Noriko Sakaida

Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma†

Many patients with chronic hepatitis caused by hepatitis C virus (HCV) infection develop liver fibrosis with high risk for hepatocellular carcinoma (HCC), but the mechanism underling this process is unclear. Conversely, transforming growth factor beta (TGF‐β) activates not only TGF‐β type I receptor (TβRI) but also c‐Jun N‐terminal kinase (JNK), which convert the mediator Smad3 into two distinctive phosphoisoforms: C‐terminally phosphorylated Smad3 (pSmad3C) and linker‐phosphorylated Smad3 (pSmad3L). Whereas the TβRI/pSmad3C pathway suppresses epithelial cell growth by upregulating p21WAF1 transcription, JNK/pSmad3L‐mediated signaling promotes extracellular matrix deposition, partly, by upregulating plasminogen activator inhibitor 1 (PAI‐1). We studied the domain‐specific Smad3 phosphorylation in biopsy specimens representing chronic hepatitis, cirrhosis, or HCC from 100 patients chronically infected with HCV, and correlated Smad3 phosphorylation with clinical course. As HCV‐infected livers progressed from chronic hepatitis through cirrhosis to HCC, hepatocytic pSmad3L/PAI‐1 increased with fibrotic stage and necroinflammatory grade, and pSmad3C/p21WAF1 decreased. Of 14 patients with chronic hepatitis C with strong hepatocytic pSmad3L positivity, 8 developed HCC within 12 years; only 1 of 12 showing little pSmad3L positivity developed HCC. We further sought molecular mechanisms in vitro. JNK activation by the pro‐inflammatory cytokine interleukin‐1β stimulated the pSmad3L/PAI‐1 pathway in facilitating hepatocytic invasion, in the meantime reducing TGF‐β‐dependent tumor‐suppressive activity by the pSmad3C/p21WAF1 pathway. Conclusion: These results indicate that chronic inflammation associated with HCV infection shifts hepatocytic TGF‐β signaling from tumor‐suppression to fibrogenesis, accelerating liver fibrosis and increasing risk for HCC. (HEPATOLOGY 2007;46:48–57.)

Cyclin-D1-gene amplification is a more potent prognostic factor than its protein over-expression in human head-and-neck squamous-cell carcinoma.

To evaluate the prognostic significance of cyclin D1 protein/gene expressions in human head‐and‐neck squamous‐cell carcinoma (HNSCC), we examined amplification of the cyclin‐D1 gene (CCND1) by the differential PCR method and over‐expression of cyclin‐D1 protein by immunohistochemistry in 45 paraffin‐embedded sections from HNSCC. Amplification of CCND1 was found in 10 (22%) cases and over‐expression of cyclin D1 was found in 24 (53%) cases. CCND1 amplification was also found in 3 (25%) of 12 cases of dysplastic lesions adjacent to HNSCC. The overall 5‐year survival of patients with CCND1 amplification or with protein over‐production was significantly lower than that of patients without (p < 0.0001 and p < 0.05, respectively). However, with multivariate analysis, only amplification of CCND1 retained an independent prognostic value (p = 0.0018). These suggest that CCND1 amplification occurs at early stages of HNSCC tumorigenesis and is a more useful prognostic factor than over‐expression of cyclin D1 in HNSCC. Int. J. Cancer 74:576–581, 1997.© 1997 Wiley‐Liss, Inc.

Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-β signaling from tumor suppression to oncogenesis in early chronic hepatitis B†

Hepatitis B virus X (HBx) protein is suspected to participate in oncogenesis during chronic hepatitis B progression. Transforming growth factor β (TGF‐β) signaling involves both tumor suppression and oncogenesis. TGF‐β activates TGF‐β type I receptor (TβRI) and c‐Jun N‐terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become C‐terminally phosphorylated Smad3 (pSmad3C) and linker‐phosphorylated Smad3 (pSmad3L). Reversible shifting of Smad3‐mediated signaling between tumor suppression and oncogenesis in HBx‐expressing hepatocytes indicated that TβRI‐dependent pSmad3C transmitted a tumor‐suppressive TGF‐β signal, while JNK‐dependent pSmad3L promoted cell growth. We used immunostaining, immunoblotting, and in vitro kinase assay to compare pSmad3L‐ and pSmad3C‐mediated signaling in biopsy specimens representing chronic hepatitis, cirrhosis, or hepatocellular carcinoma (HCC) from 90 patients chronically infected with hepatitis B virus (HBV) with signaling in liver specimens from HBx transgenic mice. In proportion to plasma HBV DNA levels, early chronic hepatitis B specimens showed prominence of pSmad3L in hepatocytic nuclei. HBx‐activated JNK/pSmad3L/c‐Myc oncogenic pathway was enhanced, while the TβRI/pSmad3C/p21WAF1 tumor‐suppressive pathway was impaired as human and mouse HBx‐associated hepatocarcinogenesis progressed. Of 28 patients with chronic hepatitis B who showed strong oncogenic pSmad3L signaling, six developed HCC within 12 years; only one of 32 patients showing little pSmad3L developed HCC. In contrast, seven of 30 patients with little Smad3C phosphorylation developed HCC, while no patient who retained hepatocytic tumor‐suppressive pSmad3C developed HCC within 12 years. Conclusion: HBx shifts hepatocytic TGF‐β signaling from the tumor‐suppressive pSmad3C pathway to the oncogenic pSmad3L pathway in early carcinogenic process. Hepatocytic pSmad3L and pSmad3C assessment in HBV‐infected liver specimens should prove clinically useful for predicting risk of HCC. (HEPATOLOGY 2009.)

Malignant rhabdoid tumor of the liver: case report and literature review.

A case of malignant rhabdoid tumor (MRT) occurring as a primary hepatic neoplasm in a 12‐month‐old Japanese female infant is presented. The patient had a slight fever for 2 weeks and presented with a palpable mass in her left hypochondrial region. After admission, the hepatic artery was embolized due to intra‐abdominal hemorrhage arising from the tumor. The patient received chemotherapy with cisplatin, cyclophosphamide and adriacin. Despite treatment, the patient developed dyspnea, pancytopenia and disseminated intravascular coagulation. Rupture of the tumor resulted in death within 3 weeks. A limited abdominal autopsy revealed that the liver weighed 1240 g and was occupied by multiple hemorrhagic and/or necrotic tumor nodules. Histologically, neoplastic cells had an abundant eosinophilic cytoplasm containing paranuclear inclusions, and vesicular nuclei with a centrally located prominent nucleolus. Ultrastructurally, the cytoplasmic inclusions were composed of whorled filaments measuring 10 nm. Immunohistochemically, almost all of the neoplastic cells were positive for vimentin and cytokeratins (CK) 8 and 18, some were positive for CK 7 and 19, while none were positive for CK 1, 10, 13–17 and 20. The tumor cells did not express desmin, myoglobin, and α‐fetoprotein. We found 18 cases of MRT of the liver published in English language literature and then, adding the present case, we summarized the 19 cases. Hepatic MRT is an uncommon neoplasm. However, it should be considered in the differential diagnosis of an aggressive liver neoplasm in childhood.

Serous microcystic adenoma (glycogen-rich cystadenoma) of the pancreas: Study of 11 cases showing clinicopathological and immunohistochemical correlations

Serous microcystic adenoma of the pancreas, also known as microcystic adenoma, glycogen‐rich cystadenoma or serous cystadenoma, is an uncommon benign tumor. We have studied 11 cases involving eight women and three men. The average age at diagnosis was 61.7 years. Four tumors were discovered incidentally. Tumors varied from 1.2 to 20 cm in maximum diameter and all were multicystic. Within the pancreas, three were located in the pancreas head, one involved the head and body, one was located in the body, five were in the tail, and one occupied the whole pancreas. Central stellate scar was seen in five (45%) cases. Histologically, all tumors were composed of microglandular cysts lined by clear epithelial cells rich in glycogen, which were separated by fibrocollagenous stroma. The expression of keratin in clear epithelial cells resembled that in ductal and/or centroacinar cells, but not acinar cells. α‐Smooth muscle actin (SMA)‐positive myoepithelial cells and stromal amyloid deposits were not detected. Ultrastructurally, fibrocollagenous stroma was composed of α‐SMA‐positive myofibroblasts and endothelial cells embedded in thick collagen bundles. Regardless of female propensity, estrogen and progesterone receptors were not detected. Therefore, female predominance in this tumor remains to be elucidated.

Multiple Hepatoblastomas Associated with Trisomy 18 in a 3-Year-Old Girl

A very rare case of full trisomy 18 associated with multiple hepatoblastomas is reported. The patient also had ventricular septal defect and patent ductus arteriosus, which were repaired at 6 months of age. After the cardiac surgery, she was noted to have an abdominal mass and an elevated serum alpha-fetoprotein level. A partial hepatic lobectomy was performed at 7 months of age, and the resected tumor was diagnosed as a fetal-type hepatoblastoma. At 2 years and 4 months of age, a chest radiography disclosed an elevated left diaphragm, and abdominal ultrasonography demonstrated a tumor in the left hepatic lobe. The resected tumor was also diagnosed as a fetal-type hepatoblastoma. Chromosomal analysis demonstrated that the karyotypes of peripheral blood and hepatic tumor cell obtained on two occasions were both 47,XX, +18. She has no evidence of recurrence at 3 years of age without specific therapy.

Neo-adjuvant Chemoradiation Therapy Using S-1 Followed by Surgical Resection in Patients with Pancreatic Cancer

ObjectiveThe aim of this study was to compare short-term surgical results in pancreatic cancer patients who underwent surgical resection after neo-adjuvant chemoradiation therapy (NACRT) using S-1.MethodsThe study population comprised 77 patients with pancreatic cancer between 2006 and 2010. Out of 34 patients who underwent staging laparoscopy between 2008 and 2010, 31 patients without occult distant organ metastasis underwent chemoradiation and of whom 30 underwent pancreatectomy (NACRT group). Of the other 43 patients, 36 underwent surgical resection in 2006–2008, followed by adjuvant therapy (adjuvant group). The primary endpoint was frequency of pathological curative resection (R0).ResultsThe new regimen of NACRT was feasible and safe. Twenty-eight of 30 (93%) patients in the NACRT group had R0 resection, which was significantly higher than in the adjuvant group (21 of 36 patients, 58%, p = 0.005). The number and extent of metastatic lymph nodes in the NACRT group (1 (0–25), N0/1; 18 of 38) was significantly lower than in the adjuvant group (2 (0–19), N0/1; 23 of 30), p = 0.0363). The frequency of intractable ascites in the NACRT group (eight of 30) was significantly higher than in the adjuvant group (two of 36, p = 0.035).ConclusionNeo-adjuvant chemoradiation therapy using S-1 followed by pancreatectomy can improve the rate of pathologically curative resection and reduces the number and extent of lymph node metastasis.

Carcinosarcoma arising in mixed epithelial and stromal tumor of the kidney

Mixed epithelial and stromal tumor of the kidney (MESTK) is characterized macroscopically by a mixture of solid and cystic parts and microscopically by a mixture of an epithelial component resembling collecting ducts and showing müllerian differentiation in a stromal component (1–3). We here report the first case of carcinosarcoma suggesting malignant müllerian mixed tumor arising in MESTK. A 54-year-old woman presented with macroscopic hematuria. A renal tumor measuring 7.6 cm in maximum diameter was observed in the upper pole of the left kidney. No tumors were seen in the uterus or ovaries. Metastatic disease was ruled out. The patient died of systemic metastases 5 months after radical nephrectomy. Metastases were not histologically confirmed. Macroscopically, the tumor had a predominantly cystic appearance with solid areas; microscopically, it was composed of a mixture of epithelial and stromal components. The benignlooking epithelial cells resembled the collecting duct system, endometrial or tubal epithelium. Proliferation of the spindle cells resembled ovarian stroma or smooth muscle-like structures. The malignant neoplastic cells formed approximately 40% of the total neoplastic mass. The malignant epithelial cells showed the histologic features of adenocarcinoma with endometrioid features and pseudostratification of round to oval nuclei (Fig. 1A). Additionally, malignant stromal components resembling undifferentiated sarcoma, chondrosarcoma (Fig. 1B) or rhabdomyosarcoma (Fig. 1C) were detected. Immunohistochemically, the adenocarcinomatous and sarcomatous components were diffusely positive for CD10 (Fig. 1D). SYT-SSX fusion transcripts were not detected in the ma-

Simultaneous presence of xanthogranulomatous cholecystitis and gallbladder cancer

To the Editor: Xanthogranulomatous cholecystitis (XGC) is an unusual and destructive infl ammatory process of the gallbladder. The infl ammation often extends into adjacent structures, and XGC may be confused with a malignant neoplasm. The association of XGC and gallbladder cancer (GBC) is controversial. From April 1992 to December 2005, cholecystectomy was performed on 2012 consecutive patients. The excised gallbladder was immediately opened, and the gallbladder mucosa was macroscopically examined. If a lesion was found, intraoperative frozen-section examination was performed. Final diagnosis was made after surgery by a whole mapping examination of the resected gallbladder after surgery. Of these patients, 60 (3.0%) were histopathologically diagnosed as having XGC, and six (10%) had coexisting XGC and GBC (XGC/GBC). The characteristics of the patients with XGC/GBC are summarized in Table 1. Preoperatively, four of these patients with XGC/GBC were diagnosed with cholelithiasis, one with Mirizzi syndrome, and one with GBC. Laparoscopic cholecystectomy was performed in two patients; however, postoperative histopathological examinations revealed GBC, and additional hepatectomy and regional lymphadenectomy were therefore performed. Four patients underwent open cholecystectomy and intraoperative frozen-section examinations revealed GBC. Two of the four had additional hepatectomy and regional lymphadenectomy following the frozen-section examinations. However, the other two patients had no additional surgery because of peritoneal dissemination or the early stage of the cancer. Of the six patients, three had no recurrence and the other three died within 11 months after surgery. Histopathologic fi ndings of XGC/GBC are shown in Table 2. The depth of cancer invasion (pT classifi cation) was as follows: pT1a (limited to the mucosa) in one, pT2 (subserosa) in three, and pT3 (serosa) in two. The infl ammatory pattern of XGC was focal in two and diffuse in four patients. Neoplastic growth and infl ammatory components of XGC were unmixed in one patient, and closely mixed in fi ve. The association of XGC and GBC remains a matter of discussion.

Retracted Article: Prognostic Factors in Breast Cancer: The Value of the Nottingham Prognostic Index for Patients Treated in a Single Institution

PurposeThe Nottingham Prognostic Index (NPI) is used to predict survival in patients with breast cancer. This index is based on tumor size, lymph node stage, and histological grade and allows the stratification of patients into three different prognostic groups. Our aim was to verify the effect of some prognostic variables on survival and to establish the independent influence of each of these variables by a survival regression analysis. We applied the NPI to the same group of patients to assess its predictive power and reproducibility.MethodsWe evaluated 311 women with breast cancer treated between January 1993 and December 1998.ResultsIn a multivariate analysis (Cox proportional hazard model), only size, lymph node involvement, and histological grade were independent prognostic factors. The survival curves obtained after applying the NPI were similar to those for the factors with independent prognostic significance derived from our multivariate analysis.ConclusionThe NPI allows us to accurately predict prognosis, and we advocate its standardized use.