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A Case of Spontaneous Regression of Hepatocellular Carcinoma with Multiple Lung Metastases


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Spontaneous regression of hepatocellular carcinoma (HCC) is extremely rare. We report a case of 67-year-old man having HBV-associated HCC with multiple lung metastases which regressed spontaneously. The patient had single liver mass and received surgical resection. The mass was confirmed as HCC histopathologically. Nine years after surgical resection, a 3.3 cm sized recurred HCC was detected on the resection margin in CT scan. Transarterial chemoembolization (TACE) was performed 3 times, and lung metastases developed thereafter. The patient received 2 more sessions of TACE, however, metastatic lung nodules were in progress very rapidly. We decided to stop TACE and followed the patient regularly without any anti-cancer treatment. Nine months after development of lung metastasis, the size and number of metastatic lung nodules decreased and were not detected anymore after 14 months. Serum alpha-fetoprotein levels also decreased to normal range and no viable tumor was noted in the liver. The patient is still alive 12 years after the first diagnosis of HCC and 16 months after lung metastasis developed.
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Jpn J Clin Oncol 2001;31(9)454–458
© 2001 Foundation for Promotion of Cancer Research
Spontaneous Regression of Hepatocellular Carcinoma with Multiple
Lung Metastases: a Case Report
Masafumi Ikeda, Shuichi Okada, Hideki Ueno, Takuji Okusaka and Hitoshi Kuriyama
Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Shuichi Okada, Hepatobiliary and
Pancreatic Oncology Division, National Cancer Center Hospital, 1–1 Tsukiji
5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail:
Received February 22, 2001; ac cepted May 18, 2001
Spontaneous regression of hepatocellular carcinoma is an extraordinarily unusual phenom-
enon. We present here a case of a 75-year-old man in whom multiple lung metastases of
hepatocellular carcinoma regressed spontaneously. He underwent systemic chemotherapy for
hepatocellular carcinoma with multiple lung metastases. However, the chemotherapy was not
effective and he was therefore followed up without any anticancer treatments in an outpatient
clinic. Four months later, multiple lung nodules regressed dramatically and the serum α-
fetoprotein level decreased markedly. After an 8-month period of the regression, however,
intrahepatic lesions gradually enlarged, although multiple lung metastatic lesions remained
regressed. The mechanisms underlying this intriguing phenomenon remain unknown.
Key words: hepatocellular carcinoma – lung metastasis – spontaneous regression
Hepatocellular carcinoma (HCC) is one of the most prevalent
malignancies in the world, especially in Asia and Africa.
Although early detection of tumors and development of thera-
pies for HCC are likely to improve prognosis, the prognosis
of advanced HCC remains poor. Numerous reports have
described cases of spontaneous regression of HCC (1–33),
although the mechanisms leading to it remain unknown. There-
fore, such cases, although extremely rare, should be accumu-
lated, since this may contribute to a further understanding of
this phenomenon and lead to a new strategy for HCC treat-
ment. We report here a patient in whom multiple lung
metastases from HCC spontaneously regressed 4 months
after ineffective anticancer treatment.
This report describes a 75-year-old Japanese man with diagno-
sis of HCC accompanying multiple lung metastases (Fig. 1).
He had a past history of left pulmonary upper lobectomy for
pulmonary tuberculosis at the age of 45 years, during which he
had received a blood transfusion. He had no history of heavy
alcohol intake or habitual drug use. He had no serological
markers of hepatitis B virus, but antibody to hepatitis C virus
was detected. In February 1995, when he was 70 years old, he
was referred to our hospital with a tentative diagnosis of HCC;
liver tumors located in segment 7 of the liver were detected on
ultrasound examination as a routine check-up for chronic
hepatitis at the previous hospital. These tumors were diagnosed
as HCC by typical computed tomographic (CT) and angio-
graphic findings and elevated serum α-fetoprotein (AFP) level.
He underwent hepatic arterial infusion using lipiodol com-
bined with zinostatin stimalamer 4 mg for HCC in February
1995. Because local relapses were observed on follow-up CT,
transcatheter arterial embolization using gelatin-sponge and
lipiodol combined with zinostatin stimalamer was carried out
in August 1995. Thereafter, the follow-up examinations
including CT and AFP every 3–4 months did not show any
relapse of HCC. In November 1999, he complained of con-
sistent dry cough. His chest X-ray revealed multiple nodular
shadows in the bilateral lungs, ranging up to 2 cm in diameter
and serum AFP was markedly elevated (6750 ng/ml). These
lung nodules were diagnosed as multiple lung metastases of
HCC, although the diagnosis was not confirmed pathologi-
cally. However, abdominal CT did not demonstrate definitive
relapse of HCC in the liver. He received systemic multi-agent
chemotherapy using mitoxantrone, cisplatin and 5-fluorouracil
in December 1999 (34). However, chemotherapy was not
effective; chest X-ray and CT in January 2000 demonstrated
enlarged metastatic nodules compared with those before
chemotherapy and the serum AFP level had approximately
doubled (14 734 ng/ml) (Fig. 2). Therefore, systemic chemo-
therapy was abandoned and he was discharged for follow-up at
the outpatient clinic.
Four months after systemic chemotherapy had been aban-
doned, the multiple lung metastases dramatically decreased in
number and sizes (Fig. 3). Moreover, serum AFP also
Jpn J Clin Oncol 2001;31(9) 455
decreased markedly (99.3 ng/dl). During this period, he had
not received any anticancer treatment or medication including
herbal medicine and denied any further change in habits.
Moreover, he had not sustained trauma or infection and there
were no remarkable changes in nutrients during the period of
spontaneous regression (data not shown). This phenomenon,
therefore, was regarded as spontaneous regression of HCC
with multiple lung metastases.
After an 8-month period of spontaneous regression, the
intrahepatic lesions, which had been treated by hepatic arterial
infusion and transcatheter arterial embolization, gradually
enlarged and serum AFP began to increase again (166 ng/ml),
although multiple lung metastatic lesions remained regressed.
He underwent hepatic arterial infusion using lipiodol com-
bined with zinostatin stimalamer for intrahepatic lesions in
September 2000 and is currently being followed up at the
outpatient clinic.
Spontaneous regression of a malignant tumor, which was
defined by Everson and Cole (1) as a partial or complete invo-
lution of a malignant tumor without specific therapy being ap-
plied, is an extraordinary and unusual phenomenon. The
incidence of spontaneous regression was estimated to be one
per 60 000–100 000 cases of malignancy, almost half in-
volving renal cell carcinoma, neuroblastoma and malignant
melanoma (2,3). With regard to HCC, 34 patients demonstrat-
ing this phenomenon have been reported to date as case reports
in the English literature (4–33) (Table 1). The clinical course
of our patient also indicated that this case was a spontaneous
regression of multiple lung metastases, which was confirmed
by both the marked decrease in serum AFP level and dramatic
tumor regression shown on CT, although histological evidence
of spontaneous regression was not available.
What are the characteristics of patients demonstrating spon-
taneous regression of HCC? In previous reports, and this case,
the characteristics of the patients showing spontaneous regres-
sion did not differ from those of other patients (Table 1): most
of the patients showing spontaneous regression were men older
than 60 years with some underlying chronic liver disease, dem-
onstrating a wide range of tumor sizes, serum AFP levels and
histopathological features.
What are the causative factors leading to spontaneous regres-
sion of HCC? The mechanism leading to spontaneous regres-
sion, which may differ individually, is still puzzling, although
various causative factors have been proposed (Table 1).
Because of the rarity of this phenomenon, possible mecha-
nisms discussed in the literature originate primarily from the
analysis of individual case histories. Biological factors have
suggested in an attempt to explain spontaneous regression:
hormonal influences, reduction of nutrients necessary for
tumor growth and immunological variations. Spontaneous
regression of HCC has also been reported to develop after
abstinence from alcohol (6,19), persistent fever (7,12,21,28),
withdrawal of androgen (5,9), blood transfusion (12), massive
bleeding (8,13), rapid tumor growth (11,22), angiography
(10,17), surgical trauma (8) and use of herbal medicine
However, cases in which no evident event was observed
during the period of spontaneous regression have also been
reported (14,18,20,23–25,27,29–30,32). In our case, the mech-
Figure 1. Clinical course of the patient.
456 Spontaneous regression of HCC
anisms leading to spontaneous regression remain unknown,
because this patient had not received any medication, including
herbal medicine, and there were no evident events or changes
in his habits during this period. However, some systemic
factors may be strongly suggested to be causative, because
the regression occurred in multiple metastatic lesions of the
bilateral lungs.
In conclusion, it is difficult at present to elucidate the charac-
teristics of patients who experience spontaneous regression
and the mechanisms leading to spontaneous regression. There-
fore, cases of spontaneous regression of HCC should be accu-
mulated in the literature. Even though an individual history
cannot provide a complete explanation of the underlying
mechanisms, accumulation of such cases of spontaneous
regression will contribute to a further understanding of this
intriguing phenomenon and may also lead to a new treatment
strategy for HCC.
Figure 2. (a) Chest X-ray and (b) chest CT taken in January 2000 showing
multiple nodular lesions scattering in bilateral lungs, suggesting metastasis
from HCC.
Figure 3. (a) Chest X-ray and (b) chest CT taken in May 2000, showing
marked reduction in numbers and sizes of the nodules.
Jpn J Clin Oncol 2001;31(9) 457
cs o
ar carc
noma w
spontaneous regress
AFP, α-fetoprotein; m, male; f, female; B, hepatitis B surface antigen positive; C, hepatitis C antibody positive; +, living.
Study Reported
Gender Age
Etiology AFP Distant
Proposed mechanism of regression Survival
Johnson (5) 1972 f 5 Androgen Unknown No Complete Androgen withdrawal 14+
Gottfried (6) 1982 m 65 Alcoholic Normal No Complete Abstinence from alcohol 48+
Lam (7) 1982 m 50 B Un known Lung Complete Biological effect s triggered b y
infection, use of herbal medicine
Sato (8) 1985 m 78 Unknown 26 200 Bone Complete Gastrointestinal bleeding 62+
McCaughan No. 1 (9) 1985 m 28 Androgen Normal No Complete Androgen withdrawal 118+
McCaughan No. 2 (9) 1985 m 40 Androgen Normal No Partial Androgen withdrawal 158+
Takayasu No. 1 (10) 1986 m 38 B 16 950 No Surgically resected Subintimal injury on angiography 48+
Takayasu No. 2 (10) 1986 f 58 Unknown Normal No Partial Subintimal injury on angiography 31
Suzuki (11) 1989 m 67 Unknown 7767 No Complete Infarction due to rapid growth
(arterioportal shunt)
Tocci (12) 1990 m 79 Unknown 625 No Complete Infarction due to systemic shock 48+
Gaffey (13) 1990 m 63 Unknown 2690 No Partial Gastrointestinal bleeding, use of
macrobioti c diet
Ayres (14) 1990 f 63 Unknown 7390 Lung Partial Unknown 12+
Mochizuki (15) 1991 m 61 Unknown 221 000 Bone Complete Abscopal regression after radiation 18
Chien (16) 1992 m 65 B >10 000 No Complete Use of herbal medicine 37+
Imaoka (17) 1994 m 65 C 6609 No Surgically resected Infarction due to arterial thrombus No data
McDermott (18) 1994 f 23 Unknown Unknown No Complete Unknown 240+
Grossmann (19) 1995 m 52 Alcoholic 310 No Partial Abstinence from alcohol and smoking 14
Ozeki (20) 1996 f 69 Unknown 1050 No Surgically resected Unknown 12+
Markovic (21) 1996 m 62 B 11 No Surgically resected Biological effects by inflammatory
van Halteren (22) 1997 f 72 Unknown Unknown No Partial Infarction due to rapid growth 28+
Iwasaki (23) 1997 f 72 C 105 340 No Partial Unknown 17+
Gomez (24) 1998 m 66 C 4 Lymph
Complete Unknown 50+
Kaczynski (25) 1998 m 73 Unknown Unknown No Complete Unknown 180
Ohba (26) 1998 m 76 C 429 998 Bone Partial Abscopal regression after radiation 84+
Magalotti No. 1 (27) 1998 m 66 Alcoholic 2500 No Complete Unknown 75
Magalotti No. 2 (27) 1998 f 75 C 37 500 No Partial Unknown 29
Stoelben No. 1 (28) 1998 m 56 Unknown 3.7 No Surgically resected Biological effects triggered by
Stoelben No. 2 (28) 1998 m 74 Unknown 3850 No Surgically resected Biological effects triggered by
Magalotti No. 1 (29) 1998 m 66 Alcoholic 2500 No Complete Unknown 76
Magalotti No. 2 (29) 1998 f 75 C 37 500 No Partial Unknown 22
Toyoda (30) 1999 m 82 C 50 000 Lung Partial Unknown 21
Misawa (31) 1999 m 62 B 1400 No Complete Biological effects by arterioportal
Izushi (32) 2000 m 50 C 16. 4 No Partia l Unknown 48+
Takeda (33) 2000 m 72 C 8230 No Complete Use of herbal medicine 15+
This case m 75 C 14 734 Lung Partial Un known 12+
458 Spontaneous regression of HCC
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The principal objective of this study was to examine the quality characteristics of yanggaeng supplemented with powder derived from Sanghwang mushroom (Phellinus linteus) mycelia. We analyzed the potential of utilizing Phellinus linteus mycelia as a functional food material by estimating total polyphenol and flavonoid contents, electron-donating abilities, as well as antioxidative activities of the water and ethanol extracts of Sanghwang mushroom mycelia. The total phenol and flavonoid contents of ethanol extracts from Phellinus linteus mycelia were 0.69 mg/ml and 0.16 mg/ml, respectively, while the contents from the water extract of Phellinus linteus mycelia were 0.66 mg/ml and 0.22 mg/ml, respectively. The electron-donating abilities of ethanol and water extracts from Phellinus linteus mycelia were 88.64 and 90.29%, respectively. The ABTS radical scavenging activities of ethanol and water extracts from Phellinus linteus mycelia were 89.74 and 71.35%, respectively. In terms of color values, as the level of powder increased, the value of L (lightness) decreased, whereas those of a (redness) and b (yellowness) increased. In regard to the mechanical properties of the samples, we noted significant differences in hardness, springiness, chewiness, and gumminess (P
The PubMed and Ichushi databases were searched to identify cases of spontaneous regression of cancer that were featured in original papers and abstracts presented at conferences and these cases were examined. First,6 3 cases of spontaneous regression reported from Japan in 2011 were examined in detail. The most common types of cancer were lymphoma,hepatic carcinoma,and pulmonary cancer. The incidence of spontaneous regression was estimated at 1 per 12,000 patients with cancer and was calculated on the basis of the estimated number of patients who were newly diagnosed as having cancer during 1 year in Japan. Next, 83, 40,and 37 cases of spontaneous regression of hepatic carcinoma,pulmonary cancer,and lung metastases from primary malignant tumors,respectively,reported worldwide between 2006 and 2011, were analyzed. The cause of spontaneous regression in all 3 pathologies often involved an immunological mechanism. Other common factors that contributed to spontaneous regression were impaired tumor blood flow in patients with hepatic carcinoma,paraneoplastic syndrome in those with pulmonary cancer,and removal of the primary tumor in patients with lung metastasis.
Full-text available
Reports of metastatic hepatocellular carcinoma (HCC) without a primary liver tumor are rare. Here we present a case of isolated HCC that had metastasized to the pelvic bone without a primary focus. A 73-year-old man presented with severe back and right-leg pain. Radiological examinations, including computed tomography (CT) and magnetic resonance imaging (MRI), revealed a huge mass on the pelvic bone (13×10 cm). He underwent an incisional biopsy, and the results of the subsequent histological examination were consistent with metastatic hepatocellular carcinoma. The tumor cells were positive for cytokeratin (AE1/AE3), hepatocyte paraffin 1, and glypican-3, and negative for CD56, chromogranin A, and synaptophysin on immunohistochemical staining. Examination of the liver by CT, MRI, positron-emission tomography scan, and angiography produced no evidence of a primary tumor. Radiotherapy and transarterial chemoembolization were performed on the pelvic bone, followed by systemic chemotherapy. These combination treatments resulted in tumor regression with necrotic changes. However, multiple lung metastases developed 1 year after the treatment, and the patient was treated with additional systemic chemotherapy.
Spontaneous regression of hepatocellular carcinoma (HCC) is an extraordinarily unusual phenomenon that has been reported on nine occasions in the English-language medical literature (1± 9). The case we report here is differentiated from the others by the fact that our patient had undergone resection of the HCC (right hepatectomy), the diagnosis of which was con® rmed in the removed tissue specimen; regression occurred after recurrence of the HCC, as proved by biopsy. The recurrent HCC regressed in the absence of speci® c therapy. We do not know what causes the spontaneous regression of HCC, although immunologic or genetic phenomena that have yet to be fully understood may be implicated (9).
After a study of the 176 cases (Everson and Cole) of spontaneous regression of cancer and recent progress in immunology, the author is convinced stimulation of the immune process is the most important factor in S.R. of cancer. Stimulating factors are numerous including bacterial products, enzymes, infections, hormones, trauma, etc. Of the 176 cases reported by Everson and Cole, 71 (40%) were associated with some type of operative trauma.Since the effective anticancer agent interferon is an important protective agent (especially antiviral) in the human body, this product could readily play an important role. Immunoglobulins appear to be possible factors. The blocking and unblocking agents of the Hellströms and associates support this supposition. Elimination of carcinogens appears important, considering the remarkable disappearance of cancer of the bladder in 12 of 13 patients having diversion of the urine from the bladder to the colon by transplantation of the ureters from the bladder to the colon.Innumerable antigens unknown to us at the present time could act as stimulants to our immune system, and thus cause regression of cancer. Hormonal factors must obviously be considered, but the author is doubtful that they exert an important role.
To determine the clinical and histopathological features of a case of a spontaneous regression of hepatocellular carcinoma (HCC). HCC was found incidentally in a 73-year-old man during a laparotomy for evaluation of gastric retention. Despite no treatment being given, he improved gradually with no sign of tumour as evidenced by coeliac angiography 15 months later, as well as by explorative laparotomy after another 2 years. The patient died 15 years after the primary diagnosis of HCC, without known evidence of tumour recurrence. The patient's clinical records were reviewed, and paraffin-embedded liver tissue was re-evaluated. Both histological and immunohistochemical features were compatible with the diagnosis of a well differentiated HCC. Conceivable causes of the spontaneous regression of this and other reported cases are discussed, but the phenomenon remains enigmatic. This case with a histologically proven HCC and a very long follow-up time confirms that spontaneous regression does occur. Since the case was found incidentally our report also implies that this may not be as rare as reported.
Primary liver cancer, particularly hepatocellular carcinoma (HCC) remains a significant disease worldwide. It is among the top three causes of cancer death in the Asia Pacific region because of the high prevalence of its main etiological agents, chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. In this region, the incidence of HCC has been static over recent decades. Older age is a major risk factor; the incidence increasing sharply after age 40 years. There is a male predilection, with male to female ratio of 3:1, except in elderly Japanese with equal sex incidence or female predominance. In most Asia-Pacific countries, chronic HBV infection accounts for 75-80% of cases; Japan, Singapore and Australia/New Zealand are exceptions because of higher prevalence of HCV infection. In spite of advances in surgery, liver transplantation and newer pharmaco/biological therapies, the survival rate has improved only slightly over recent decades, and this could be attributable to earlier diagnosis ('lead-time bias'). The majority of patients present with advanced diseases, hence reducing the chance of curative treatment. The importance of HCC may decrease in two to three decades when the prevalence of chronic HBV infection decreases as a result of the universal HBV vaccination programs implemented in late 1980s in most Asia-Pacific countries, and because of reduced incidence of medical transmission of HCV. However, transmission of HCV by injection drug use, and rising prevalence of obesity and diabetes, both independent risk factors for HCC, may partly offset this decline.
In a book written by Everson and Cole (1966) on spontaneous regression 176 examples of the phenomenon were encountered in the medical literature from 1900 to 1964, supplemented by cases referred by friends. No common denominator of explanations were found. Various types of trauma (e.g., biopsy, incomplete excision), transfusions, infection, hormone changes, drugs, etc were encountered as possible causative factors. Most significant of all factors was encountered in the 13 examples of spontaneous regression of the bladder; in this series regression of the tumor occurred in 10 after transplantation of the ureters out of the bladder.
We report a 65-yr-old man with hepatitis B virus-related liver cirrhosis and biopsy-proven hepatocellular carcinoma who has undergone spontaneous regression. The tumor became impalpable, and was no longer detectable by ultrasonography and computed axial tomography, 5 and 30 months later. The alpha-fetoprotein level also decreased to normal range. The clinical course is silent, and the patient is alive and well 37 months after the initial diagnosis.