Spontaneous Regression of Hepatocellular Carcinoma: When the Immune System Stands Up to Cancer

Abstract

pontaneous regression of cancer is rare and has been observed mostly in immunogenic cancers like melanoma. A few cases of spontaneous regression of hepatocellular carcinoma (HCC) have been reported, but the mechanisms of regression have not been elucidated. Here, we report a patient with advanced HCC who experienced spontaneous regression of her tumor and present evidence for a putative immune-mediated mechanism for tumor regression. Case SeriesThe index patient is a 65-year-old female patient with alcohol-associated cirrhosis diagnosed with infiltrative 17 cm HCC with occlusive portal vein tumor thrombus and serum alpha-fetoprotein (AFP) of 40,250 ng/mL (Fig. 1A). Before treatment was initiated, she showed a spontaneous decrease in serum AFP to 250 ng/mL, prompting repeat magnetic resonance imaging, which surprisingly showed complete involution of both the primary tumor and the portal vein tumor thrombus (Fig. 1A). The only (potentially related) intervening event was the receipt of pneumococcal vaccine. Eventually, 1 year after initial diagnosis, the patient received transarterial chemoembolization for a small area of suspected recurrence. The patient is currently asymptomatic with AFP <2 ng/mL (Fig. 1B). Furthermore, under institutional review board approval, we identified 5 other patients among 5,980 patients with HCC treated at our center between 2005 and 2020 (Table 1) who had experienced sustained spontaneous regression of very large HCC or even of metastatic HCC.

Spontaneous regression of lung metastases after transarterial chemoembolization for hepatocellular carcinoma

“…Arjunan et al. [6] recently reported that a patient with HCC showing spontaneous regression showed altered immunological subsets including extremely high CD16+ NK cell and CD16+ monocyte levels and strongly suggested host-immune participation for the tumor regression in HCC. At 3 months after TACE with RFA, percentages of CD16+ NK cells and CD16+ monocytes, assayed by flow cytometry, were extremely high in this case, which was consistent with their report [6] .…”

“…However, spontaneous cancer regression has been sporadically described in various cancer types and defined as partial or complete disappearance of a malignant tumor without specific treatments [1] . Spontaneous regression of hepatocellular carcinoma (HCC) has also been reported [2] , [3] , [4] , [5] , though extremely uncommon and reported as 0.1%-0.4% [3 , 6] . Several reports [7] , [8] , [9] , [10] described that spontaneous regression of lung metastases of HCC.…”

Spontaneous Immune-Mediated Regression of Hepatocellular Carcinoma With High Tumor Mutational Burden

“…Indeed, a recent case report implicated enrichment of CD16+ NK cells in one patient with advanced HCC that spontaneously regressed. 6 Our patient's tumor exhibited a high TMB (Table 1). TMB is at least partially independent from other immunotherapy biomarkers-such as programmed death-ligand 1 11 and microsatellite instability 12 -and is associated with a primed immune system that is poised to respond to immune checkpoint inhibition in multiple cancer types.…”

“…There have been several case reports and case series demonstrating radiographic and/or pathologic evidence of spontaneous HCC regression, even at an advanced stage and sometimes completely. 6 , 8 In those instances, there was no documentation or report of the TMB status. The assembled case series that document such regression have often invoked inflammatory stimuli or other systemic or physiologic perturbations to explain the antitumor effect.…”

“…One such recent case report described a series of six patients who experienced varying degrees of HCC tumor regression, one of whom had potentially unique features of the immune microenvironment. 6 Here, we report a patient who experienced a spontaneous regression of an HCC lesion bearing a high tumor mutational burden (TMB) with a brisk-associated lymphocytic infiltrate noted on a preoperative biopsy. We therefore propose a direct mechanism—immune recognition and clearance of a TMB-high tumor, with an unclear stimulus for such antitumor activity—that may underlie rare cases of spontaneous HCC regression.…”