Hepatocellular carcinoma is the third most common cause of cancer death worldwide. Resection, liver transplantation, and ablation are the only potentially curative treatments. However, HCC is frequently accompanied by underlying liver disease, and multifocal disease additionally limits surgical options. Currently, the only approved systemic therapies for HCC are sorafenib and regorafenib, which are only beneficial with good liver function and which infrequently induces a measurable response [
Spontaneous regression of tumors is rare, estimated to occur in 1 in 60,000–100,000 patients [
A 79-year-old Chinese female with chronic hepatitis C was referred for assessment of a liver mass. The patient was asymptomatic with no signs of decompensated liver disease. Her only comorbidity was well-controlled essential hypertension, for which she took valsartan 80 mg once daily. It was not clear from the history when she had started taking valsartan. She denied taking any specific herbal remedies. She was a nonsmoker and had no history of excess alcohol ingestion.
Her physical examination on admission was unremarkable. Her liver edge was nontender and palpable 2 cm below the right costal margin. There were no stigmata of chronic liver disease. Liver enzymes and function tests were in the normal range: (bilirubin 8
Spontaneous regression of HCC. (a) Serial changes in AFP levels (expressed as Log 10) over 18 months of follow-up and the time points of CT-scans. (b) A 4 × 4 cm liver lesion and bilateral lung lesions. (b) CT scan two months after diagnosis: the liver lesion has diminished in size (2.5 × 1.5 cm), and the lung lesions are barely visible. (c) CT scan at 17 months. The
The patient was given a clinical diagnosis of hepatocellular carcinoma (HCC) with probable pulmonary metastases. She declined a liver biopsy. The disseminated state of her disease precluded ablative treatments and, because of her advanced age and frailty, she was not considered a candidate for chemotherapy.
At two months, the patient did not experience a decline in her condition, and a follow-up CT was done. The lung lesions had completely disappeared, and there was a significant decrease in the size of the primary liver lesion (Figure
We report a case of SR of HCC, which ultimately led to progression following a long period of stability in a patient who was otherwise unable to receive conventional treatments due to frailty. The case raised a number of questions, including whether there are any specific clinical features of patients who have experienced an SR; what the underlying mechanism is; whether the angiotensin receptor blocker valsartan could have contributed to the SR; and how durable an SR is in reported cases. To address these questions, we performed a review with a literature search across five databases; EMBASE, PubMed, Medline, Cochrane Library, and CINAHL. The MeSH keywords employed for the search were a hepatocellular carcinoma, spontaneous regression, cancer regression, and outcome. The search included the following dates of publication: CINAHL, 1962 to present; EMBASE, 1974 to present; Cochrane Library of Systematic Reviews, 1999–February 2017; PubMed, no data date limits available; and MEDLINE, 1946–February 2017. Papers were excluded if any treatment directed at the HCC was administered before documented regression. We analyzed all case reports of SR of HCC in the English literature, which included 89 papers reporting 106 cases. The clinical characteristics of SR and the related long-term outcomes were extrapolated.
The clinical features of 106 cases were studied in detail and are summarized in Supplementary Table
In cases reviewed, a number of putative mechanisms underlying SR of HCC have been proposed (Table
Putative mechanisms of spontaneous regression of HCC reported in the literature.
Putative mechanisms of SR | References |
---|---|
Inflammatory or immune mechanism: spontaneous, concomitant infection or inflammatory condition, abscopal effect, blood transfusion | [ |
Vascular compromise: rapid growth, vascular compression, drug effect, severe dehydration | [ |
Metabolic: weight loss, improved diabetic control | [ |
Miscellaneous or unknown drug effects: antidepressants, androgens/estrogens | [ |
Complementary and alternative medicine | [ |
Idiopathic | [ |
SR has been most commonly attributed to a robust immune response against tumor. Perhaps the best evidence for any role in tumor immunity is the association of SR with the withdrawal of immunosuppressants [
Another plausible mechanism identified in cases is a vascular compromise. Tumors such as HCC with high metabolic rates are susceptible to SR in conjunction with a sudden fall in hepatic blood flow including rapid growth [
Herbal and complementary medicines have been associated with some cases of SR. Vide infra and a mixture of Aloe arborescens, as well as Phellinus linteus, were associated with cases of SR, but the underlying mechanisms were unknown [
As far as we are aware, there have not been other cases of SR associated with angiotensin receptor blockade. The fact that both primary and metastatic sites regressed suggests that some kind of systemic effect had occurred. Admittedly, it would be highly speculative of us to attribute our case of SR to angiotensin receptor blockade. On the other hand, there is some evidence that angiotensin receptor blockade has a potentially antineoplastic effect. The role of the renin-angiotensin system (RAS) in the homeostasis of sodium, water, and potassium is well understood. In addition to the circulating RAS, there are tissues containing a local RAS, including cancers. Central to this is the role of angiotensin II, the ligand for the angiotensin receptors (AT1 and AT2). Signalling through the AT2 receptor seems to inhibit cancer progression. Du et al. demonstrated that AT2 receptor overexpression regulates proliferation of hepatocellular carcinoma cells
In the 66 cases of SR treated nonsurgically, median progression-free survival was 51 months (mo). Median overall survival of the 66 patients who had an SR but no additional treatment was 83 mo. Survival curves are depicted in Figure
Long-term survival outcomes documented in cases of spontaneous regression of HCC that were treated nonsurgically, based on cases appearing in the English literature. (a) Kaplan–Meier curve, progression-free survival. (b) Kaplan–Meier curve, overall survival.
SR is a rare phenomenon. Further studies are required to provide plausible data to identify a potential cause for SR of HCC, which is associated with excellent long-term survivals. To identify a potential mechanism of SR will be challenging. One potential means to do this is to routinely bank tissues (blood and tumor) of all cases of HCC before diagnosis and to obtain post-SR samples if they appear. Of course, due to the rare incidence of SR, obtaining such samples would represent a fortuitous event.
Spontaneous regression
Hepatocellular carcinoma
Alpha-fetoprotein
International normalized ratio
Model of end-stage liver disease
Tumor necrosis factor
Renin-angiotensin system.
This case report has been approved by the Health Research Ethics Board of Alberta (Ethics ID: HREBA.CC-18-0077).
The authors declare that they have no conflicts of interest.
The manuscript was prepared by MBYC, NT, CC, and OFB. Clinical data were provided by FRS and KWB. All authors reviewed and approved the final manuscript. Moaz B. Y. Chohan and Nick Taylor contributed equally to this work.
Table S1: patient’s clinical history organized as a timeline. Table S2: characteristics of patients with spontaneous regression (SR) of HCC. Table S3: resected cases of HCC that regressed spontaneously, with radiographic and pathologic features that demonstrate vascular insufficiency and/or an inflammatory response.