spontaneous necrosis or regression of malignant tumors has been reported mainly in neuroblastoma , renal cell carcinoma , malignant melanoma , malignant lymphoma and leukemia .
it is a rare event occurring with a rate of 1 in 60,000100,000 tumors   and has also been reported in hepatocellular carcinoma ( hcc ) . in 1972 , spontaneous regression of hcc was first described in a 3-year - old girl who had developed biopsy - proven hcc while on chronic androgen - anabolic steroid treatment for aplastic anemia . since this initial report , several mechanisms have been suggested to explain the etiology of spontaneous regression of hcc , including the administration of herbal remedies [ 4 , 5 ] or the withdrawal of a possible causative agent such as alcohol , tobacco   or exogenous androgens [ 3 , 7 ] . in spite of various opinions ,
its mechanism is unclear and there have been few reports with evidence based on a scientific basis , such as radiological findings and histological examinations .
here we report a case of spontaneous massive necrosis of hcc with various histological examinations of narrowing and occlusion in the arteries and portal veins , and review the literature with special reference to its pathological findings .
a 77-year - old man , who had alcoholic liver damage , had a fever and right hypochondriac pain .
ultrasonography showed a heterogeneous liver mass in the caudate lobe of the liver with a diameter of approximately 3 cm that had a hyper- and a hypoechoic area .
contrast ct showed the tumor to have a ring enhancement area and a high- to low - density round area ( fig .
these imaging studies indicated a liver abscess , and the patient received an antibiotic treatment , whereupon his symptoms soon improved .
one month later , he underwent contrast ct again ; the tumor had not shrunk , and moreover its density had become stronger .
therefore , he was suspected to have a liver tumor such as metastatic liver tumor .
his gastrointestinal tract was checked by esophagogastroduodenoscopy and colonoscopy , but his doctor could not reveal the primary site . moreover , his doctor performed positron emission tomography - ct ( pet - ct ) and magnetic resonance imaging ( mri ) .
the t1-weighted image showed a high - intensity round area in a low - intensity area , the t2-weighted image showed a high - intensity round area in a low - intensity area , and gadoxetic acid - enhanced mri showed a slightly contrasted low - intensity area in the same segment ( fig .
cellular and structural atypia , enlarged hyperchromatic nuclei and two or three layers of trabecular pattern , which indicated moderately differentiated hcc , were found in the specimen ( fig .
his blood test data before surgical treatment were as follows : white blood cell count 3,470/l ( normal 3,5009,000/l ) , red blood cell count 380  10/l ( normal 450550  10/l ) , serum hemoglobin concentration 13.1 g / dl ( normal 1418 g / dl ) , serum platelet count 15  10/l ( normal 1444  10/l ) , serum aspartate aminotransferase 39 iu / l ( normal 1333
iu / l ) , serum gamma glutamic transpeptidase 304 iu / l ( normal 1047
iu / l ) , total serum bilirubin 0.9 mg / dl ( normal 0.31.2 mg / dl ) , serum albumin 3.7 g / dl ( normal 4.05.0 g / dl ) , and serum c - reactive protein 0.03 mg / dl ( normal < 0.1 mg / dl ) .
the serum concentration of proteins induced by vitamin k antagonism or absence ( pivka - ii ) was 19 mau / ml ( normal < 40 mau / ml ) , and that of alpha - fetoprotein was 5.6 ng / ml ( normal < 6.2 ng / ml ) , carcinoembryonic antigen was 8.6 ng / ml ( normal < 3.2 ng / ml ) , and carbohydrate antigen 19 - 9 was 27.5 u / ml ( normal < 37.0 u / ml ) .
the child - pugh classification of his liver belonged to category a. extended left hepatic and caudate lobectomy was performed 18 days after the biopsy .
the tumor consisted of viable and necrosis areas with well - demarcated nodular lesions in the caudate lobe ( s1 ) . the viable tumor size was 11 mm in diameter ( fig .
histological examination showed a trabecular and pseudo - glandular structure with enlarged nuclei and hyperchromatins , which indicated moderately differentiated hcc in the viable area ( fig .
the necrosis area consisted of sclerotic fibrous stroma and liquefaction , and hyalinized degeneration with hemosiderin - laden macrophages , plasmacytes and fibroblasts was found ( fig .
. 3f ) and mild chronic inflammation in fibrously enlarged portal areas were found in the necrotic area .
the non - cancerous area of his liver showed mild chronic inflammatory infiltrate in the bridging fibrosis .
he is presently doing well and has no sign of any recurrent tumor 7 months after the operation .
spontaneous regression among patients with hcc was reported to happen in 0.4% . up to date , many spontaneous regressions of hcc have been described and various mechanisms have been proposed .
first , it has been proposed that immunological reactions may bring about the tumor regression .
for example , biopsy   and fever   might trigger immunological reactions and bring about tumor regression .
several reports documented the presence of elevated cytokine levels , suggesting a systemic inflammatory response .
il-18 has been shown to induce interferon gamma production by t cells and natural killer cells , thus potentially producing enhanced cytotoxic activity targeted at cancer cells .
proposed a similar mechanism after detecting elevated levels of natural killer cell activity , il-2 , il-6 , il-12 and interferon gamma throughout the course of the patient 's spontaneous regression .
second , the current analysis revealed multiple patients in whom regression appeared to be associated with tumor hypoxia .
several occurrences were related to occlusion of either the hepatic artery or the portal vein , which probably led to a direct ischemic insult .
other patients experienced profound systemic hypoperfusion , such as sustained hypotension associated with a massive variceal bleed .
tumor hypoxia as a mechanism is intuitively appealing in that it mirrors established treatment modalities for hcc . for example , both hepatic artery embolization and the agent sorafenib can be considered to rely upon the induction of tumor hypoxia for their effect .
most cases of spontaneous regression of hcc were diagnosed by radiological findings . on the other hand ,
almost all reports only mentioned the tissue type of hcc , and few reports mentioned detailed histological examination .
for example , 11 reports showed the findings of inflammatory cell infiltration , 3 reports arterial thrombosis , 2 reports portal vein thrombosis and 1 report hepatic venous thrombosis .
histological examination showed various findings of inflammatory cell infiltration in the specimen , narrowing and occlusion in the arteries and portal veins , and liquefaction and hyalinized degeneration of the tumor .
this seems to be the first report of spontaneous necrosis of hcc having all of these various histological findings together .
it was suggested that fever and biopsy were the triggers of the necrosis , and these suspected triggers would bring about the narrowing and occlusion in the arteries and portal veins .
therefore , we suspected that inflammatory cell infiltration was not the cause , but the result of the degeneration of this case . on the other hand , it is possible to think that the fever and right hypochondriac pain were not the cause , but the result of the spontaneous necrosis of hcc .
thickening of the vessel wall intima caused tumor hypoxia , which in turn caused the degeneration of hcc , and the patient felt a fever and right hypochondriac pain at that moment . considering that thickening of the vessel wall intima and portal vein thrombosis were confined to the tumor area , cytokines produced in the tumor cells may relate to thickening of the vessel wall intima and thrombus formation .
for example , tumor growth factor beta accelerates thickening of the vessel wall intima   and promotes production of plasminogen activator inhibitor-1 , which leads to thrombus formation [ 15 , 16 ] . according to previous reports , including ours
, it is sure that the mechanism of the spontaneous regression of hcc , just as that of other tumor regression , is complex
. therefore further findings , particularly concerning the progress of the immunological status during tumor regression and detailed histological examinations , will be essential to elucidate the mechanism of spontaneous regression of hcc .
 we herein present the case of a 77-year - old man who had fever and right hypochondriac pain . 
 he visited his doctor and underwent contrast computed tomography ( ct ) , and he was suspected to have a liver abscess . 
 he received an antibiotic treatment and his symptoms soon disappeared , but the tumor did not get smaller and its density on contrast ct image got stronger . 
 he underwent biopsy and moderately differentiated hepatocellular carcinoma ( hcc ) was found . extended left hepatic and caudate lobectomy was performed . 
 histological examination showed moderately differentiated hcc with narrowing and occlusion both in the arteries and portal veins associated with mild chronic inflammation . 
 the mechanisms of spontaneous regression of hcc , such as immunological reactions and tumor hypoxia , have been proposed . in our case , 
 histological examination showed the same findings . 
 however , the mechanism is complex , and therefore further investigations are essential to elucidate it . 
Introduction
Case Report
Discussion
Disclosure Statement