Prognostic grade for resecting hepatocellular carcinoma: multicentre retrospective study.

BACKGROUND: Surgical treatment for hepatocellular carcinoma (HCC) is advancing, but a robust prediction model for survival after resection is not available. The aim of this study was to propose a prognostic grading system for resection of HCC. METHODS: This was a retrospective, multicentre study of patients who underwent first resection of HCC with curative intent between 2000 and 2007. Patients were divided randomly by a cross-validation method into training and validation sets. Prognostic factors were identified using a Cox proportional hazards model. The predictive model was built by decision-tree analysis to define the resection grades, and subsequently validated. RESULTS: A total of 16 931 patients from 795 hospitals were included. In the training set (8465 patients), four surgical grades were classified based on prognosis: grade A1 (1236 patients, 14.6 per cent; single tumour 3 cm or smaller and anatomical R0 resection); grade A2 (3614, 42.7 per cent; single tumour larger than 3 cm, or non-anatomical R0 resection); grade B (2277, 26.9 per cent; multiple tumours, or vascular invasion, and R0 resection); and grade C (1338, 15.8 per cent; multiple tumours with vascular invasion and R0 resection, or R1 resection). Five-year survival rates were 73.9 per cent (hazard ratio (HR) 1.00), 64.7 per cent (HR 1.51, 95 per cent c.i. 1.29 to 1.78), 50.6 per cent (HR 2.53, 2.15 to 2.98), and 34.8 per cent (HR 4.60, 3.90 to 5.42) for grades A1, A2, B, and C respectively. In the validation set (8466 patients), the grades had equivalent reproducibility for both overall and recurrence-free survival (all P < 0.001). CONCLUSION: This grade is used to predict prognosis of patients undergoing resection of HCC.

Significance of the surgical hepatic resection margin in patients with a single hepatocellular carcinoma.

BACKGROUND: The impact of a wide surgical margin on the outcome of patients with hepatocellular carcinoma (HCC) has not been evaluated in relation to the type of liver resection performed, anatomical or non-anatomical. The aim of this study was to evaluate the impact of surgical margin status on outcomes in patients undergoing anatomical or non-anatomical resection for solitary HCC. METHODS: Data from patients with solitary HCC who had undergone non-anatomical partial resection (Hr0 group) or anatomical resection of one Couinaud segment (HrS group) between 2000 and 2007 were extracted from a nationwide survey database in Japan. Overall and recurrence-free survival associated with the surgical margin status and width were evaluated in the two groups. RESULTS: A total of 4457 patients were included in the Hr0 group and 3507 in the HrS group. A microscopically positive surgical margin was associated with poor overall survival in both groups. A negative but 0-mm surgical margin was associated with poorer overall and recurrence-free survival than a wider margin only in the Hr0 group. In the HrS group, the width of the surgical margin was not associated with patient outcome. CONCLUSION: Anatomical resection with a negative 0-mm surgical margin may be acceptable. Non-anatomical resection with a negative 0-mm margin was associated with a less favourable survival outcome.

ANTECEDENTES: El impacto de un margen quirúrgico (surgical margin, SM) amplio en el resultado de pacientes con carcinoma hepatocelular (hepatocellular carcinoma, HCC) no ha sido evaluado en relación con el tipo de resección hepática realizada: anatómica o no anatómica. El objetivo del presente estudio fue evaluar el impacto del estado del SM en los resultados en pacientes sometidos a resección anatómica o no anatómica por un HCC solitario. MÉTODOS: Los datos de pacientes con un HCC solitario sometidos a resección parcial no anatómica (grupo Hr0) o resección anatómica de un segmento de Couinaud (grupo HrS) entre 2000 y 2007 se obtuvieron a partir de una base de datos nacional de Japón. En los grupos Hr0 y HrS se evaluaron la supervivencia global y la supervivencia libre de recidiva asociadas al estado microscópico del SM y a la amplitud del SM. RESULTADOS: Se incluyeron un total de 4.457 pacientes en el grupo Hr0 y 3.507 en el grupo HrS. Un SM microscópico positivo se asoció con una pobre supervivencia global en ambos grupos. Un SM negativo, pero a una distancia de 0 mm se asoció con una peor supervivencia global y libre de recidiva en comparación con aquellos asociados a un SM más amplio, solo en el grupo Hr0. En el grupo HrS, la amplitud del SM no se asoció con los resultados del paciente. CONCLUSIÓN: La resección anatómica con un SM negativo a una distancia de 0 mm puede ser aceptable. La resección no anatómica con un SM negativo a una distancia de 0 mm se asoció con resultados de supervivencia menos favorables.

Effect of hepatic arterial infusion chemotherapy of 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma in the Nationwide Survey of Primary Liver Cancer in Japan.

BACKGROUND: The efficacy of hepatic arterial infusion chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC) remains unclear. METHODS: The outcome of 476 patients with HCC who underwent hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin (HAIC) were compared with 1466 patients who did not receive active therapy. RESULTS: A survival benefit of the therapy after adjusting for known risk factors was observed (hazard ratio, 0.48; 95% CI, 0.41-0.56; P<0.0001). In propensity score-matched analysis (n=682), median survival time was longer for patients who underwent chemotherapy (14.0 months) than for patients who did not receive active treatment (5.2 months, P<0.0001). CONCLUSION: For advanced HCC, HAIC is considered to be an effective treatment.

Clinicopathologic comparison of hepatitis B virus-related and hepatitis C virus-related hepatocellular carcinoma.

137 cases of hepatocellular carcinoma associated with cirrhosis that had undergone resection between 1991-95 have been analyzed. One hundred and three had hepatitis C (positive for anti HCV alone) and 34 hepatitis B (positive for HBsAg alone). The hepatitis C cases were older and were associated with more severe cirrhosis. The tumors from hepatitis B cases were on average larger and histologically less-differentiated, and were more likely to occur in the background of macronodular cirrhosis than hepatitis C cases.

p53 overexpression in small hepatocellular carcinomas containing two different histologic grades.

There is evidence to suggest that a focus of less-differentiated hepatocellular carcinoma (HCC) may arise within a pre-existing well-differentiated HCC, eventually replacing it. In the present study, the p53 tumor suppressor gene was analyzed by immunohistochemistry in 31 hepato-cellular carcinomas (HCCs) containing two or more regions in the same nodule with different histologic grades. p53 was overexpressed in the nucleus in 13 of 31 HCCs (42%), in seven of which p53 overexpression was seen only in the less-differentiated area of the tumor. This suggests that overexpression of presumed mutant p53 may have contributed to dedifferentiation during the development of HCC.

Hepatocellular carcinoma with sarcomatous change: a special reference to the relationship with anticancer therapy.

Among 579 autopsy cases of hepatocellular carcinoma (HCC), 55 cases (9.4%) exhibited a sarcomatous appearance. The incidence of HCC with a sarcomatous appearance has been increasing over the past 17 years. A sarcomatous appearance was found in 20 out of 335 autopsy cases of HCC (5.9%) during the 12 years from 1969 to 1980, and in 35 out of 244 autopsy cases of HCC (14.3%) during the last 6 years, when effective anticancer therapies, such as the one-shot injection of anticancer agents into the hepatic artery (one-shot therapy) and transcatheter arterial embolization (TAE), have become popular. A sarcomatous appearance was found in 20.9% of the cases undergoing anticancer therapy and in 4.2% of the cases not undergoing anticancer therapy. Among the various anticancer therapies, the sarcomatous appearance was most frequent (27.6%) in cases with repeated TAE. Thus, a close relationship between the sarcomatous appearance in HCC and anticancer therapies was suggested. Regarding the development of the sarcomatous appearance, we presume that it may be caused by the phenotypic change of HCC cells caused by anticancer therapy, or that a number of factors, including anticancer therapy, may accelerate the proliferation of the sarcomatous cells existing in the original tumor as one of the histological components. In order to clarify the true nature of sarcomatous lesions in HCC, further histological and biological studies are required.

A case of cystic lymphangioma of the pancreas.

We report a case of a 58-year-old man presenting with a mild attack of upper abdominal pain and who was found to have a swollen pancreatic body and tail. Pathological study of the resected mass revealed cystic lymphangioma. Only 30 cases of lymphangioma of the pancreas, including our case, have been reported to date. Here we present this case in detail and discuss the differential diagnosis of cystic lesions in the pancreas.

Clinicopathologic study on cholangiolocellular carcinoma.

We clinicopathologically studied 6 resected cases of cholangiolocarcinoma (CLC) including 2 referred cases from other hospitals. The frequency of CLC was 0.56% of the 708 consecutively resected cases of primary liver cancer and the mean age of CLC cases was 66 years. Three of the 6 cases (50%) were hepatitis C virus antibody (HCVab) positive, one (17%) was hepatitis B virus surface antigen (HBsAg) positive, and 2 (33%) were negative to both HCVAb and HBsAg. Serum levels of alpha-fetoprotein were slightly elavated only in 1 case. Clinically, 4 cases were diagnosed as hepatocellular carcinoma (HCC) and 2 cases as cholangiocellular carcinoma (CCC). Grossly, CLCs were whitish in color and solid, not encapsulated, and resembled CCC. Histologically, the tumor cells had eosinophilic cytoplasm with ovoid nuclei, and mild atypia. The tumor proliferated in an anastomosing pattern of Hering's canal-like small glands with an abundant fibrous stroma. Four of the 6 tumors (83%) consisted of only CLC and other 2 tumors contained CCC-like area and HCC-like area in a part of the nodules, respectively. Immunohistochemically, all tumors were positive to cytokeratin (CK) 7. CK8 were also positive in all of 6 cases. These results revealed that CLC had the clinical features resembling HCC but the morphologic features resembling CCC. It is suggested that CLC cells might be derived from Hering's canal or stem cells which have the intermediate features between hepatocytes and bile duct epithelium.

Antineoplaston treatment for advanced hepatocellular carcinoma.

Antineoplaston A10 injection (antineoplaston A10 I) exhibited cystostatic growth inhibition of human hepatocellular carcinoma (HCC) cells in vitro and showed minimum adverse effects in a phase I clinical trial. Advanced HCC is hard to control because the potent anticancer drugs or embolizations easily induce hepatic failure. We review herein 2 cases of advanced HCC treated with antineoplaston A10 I. Both cases showed interesting responses to antineoplaston A10 I. One showed massive coagulation necrosis of tumors after intra-arterial infusion of antineoplaston A10 I and the other showed resolution of portal vein tumor thrombosis with systemic infusion of antineoplaston A10 I. The usefulness of anti-neoplaston A10 I in terminal staged HCC is discussed.

Hepatocellular carcinoma with sarcomatous change.

We studied clinicopathological and immunohistochemical features of hepatocellular carcinoma (HCC) with sarcomatous change among surgically resected HCC cases. Among 308 HCC cases, 6 (1.9%) showed partial (5 cases) or entire (1 case) sarcomatous change. Only 1 case received preoperative anti-cancer therapy among the 6 cases, suggesting that sarcomatous change is not always related to anti-cancer therapy. Immunohistochemically, the sarcomatous components were positive for albumin and alpha 1-antichymotrypsin and negative for alpha-fetoprotein in all cases. Expressions of intermediate filament-related proteins (e.g., cytokeratin and vimentin) in the sarcomatous components were heterogeneous. The sarcomatous components showed stronger expressions of p53 protein and/or mouse double minute-2 protein, and higher proliferating cell nuclear antigen labeling index, suggesting their high proliferative activity and high malignant potential.

Clinicopathologic study on hepatocellular carcinoma negative for hepatitis B surface antigen and antibody to hepatitis C virus.

Among 326 consecutively resected cases of hepatocellular carcinoma (HCC), we studied clinicopathologic features of 13 cases (NBNC-HCC) negative for hepatitis B surface antigen (HBsAg), antibody to HBsAg (HBsAb), antibody to hepatitis B core antigen (HBcAb), hepatitis B envelope antigen (HBeAg), antibody to HBeAg (HBeAb), and antibody to hepatitis C virus (HCVAb). Forty-four HCC cases positive only for HBsAg (B-HCC) and 232 cases positive only for HCVAb (C-HCC) were studied as controls. Clinically, NBNC-HCC cases showed good liver function reserve. None of NBNC-HCC cases had periodic medical check ups and HCC was detected in 12 cases (92.3%) incidentally. Pathologically, the mean tumor diameter was significantly larger and the histologic grade was less differentiated in NBNC-HCC cases than in B-HCC and C-HCC cases. In the background liver, liver cirrhosis was associated in 15.4% of NBNC-HCC cases, 50.0% of B-HCC and 38.2% of C-HCC cases. The degree of inflammation and fibrosis was less in NBNC-HCC cases, and two cases (15.4%) had almost normal liver histology. In NBNC-HCC cases, synchronous and metachronous multicentric occurrence was not observed. In B-HCC cases, synchronous multicentric occurrence was found in 1 case (20.0%), but no metachronous multicentric occurrence. In C-HCC cases, synchronous and metachronous multicentric occurrence was found in 13 (43.3%) and 8 (30.8%) cases, respectively. However, the cumulative recurrence-free rate was not significantly different among the three groups. Accordingly, it was suggested that better prognosis could be expected in NBNC-HCC cases compared with B- and C-HCC cases, if the cancer could be detected in the early stage.

Role of urinary arginine vasopressin in the sodium excretion in patients with chronic renal failure.

Patients with chronic renal failure show almost equal levels of sodium excreted in the urine as healthy subjects through an increase of the fractional excretion sodium (FE(Na)). The mechanisms of this adaptation, however, are unknown. Recently, urinary arginine vasopressin (AVP) has been shown to inhibit the antidiuretic action of plasma AVP in the collecting ducts of rabbits and rats. In this article, the roles of plasma and urinary AVP are examined with other hormones in the sodium excretion of 57 patients with chronic renal disease. The fractional excretion of AVP, plasma atrial natriuretic peptide (ANP) and endothelin-1 (ET-1), urinary ET-1, and FE(ET-1) correlated with the decrease of creatinine clearance (Ccr). Multiple and stepwise regression analyses showed that FE(AVP) is the major dependent determinant for FE(Na) (adjusted r2 = 0.78). These results suggest that the increase of AVP excretion per remaining nephron could be a cause of the increase of FE(Na) in patients with renal failure. Although plasma AVP works as an antidiuretic hormone, urinary AVP serves as an intrinsic diuretic, especially in patients with chronic renal failure.

Apocrine adenocarcinoma arising in cystic teratoma of the ovary.

We present a rare case of an apocrine adenocarcinoma arising in a mature cystic teratoma of the ovary. The patient, a 41-year-old woman, was admitted to the hospital with low back pain and hypermenorrhea. A unilocular cystic tumor, measuring 5.5 x 5.0 cm in diameter, was found in her right ovary, and was removed. The tumor contained a mural nodule, measuring 8 x 7 mm in diameter. Microscopically, the unilocular cystic tumor was a teratoma consisting of mature cutaneous tissue with numerous hairs. The mural nodule was composed mostly of cords of epithelial cells with an infiltrative fashion and anastomosing tubular structures, which were lined partly by cells with eosinophilic cytoplasm and decapitation secretion. The cytoplasm contained iron granules as well as granules that were stained with periodic acid-Schiff, with and without diastase digestion.

Schwannoma in the sigmoid colon: report of a case.

Schwann cell tumor occurring in the intestines is rare. A 68-year-old female came to our hospital because of hematemesis. Barium enema and colonoscopic examination revealed submucosal tumor in the sigmoid colon. Laboratory data showed mild anemia. No other abnormal finding was found in the blood chemistry. Tumor marker levels of carcinoembryonic antigen (CEA), CA19-9, alpha feto protein (AFP) and neuron specific enolase (NSE) were within normal limits. The exploratory laparotomy confirmed a large sigmoid colon tumor. She received sigmoid colectomy. The resected specimen was a submucosal tumor with central depression, measuring 4.7 x 3.5 x 3.0 cm in size. The cut surface of the tumor was yellowish hue with necrosis. Histological examination showed spindle-shaped tumor cells with palisading comma-shaped nuclei and the nuclear pleomorphism. Immunohistochemical examination revealed that the tumor was positive for S-100 protein staining, and negative for Actin and for H.H.F. staining. These findings showed that this tumor was of Schwann cell origin. We report here the case in detail of a schwannoma in the sigmoid colon.

Biliary hamartomas simulating multiple hepatic metastasis on imaging findings.

We encountered a 62-year-old female with advanced gastric cancer, in whom multiple nodular lesions in the liver, which were depicted as small low density areas, less than 5 mm in diameter, on computed tomography and demonstrated as a heterogenic pattern on ultrasonograms. This patient was suspected to have multiple liver metastases of gastric cancer. She deteriorated gradually and died of respiratory failure due to lung metastasis. At autopsy these hepatic nodular lesions were biliary hamartomas. Biliary hamartoma is a lesion usually identified microscopically, and there have been only 8 cases including ours, which were depicted on images. Along with a remarkable advance in imagings, it should become more important to differentiate biliary hamartoma from malignant hepatic neoplasms on images.

Squamous cell carcinoma of the ovary--a case report.

A 68-year-old woman presented a one-month history of lower abdominal pain and weight loss, and was admitted to our hospital. On physical examination, a large hard mass was palpated in her right lower abdomen. An ultrasonograph and computed tomographic (CT) scan revealed a right ovarian tumor that measured 6.9 x 4.9 cm in size. A total hysterectomy and bilateral salpingo-oophorectomy were performed. The postoperative diagnosis of the tumor was squamous cell carcinoma (SCC) of the ovary. She died of infection and disseminated intravascular coagulation 5 months after surgery. The clinical and autopsy examinations did not show the primary lesions of SCC except in the right ovary. Mature cystic teratoma, Brenner tumor and endometriosis, which are ordinary regarded as the histogenesis of ovarian SCC, were not found, but a few surface epithelial inclusion cysts with squamous metaplasia were observed in non-cancerous area of the right ovary, and the contiguous transition from the metaplastic cyst wall to SCC was confirmed by stepwise serial sections. The present case suggests that the surface epithelium of ovary could be the fourth possibility in the histogenesis of the ovarian SCC.

Incidence of hepatitis D virus infection in Japanese patients with hepatocellular carcinoma--immunohistochemical investigation of the delta antigen.

In order to clarify the incidence of the delta agent among hepatocellular carcinomas (HCCs) in Kurume, where the hepatitis B infection and its related HCC are most prevalent in Japan, liver tissues from sero hepatitis B surface antigen-positive autopsy cases, with or without HCC, were immunohistochemically investigated for detection of the delta antigen. Only one patient (1.7%) among 58 patients with HCC was found to have delta-antigen in the nuclei in the hepatocytes, which were diffusely distributed throughout the non-cancerous liver. None of 26 patients with liver cirrhosis showed delta-antigen in the liver tissue. The incidence is so low that the delta agent is unlikely to have a role in the development of HCC in our areas.

[Familial cerebral aneurysms in three families, with two sibling pairs].

The authors describe two pairs of siblings and a mother-son with cerebral aneurysms and the characteristics of familial intracranial aneurysms are briefly discussed. Family 1: A 54-year-old hypertensive woman (case 1) developed subarachnoid hemorrhage and a saccular aneurysm at the proximal portion of the left anterior cerebral artery was demonstrated on the angiogram. An azygos anterior cerebral artery was found as an associated anomaly. A 53-year-old hypertensive woman (case 2), a younger sister of case 1, suffered from subarachnoid hemorrhage and a saccular aneurysm at the distal portion of the right anterior cerebral artery was found on the angiogram. Vertebral angiogram showed bilateral fenestration of the extracranial vertebral arteries as a coincidental anomalies. Neck clipping for the aneurysms were successfully done in these two cases. Family 2: A 52-year-old hypertensive woman (case 3) suffered from subarachnoid hemorrhage and vertebral angiogram demonstrated a saccular aneurysm at the distal portion of the right posterior inferior cerebellar artery. The aneurysm was re-bled before surgical intervention and she died five days after admission. A 65-year-old hypertensive woman (case 4), an elder sister of case 3, was admitted with subarachnoid hemorrhage. Vertebral angiogram showed a saccular aneurysm on the proximal portion of the left posterior inferior cerebellar artery at the junction of the vertebral artery and a massive extravasation of the contrast medium from the aneurysm. The patient died three days after the onset before surgical intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pathomorphologic characteristics and differential diagnosis of small hepatocellular carcinoma].

Recent advances in various diagnostic imagings have made possible early diagnosis of hepatocellular carcinoma (HCC). Grossly, small HCCs of the early stage up to around 1.5 cm in diameter are vaguely demarcated from surrounding liver tissue. Such minute tumors are classified as small HCC with indistinct margins. Histologically, these tumors consist of uniform distribution of well-differentiated cancerous tissues, which are characterized by increased cell density with increased nuclear/cytoplasmic ratio, irregular thin-trabecular pattern with occasional pseudoglandular structure, and frequent fatty and/or clear cell change. In all small HCCs with indistinct margins, varying numbers of portal tracts are contained within the cancerous tissues. None of them represents invasion of the portal vein or intrahepatic metastasis. Thus, small HCC with indistinct margins is considered to be HCC of the earliest stage that can be clinically detected at this moment. Along with the increase of resected small HCCs, hyperplastic lesions such as adenomatous hyperplasia (AH) and atypical AH, which are difficult to differentiate from well-differentiated HCC have also been found. Atypical AH is considered a borderline malignancy. Some focal nodular hyperplasias and liver cell adenomas are also difficult to differentiate from well-differentiated HCC. It should be recalled that some metastatic tumors such as carcinoid tumor, renal cell carcinoma and hepatoid adenocarcinoma also resemble HCC.

[Indication and limitation of microwave coagulation therapy for stage IV-A hepatocellular carcinoma].

Patients with stage IV-A hepatocellular carcinoma have been considered to have dismal prognosis. However, among them there are many of patients with multiple carcinoma of multicentric origin, whose prognosis is not necessarily poor. For treatment of multiple carcinoma, preoperative evaluation for the malignant aggressiveness of each nodule, and for liver function impairment is essential. Although hepatic resection has a high curability, resection sometimes impair long term survival because of postoperative deterioration of liver function. In this point, heat ablation therapy such as microwave coagulation therapy is favorable treatment, and for some nodules at early stage heat ablation therapy would have a sufficient curability to achieve long term survival. Authors decide on the selection of treatment (resection or heat ablation therapy) according to preoperative evaluation for the malignant aggressiveness by diagnosis of tumor gross type, and for the degree of liver impairment by serum hyaruronic acid level.