See article on page 1079

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Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers around the world, with a high mortality rate and increasing incidence. 1 Without treatment, HCC, particularly HCC diagnosed at an advanced stage, usually leads to death within a few months, and long-term survival is an exception. 2 Spontaneous regression (SR) of a malignant tumour in a person is, although rare, a well-recognized fact. 3 Spontaneous regression was defined by Everson and Cole as a partial or complete involution of a malignant tumour without a specific therapy being applied. 4 It has been estimated that SR of neoplasia occurs no more than once in 60 000–100 000 patients with cancer. 3 Spontaneous regression has been reported in a variety of malignant diseases including HCC, but cancer of the kidney, neuroblastoma, and malignant melanoma are major types of tumours showing SR. 3

Spontaneous regression of HCC is extremely rare and, in particular, complete SR is an extraordinarily unusual phenomenon. However, to date, more than 20 patients with SR have been published as case reports in the English literature. In these reports, SR was defined by serum α-fetoprotein (AFP) levels, imaging diagnosis such as computed tomography and ultrasonography, and occasionally also by histological examination. The profile of patients who experience spontaneous HCC regression does not differ from that of other HCC patients: the patients with SR were, for the most part, men greater than 60 years of age with some underlying liver disease (viral or alcoholic) demonstrating a wide range of tumour sizes, serum AFP levels, and histopathological features. In experimental animals, there is no accepted model for spontaneous HCC regression.

The biological nature of SR is poorly understood. The precise mechanisms leading to SR, which may differ individually, remain unclear, although various causes have been proposed. 3–5 Because of the rarity of this intriguing phenomenon, possible mechanisms discussed in the literature originate primarily from the analysis of individual case histories. Incorrect initial diagnoses aside, biological factors suggested in an attempt to explain SR include hormonal influences, withdrawal of agents required for tumour growth, deprivation of oxygen and nutrients, intake of unconventional medicine, and improvement of immune system activities. 3–5 Several authors consider the mechanism of SR to be multifactorial. In the case of HCC, SR has been reported to develop after various situations such as androgen withdrawal, alcohol withdrawal, use of herbal medicine, and infection in the tumour. 6–9 In addition, disruption of the blood supply to HCC, due to rapid tumour growth, angiography, surgical trauma, and massive bleeding, can lead to tumour necrosis of this oxygen-sensitive malignancy. 10,11

This is the background of the paper by Takeda et al., published in this issue of the Journal of Gastroenterology and Hepatology. 9 They reported a rare case of SR of HCC with liver cirrhosis, which was caused by hepatitis C virus. Spontaneous regression was confirmed by both the dramatic decrease in serum AFP and protein induced by vitamin K absence or antagonist II levels and complete tumour regression shown in computed tomography. It coincided with the intake of herbal medicines such as crude extract of Agaricus blazei Murill and tahibo tea. This SR was consistent with that defined by Everson and Cole. 4 Although the possibility that the use of such herbal medicines facilitated SR could not be ruled out, the precise mechanism of SR remains unclear. Some clinicians may have encountered similar cases of spontaneous HCC regression, but not many. However, it would be difficult to report such cases, because clinical data are often insufficient to cover the whole histories of patients.

Among the numerous proposed mechanisms of SR, immunological factors, which have yet to be fully understood, may play the most important role in this rare phenomenon. To date, accumulating evidence suggests that there is an immunological surveillance system in our body, in which many lymphocyte subsets, including natural killer cells, extrathymic T cells, and conventional T cells, are accumulating in the sites of malignant tumours. 12–14 Depending on the phenotype of tumours, (e.g. the expression level of monomorphic or polymorphic major histocompatibility complex (MHC) antigens as well as tumour antigens on tumour cells), the infiltration of certain lymphocyte subsets might be determined. In typical cases, a mixture of lymphocyte subsets is eventually present at the tumour site. If such an infiltration of the lymphocytes is at a desirable level, tumour progression might be suppressed and SR might have sometimes occurred.

The physical and mental conditions of the patients at the time when the onset of tumour malignancy begins should also be considered. Although the malignancy is induced by genetic mutations of some oncogenes, physical or mental stress sometimes seems responsible for such an induction. It is possibly mediated by the following steps: stress [RIGHTWARDS ARROW] sympathetic nerve activation [RIGHTWARDS ARROW] circulation failure and granulocytosis (i.e. granulocytes have surface adrenergic receptors) [RIGHTWARDS ARROW] damage to cells and acceleration of cell growth. Indeed, some hard workers and some persons with mental stress show a tendency to develop tumour malignancy. Such stress simultaneously induces immunosuppressive conditions and results in acceleration of the onset of malignancy. 15,16 If patients become free from such stress even after the onset of tumour malignancy (with or without some non-specific therapy), there is a possibility that their immunolgical system will be restored and SR of the tumours induced.

Well-documented cases of spontaneous HCC regression should receive attention, and complete publication of such SR cases should be continued. Even though an individual history cannot provide a complete explanation of the underlying mechanisms, accumulation of such data should enhance the understanding of this intriguing phenomenon. If we could elucidate the biological nature of SR, we will know more about the cause and the cure of cancer. Moreover, the mechanisms leading to SR may improve the effectiveness of anti-cancer treatments in the future.


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