Now You See It, Now You Don't!—Spontaneous Complete Necrosis and Reappearance of Hepatocellular Carcinoma

Abstract

Spontaneous regression of hepatocellular carcinoma (HCC) is a rare phenomenon caused by complex multifactorial mechanisms. We report the case of a 76-year-old male with a history of chronic liver disease and HCC who experienced complete spontaneous tumor regression followed by recurrence. The regression may have been triggered by ischemia from portal vein thrombosis and systemic inflammation. Key mechanisms behind spontaneous regression include tumor hypoxia and immune responses. This case highlights the complexity of spontaneous regression and its potential role in developing novel cancer therapies.

Keywords

ischemia - hypoxia - cirrhosis - thrombus - cytokine - immune

Introduction

Spontaneous tumor regression is a rare phenomenon, occurring in approximately 1 in 60,000 to 100,000 tumors.[1] It has been observed in benign and malignant tumors, including metastatic deposits.[2] The majority of reported cases involve renal cell carcinomas, choriocarcinomas, melanomas, and neuroblastomas.[3] Accounts describing its incidence in hepatocellular carcinoma (HCC) are extremely rare, with only approximately 100 cases documented till date. Here, we present an interesting case of complete spontaneous regression of HCC, followed by recurrence during follow-up.

Case Report

A 76-year-old male with a history of metabolic dysfunction-associated steatotic liver disease-related cirrhosis, diagnosed in 2020, presented to the outpatient department with complaints of fatigue, decreased sleep, and reduced appetite over the past month. There was no history of weight loss, abdominal distension, vomiting, or melena. The patient also had a prior history of small, low-risk esophageal varices. His personal history was unremarkable for addictions or the use of alternative medications.

Laboratory investigations revealed a low platelet count of 117 × 10^3/µL (normal range: 150–450 × 10^3/µL), along with an elevated erythrocyte sedimentation rate of 41 mm/h (normal range: 0–15 mm/h). Hemoglobin and leukocyte counts were within normal limits. Prothrombin time (PT) was mildly prolonged, with an international normalized ratio (INR) of 1.42 and a PT of 18.7 seconds (normal range, PT: 12.6–14.5 seconds, INR: 0.8–1.08). Liver and kidney function tests were largely unremarkable, except for elevated alkaline phosphatase (168 U/L, normal range: 46–116 U/L) and gamma-glutamyl transferase (198 U/L, normal range: 0–73 U/L). Additionally, serum α-fetoprotein (AFP) was elevated at 187.5 ng/mL (normal range: 0–8.1 ng/mL).

Serological assays done to rule out other causes of chronic liver disease (CLD) were negative for viral and autoimmune markers. The patient had a Model for End-Stage Liver Disease score of 11 and was classified as having Child–Pugh class A status (5 points).

In view of the elevated AFP levels, an ultrasound examination was performed, confirming the presence of CLD and identifying a well-defined focal lesion in the right lobe of the liver. No ascites were observed. A triphasic computed tomography (CT) scan of the abdomen was then performed, which revealed a 5.2 × 5.0 × 5.1 cm sized arterial phase-enhancing lesion in the segment VII of the liver, exhibiting washout on the venous and delayed phase images, consistent with a LIRADS-5 (Liver Imaging Reporting and Data System) lesion ([Fig. 1]). No evidence of portal vein thrombosis (PVT) or extrahepatic spread was noted on the CT scan. A diagnosis of CLD with HCC (Barcelona Clinic Liver Cancer stage A) was made. Due to financial constraints, the patient declined liver transplant. Thus, an elective transarterial chemoembolization (TACE) procedure was planned for him 2 weeks later.

Fig. 1 Images from the contrast-enhanced computed tomographic (CT) scan of abdomen of the patient. Arterial phase axial (A) and coronal (B) images showing a well-defined arterial phase enhancing lesion in the right lobe of the liver (solid arrows). The lesion shows washout of contrast on the subsequent venous (C) and equilibrium (D) phase images (dashed arrows).

Two days prior to the scheduled TACE procedure, the patient got admitted to the hospital with right upper quadrant pain, low-grade fever, and mild abdominal distension. Liver function tests revealed new-onset jaundice, with a total bilirubin level of 11.3 mg/dL. Ultrasonography showed minimal ascites with mild increase in the size of the HCC. Consequently, a contrast-enhanced CT scan of the abdomen was scheduled for further investigation. The CT scan revealed an increase in the size of the liver lesion to 6.1 × 5.5 × 5.5 cm, with complete loss of arterial phase enhancement ([Fig. 2]). Additionally, there was development of occlusive nonenhancing bland thrombosis involving the right and left portal vein branches ([Fig. 3]), part of main portal vein as well as partial nonocclusive thrombus in the intrahepatic part of the inferior vena cava (IVC). Branches of right hepatic artery supplying the segment VII of the liver (which had the lesion) were patent. The scan also showed mild perihepatic fluid accumulation. AFP levels at this time had decreased to 94 ng/mL. Inflammatory marker C-reactive protein was elevated at 114 mg/dL (normal value: 0–5) and serum procalcitonin was also mildly raised at 1.03 ng/mL (normal value: < 0.5). As a result, the planned TACE procedure was cancelled and the patient was started on intravenous antibiotics along with other supportive measures.

Fig. 2 Axial (A) and coronal (B) images from the follow-up computed tomographic (CT) scan of the patient showing complete lack of arterial phase enhancement within the previously seen lesion (solid arrows) with interval appearance of mild perihepatic free fluid (dashed arrow in A).

Fig. 3 Axial images from the follow-up computed tomographic (CT) scan of the patient showing occlusive thrombus in the right and left branches of the portal vein (solid arrows in A). The thrombus shows complete resolution on the subsequent follow-up scan (arrow in B).

The details of the blood investigations conducted both prior to and following the hospital admission are summarized in [Table 1].

Table 1 Laboratory parameters of the patient before and after admission

Variables	Preadmission value (normal range)	Postadmission value (normal range)
Total bilirubin (mg/dL)	1.2 (0.3–1.2)	11.3 (0.3–1.2)
Direct bilirubin (mg/dL)	0.42 (0–0.3)	8.2 (0–0.3)
Indirect bilirubin (mg/dL)	0.78 (0.2–0.9)	3.09 (0.2–0.9)
Albumin (g/dL)	4.1 (3.5–5.2)	3.3 (3.5–5.2)
Alanine aminotransferase (ALT) (U/L)	29 (10–39)	81 (10–39)
Aspartate aminotransferase (AST) (U/L)	82 (0–34)	155 (0–34)
Alkaline phosphatase (U/L)	168 (46–116)	377 (46–116)
Creatinine (mg/dL)	0.9 (0.7–1.3)	0.8 (0.7–1.3)
C-reactive protein (mg/dL)	(0–5)	114.5 (0–5)
AFP (ng/mL)	187.5 (0–8.1)	90.3 (0–8.1)
INR	1.42 (0.9–1.08)	1.46 (0.9–1.08)
Hemoglobin (g/dL)	15.7 (13–16)	13.5 (13–16)
Total leukocyte count (× 10^3/uL)	8.1 (4–11)	8.4 (4–11)
Platelet count (× 10^3/uL)	117 (150–450)	97 (150–450)
Procalcitonin (ng/mL)		1.03 (< 0.5)
Lactate dehydrogenase (U/L)		295 (125–220)

Abbreviations: AFP, α-fetoprotein; INR, international normalized ratio.

The patient's abdominal pain and fever subsided within a day after admission and he was subsequently discharged and placed on outpatient follow-up. During the follow-up 1 month later, the patient was asymptomatic but the AFP levels had increased significantly to 418 ng/mL, prompting a repeat CT scan. The scan revealed a recurrence of HCC, with a 4.2 × 4.1 × 4 cm lesion showing nodular areas of arterial enhancement at the periphery and washout in the venous phase ([Fig. 4]). The bland thrombus within the portal vein and IVC had completely resolved ([Fig. 3]). The patient was advised to undergo a TACE procedure but refused due to financial constraints and was lost to follow-up.

Fig. 4 Arterial phase axial (A) and coronal (B) computed tomographic (CT) scan images showing interval appearance of nodular enhancing areas (solid arrows) in the periphery of the necrosed lesion. Contrast washout is seen on axial (C) and coronal (D) equilibrium phase images (dashed arrows).

Discussion

Spontaneous regression of a tumor refers to its partial or complete disappearance without any medical intervention. This phenomenon can occur simultaneously in both the primary tumor and its metastases, or at different times. Various factors have been associated with spontaneous tumor regression, including the use of herbal medications, high-grade fever resulting from infections, withdrawal of potential causative agents such as alcohol, tobacco, or exogenous androgens, immune responses, compromised blood supply, vascular injury from angiography, the abscopal effect of radiation, and rapid tumor growth.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Exact mechanism behind spontaneous tumor regression is complex and multifactorial. However, two key mechanisms that have been implicated are tumor hypoxia and the activation of the systemic inflammatory response.[13]

Occlusion of the hepatic artery or portal vein can directly impact the blood supply to HCC, potentially leading to ischemic injury and subsequent tumor regression. Additionally, severe hypoperfusion resulting from any cause of bleeding, particularly variceal bleeding in patients with CLD, may also induce tumor ischemia.[13] This ischemic mechanism is the basis for TACE in the treatment of HCC.[17] Overall tumor size may also increase after ischemic injury due to the associated inflammatory response.

Tumor hypoxia alone cannot account for the majority of cases of tumor regression, particularly in instances involving metastatic tumors, as systemic inflammation plays a significant role as well. Studies have shown elevated cytokine levels in patients experiencing spontaneous regression of HCC, with increased levels of interleukin (IL)-2, IL-6, IL-12, and interferon-gamma observed throughout the course of regression in certain individuals.[13] [18] [19] Resected HCC specimens with lymphocytic infiltration tend to have a better prognosis compared with those without such infiltration.[20] Various factors in the tumor microenvironment, such as matrix metalloproteinases, inhibit cancer cell proliferation and activate the immune system, particularly through natural killer cells, which in turn induce apoptosis and promote tumor regression.[2] These principles are also applied in immunotherapy for HCC, using approaches such as cytokine therapy, tumor-associated antigen therapy, immune checkpoint inhibitors, and cell transfer immunotherapy.

Malignancy is known to induce a hypercoagulable state, increasing the risk of venous thromboembolic complications in patients. This is attributed to the overexpression of tissue factors, excessive platelet activation due to cancer-associated procoagulant proteins, and the increased release of cytokines.[21] HCC often develops in the context of liver cirrhosis. The fragile and imbalanced hemostatic environment in liver cirrhosis can easily be disrupted, shifting toward a thrombotic state, particularly when conditions like HCC are superimposed.[22] [23] [24] [25] [26] PVT is the most common thrombotic complication in cirrhotic patients with HCC, with a 1-year incidence ranging from 7.4 to 24%.[22] Studies have reported higher platelet counts in cirrhotic patients with HCC compared with those without HCC, particularly in patients belonging to Child–Pugh class A.[26] [27] [28] [29]

In our case, newly developed PVT and IVC thrombosis, along with ascites and sudden increase in the overall tumor size (resulting in it outgrowing its own blood supply), may have caused hypoxic injury to the tumor, potentially leading to its spontaneous regression. Systemic inflammation, possibly a consequence of or contributing to the hypoxic insult, could also have played a role in the spontaneous resolution of the tumor, as evidenced by raised inflammatory markers and presence of fever in the patient.

The clinical response and long-term outcomes following spontaneous resolution of HCC are not well described. In our case, tumor recurrence was observed on a follow-up scan within 45 days, though the patient did not show any clinical deterioration. The available literature on this topic is limited, with survival rates varying widely, ranging from 2 to 240 months, and a median survival of 45 months.[6]

Conclusion

Spontaneous regression, although extremely rare, has been observed in HCC and uncovering its underlying mechanisms could pave the way for novel treatment approaches. Tumor hypoxia and systemic inflammation are key factors in this process, although the precise mechanism is complex and multifactorial.

Conflict of Interest

None declared.

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Publication History

Article published online:
02 April 2025