|Year : 2020 | Volume
| Issue : 7 | Page : 1710-1713
Spontaneous regression of recurrent hepatocellular carcinoma with multiple lung metastases
Zhao Liu1, Jian-Wei Zou1, Wei-Li Wang2, Zhi Li1
1 Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
2 State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou, Jiangsu, China
|Date of Submission||07-Jun-2020|
|Date of Decision||06-Aug-2020|
|Date of Acceptance||08-Jan-2021|
|Date of Web Publication||9-Feb-2021|
State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu 215 123
Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006
Source of Support: None, Conflict of Interest: None
Spontaneous regression (SR) of hepatocellular carcinoma (HCC) is a rare phenomenon but its true incidence is much higher than expected. We report a recurrent HCC who experienced SR both in intrahepatic lesion and lung metastasis. Serum alpha-fetoprotein decreased dramatically from more than 1000 μg/L to normal range. In addition, we reviewed 11 similar case reports published in recent 5 years. We find that the interval from diagnosis to the recognition of SR is very short (4 m, 1–14 m). Therefore, we speculate the mechanism of SR should be a severe systemic reaction, and immune activation is the most likely conjecture.
Keywords: Hepatocellular carcinoma, spontaneous regression, transcatheter arterial chemoembolization
|How to cite this article:|
Liu Z, Zou JW, Wang WL, Li Z. Spontaneous regression of recurrent hepatocellular carcinoma with multiple lung metastases. J Can Res Ther 2020;16:1710-3
| > Introduction|| |
Spontaneous regression (SR) of malignant tumors was initially defined by Cole and Everson in 1956, as the partial or complete disappearance of a malignant tumor in the absence of any treatment or in the presence of therapy that is considered inadequate to exert a significant influence on neoplastic disease. Although the incidence is extremely low, SR has been reported in almost all malignancies, among which malignant melanoma, neuroblastomas, and renal cell carcinoma are more common.
Hepatocellular carcinoma (HCC) is one of the most malignant cancers that rank the fifth leading cause of cancer-related death in the world. The average survival of advanced HCC with extrahepatic metastasis was only half a year. Transcatheter arterial chemoembolization (TACE) is the widely accepted approach for unresectable HCC. Nevertheless, its main effect is to control intrahepatic lesions, with no therapeutic effect on extrahepatic metastases. Here, we report a recurrent HCC who experienced SR both in intrahepatic lesion and lung metastasis. In addition, we also reviewed 11 similar case reports,,,,,,,,,, published in the recent 5 years.
| > Case Report|| |
A 67-year-old male was admitted to our hospital for liver tumors identified on color Doppler ultrasound during routine physical examination in September 2012. His medical history included type 2 diabetes mellitus and treated with metformin and hepatitis C infection without treatment. There were no abnormalities in laboratory tests except a higher baseline serum alpha-fetoprotein (AFP) (69.07 μg/L). The contrast-enhanced computed tomography (CT) revealed a 25 mm tumor in segment 3 and a 44 mm tumor in segment 6. The tumors were significantly enhanced during the early-phase CT and were washed out during the equilibrium phase. There was no portal vein invasion, no abdominal lymph node metastasis, and no lung metastasis in the initial CT scan. Hepatectomy was performed on September 27, 2012. Histopathological diagnosis was moderately differentiated HCC.
One month after surgery, serum AFP decreased to 24.2 μg/L. Nevertheless, contrast-enhanced abdominal CT revealed multiple abnormally small enhancement lesions in the liver that were highly suggestive of recurrence. TACE was then performed to control the recurrent lesions. Hepatic artery angiography showed multiple small tumor stain in the liver. Chemotherapeutics (40 mg pirarubicin, 100 mg oxaliplatin, and 1000 mg fluorourea) was infused slowly through a microcatheter in the proper hepatic artery. Embolization of the lesions using 4 ml iodized oil was then performed until tumor stain disappeared. Since then, serum AFP continued to increase [Figure 1], and intrahepatic lesions with enhancement persisted on CT or magnetic resonance (MR) scans. Repeated TACE procedures were performed at 4, 7, and 10 months after surgery. The chemotherapy regimen and dosage were the same as the first TACE. The dosage of iodized oil ranged from 2 ml to 6 ml. Tumor stain was on the increase in the angiography of each TACE.
In November 2013 (14 months after surgery), the patient developed bloody sputum during routine follow-up. Chest CT showed multiple metastases in both lungs [Figure 2]. Abdominal enhanced MR imaging (MRI) showed multiple small lesions in the liver. Serum AFP rose to more than 1000 μg/L [Figure 1]. He refused sorafenib and any other treatment options. Discharged weeks later, he took Chinese herbal medicine (Brucea javanica capsule) irregularly. Five months later (19 months after surgery), the patient admitted again. The symptom of bloody sputum disappeared. Surprisingly, chest CT showed that the lung metastasis disappeared completely [Figure 2]. Moreover, no hepatic masses were detected on the abdominal enhanced CT except perfusion disorder. Serum AFP decreased dramatically to normal range (10.9 μg/L) [Figure 1]. The patient refused an abdominal MRI or further treatment and continued to take B. javanica.
|Figure 2: Spontaneous regression of lung metastases. (a-c) CT scans prior to SP. (d-f) CT scans 5 months later. SP: Spontaneous regression, CT: Computed tomography|
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Ten months later (29 months after surgery), the patient was admitted again. Enhanced CT showed a 35 mm new masse in the right lobe of the liver. TACE was then performed. After that, repeated TACE procedures were performed at 39, 49, and 61 months after surgery. The intrahapatic lesions progressed persistently but slowly. He developed portal vein tumor thrombus and ascites eventually and died of hepatic failure in May 2018. The overall survival of this patient was 68 months. Until death, the tumor was only detected in the liver, without any abdominal lymphadenopathy or lung metastasis detected on CT scan. Since SR, serum AFP was always within the normal range despite the intrahepatic recurrence [Figure 1].
| > Discussion|| |
SR of HCC is a rare phenomenon and its true incidence is difficult to determine. Nevertheless, it is much higher than expected. Oquiñena et al. collated data from 10 randomized controlled trials published between 1978 and 2007, involving 1640 patients with HCC. Based on the incidence of regression in the control groups that received the best supportive treatment or placebo, it was calculated to be 0.406%.
In this case, SR occurred at 5 months after the presentation of lung metastasis. The patient refused sorafenib and any other formal treatment. He took B. javanica capsule irregularly. As an auxiliary drug, B. javanica capsule was used in many malignant tumors in China. However, there is no definite evidence supporting its therapeutic effect on HCC. It belongs to the “therapy that is considered inadequate to exert a significant influence on neoplastic disease” in the Cole's definition. Chest CT before and after SR confirms the complete regression of pulmonary metastases. Unfortunately, abdominal contrast-enhanced MR was not performed after SR. The sensitivity of enhanced CT to small HCC is not as high as that of MR. However, serum AFP decreased from more than 1000 μg/L before SR to 10.9 μg/L after SR. AFP response is consistent with imaging response in the evaluation of treatment for HCC. This confirms the SR of intrahepatic lesions.
In our case, serum AFP continued to rise before SR and decreased to the normal range after SR. Despite recurrence occurred 10 months after SR, serum AFP was always within the normal range until the death [Figure 1]. This indicates that the biological behavior of recurrent lesions after SR may be different from that of the original tumors.
The phenomenon of SR indicates that an antitumor mechanism exists in the human body. Further investigation of the SR cases is expected to elucidate the etiology and management of this phenomenon. Nevertheless, it is difficult to accumulate many cases in any center. Case reports and review of case reports may be a good method for the research on this topic. Since SR of a 3-year-old HCC confirmed by biopsy, which was first reported by Johnson et al. in 1972, more than 90 cases with SR of HCC have been reported in the English literature. We reviewed 11 case reports published in recent 5 years and our case. The main information is shown in [Table 1].
|Table 1: Clinical characteristics of spontaneous regression of hepatocellular carcinoma|
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Several regularities should be noted from [Table 1]. First, if complete SR achieved in primary lesions, metastases are necessary to regress. However, if metastases regress complete, primary lesions may or may not regress. This could be explained in theory. The genotypes of the metastases come from primary lesions, and the genotypes of primary lesions include and may be more than that of metastases. Second, the interval from diagnosis to the recognition of SR is very short (4 m, 1–14 m). Therefore, the mechanism of SR should be a severe systemic reaction, and immune activation is the most likely conjecture.
In summary, SR of HCC is a rare but existent phenomenon. It is too early to assess its mechanism. Further investigation of this phenomenon is expected to develop a novel treatment approach for HCC.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This work is supported by a grant from “Six one projects” for high-level health personnel of Jiangsu Province (LGY2018077).
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Cole WH, Everson TC. Spontaneous regression of cancer: Preliminary report. Ann Surg 1956;144:366-83.
Sakamaki A, Kamimura K, Abe S, Tsuchiya A, Takamura M, Kawai H, et al
. Spontaneous regression of hepatocellular carcinoma: A mini-review. World J Gastroenterol 2017;23:3797-804.
Zhang HM, Shi YX, Sun LY, Zhu ZJ. Hepatocellular carcinoma recurrence in living and deceased donor liver transplantation: a systematic review and meta-analysis. Chin Med J (Engl) 2019;132:1599-609.
Zuo TY, Liu FY, Wang MQ, Chen XX. Transcatheter arterial chemoembolization combined with simultaneous computed tomography-guided radiofrequency ablation for large hepatocellular carcinomas. Chin Med J (Engl) 2017;130:2666-73.
Chohan MB, Taylor N, Coffin C, Burak KW, Bathe OF. Spontaneous regression of hepatocellular carcinoma and review of reports in the published English literature. Case Rep Med 2019;2019:9756758.
Taniai T, Shirai Y, Shiba H, Sakamoto T, Furukawa K, Yanaga K. Spontaneous pathological complete regression of hepatocellular carcinoma. Case Rep Gastroenterol 2018;12:653-9.
Koya Y, Suzuki T, Tai M, Ichii O, Matsuhashi N, Ejiri Y, et al
. Spontaneous regression of hepatocellular carcinoma with portal vein tumor thrombus. Case Rep Gastroenterol 2018;12:411-9.
Goto Y, Uchino Y, Sasaki S, Shirahama N, Nomura Y, Akiba J, et al
. Complete spontaneous necrosis of hepatocellular carcinoma accompanied by portal vein tumor thrombosis: A case report. Int J Surg Case Rep 2018;44:220-5.
Alam MA, Das D. Spontaneous regression of hepatocellular carcinoma-a case report. J Gastrointest Cancer 2017;48:194-7.S
Noij DP, van Der Linden PW. Spontaneous regression of hepatocellular carcinoma in a Caucasian male patient: A case report and review of the literature. Mol Clin Oncol 2017;6:225-8.
Saito R, Amano H, Abe T, Fujikuni N, Nakahara M, Yonehara S, et al.
Complete spontaneous necrosis of hepatocellular carcinoma confirmed on resection: A case report. Int J Surg Case Rep 2016;22:70-4.
Pectasides E, Miksad R, Pyatibrat S, Srivastava A, Bullock A. Spontaneous regression of hepatocellular carcinoma with multiple lung metastases: A case report and review of the literature. Dig Dis Sci 2016;61:2749-54.
Heron V, Fortinsky KJ, Spiegle G, Hilzenrat N, Szilagyi A. Resected hepatocellular carcinoma in a patient with crohn's disease on azathioprine. Case Rep Gastroenterol 2016;10:50-6.
Yang SZ, Zhang W, Yuan WS, Dong JH. Recurrence of hepatocellular carcinoma with epithelial-mesenchymal transition after spontaneous regression: A case report. Medicine (Baltimore) 2015;94:e1062.
Okano A, Ohana M. Spontaneous regression of hepatocellular carcinoma: Its imaging course leading to complete disappearance. Case Rep Oncol 2015;8:94-100.
Oquiñena S, Guillen-Grima F, Iñarrairaegui M, Zozaya JM, Sangro B. Spontaneous regression of hepatocellular carcinoma: A systematic review. Eur J Gastroenterol Hepatol 2009;21:254-7.
Memon K, Kulik L, Lewandowski RJ, Wang E, Ryu RK, Riaz A, et al
. Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis. J Hepatol 2012;56:1112-20.
Johnson FL, Lerner KG, Siegel M, Feagler JR, Majerus PW, Hartmann JR, et al
. Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 1972;2:1273-6.
[Figure 1], [Figure 2]