phase axial image demonstrates faint perception of lesion's capsule (arrow).1C.Delayed phase axial image reveals wash-out and capsular perception (arrow).1D.Arterial phase axial image now demonstrates a 6mm x 5mm lesion, which has significantly decreased in size from the previous 26mm x 18mm lesion seen 7 months earlier (Figure 1A).A barely perceptible 5mm low attenuation lesion is seen on portovenous phase (1E) and delayed phase (1F).

Table 1 :
).Several other factors, namely inflammation, immunological factors, and reduction in blood supply leading to tumor hypoxia have also been suggested as likely mechanisms behind spontaneous regression of HCC, but the precise pathogenesis The trend of HCV RNA, AFP, and the size of the liver mass at initial visit, during HCV treatment and at last visit.