Yoshie Shimoyama

Age-Related EBV-Associated B-Cell Lymphoproliferative Disorders Constitute a Distinct Clinicopathologic Group: A Study of 96 Patients

Purpose: We have recently reported EBV+ B-cell lymphoproliferative disorders (LPD) occurring predominantly in elderly patients, which shared features of EBV+ B-cell neoplasms arising in the immunologically deteriorated patients despite no predisposing immunodeficiency and were named as senile or age-related EBV+ B-cell LPDs. To further characterize this disease, age-related EBV+ B-cell LPDs were compared with EBV-negative diffuse large B-cell lymphomas (DLBCL). Experimental Design: Among 1,792 large B-cell LPD cases, 96 EBV+ cases with available clinical data set were enrolled for the present study. For the control group, 107 patients aged over 40 years with EBV-negative DLBCL were selected. We compared clinicopathologic data between two groups and determined prognostic factors by univariate and multivariate analysis. Results: Patients with age-related EBV+ B-cell LPDs showed a higher age distribution and aggressive clinical features or parameters than EBV-negative DLBCLs: 44% with performance status >1, 58% with serum lactate dehydrogenase level higher than normal, 49% with B symptoms, and higher involvement of skin and lung. Overall survival was thus significantly inferior in age-related EBV+ group than in DLBCLs. Univariate and multivariate analyses further identified two factors, B symptoms and age older than 70 years, independently predictive for survival. A prognostic model using these two variables well defined three risk groups: low risk (no adverse factors), intermediate risk (one factor), and high risk (two factors). Conclusions: These findings suggest that age-related EBV+ B-cell LPDs constitute a distinct group, and innovative therapeutic strategies such as EBV-targeted T-cell therapy should be developed for this uncommon disease.

Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients.

Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder (aEBVLPD) is a disease group characterized by EBV-associated large B-cell lymphoma in elderly without predisposing immunodeficiency. In nearly one- third of cases, aEBVLPD occurs as a polymorphous subtype with reactive cell-rich components, bearing a morphologic similarity to classic Hodgkin lymphoma (cHL). The aim of this study was to clarify clinicopathologic differences between the polymorphic subtype of aEBVLPD (n = 34) and EBV(+) cHL (n = 108) in patients aged 50 years or older. Results showed that aEBVLPD was more closely associated with aggressive clinical parameters than cHL, with a higher age at onset (71 vs 63 years); lower male predominance (male-female ratio, 1.4 vs 3.3); and a higher rate of involvement of the skin (18% vs 2%), gastrointestinal tract (15% vs 4%), and lung (12% vs 2%). aEBVLPD was histopathologically characterized by a higher ratio of geographic necrosis, greater increase (> 30%) in cytotoxic T cells among background lymphocytes, higher positivity for CD20 and EBNA2, and absence of CD15 expression. As predicted by the clinical profile, aEBVLPD had a significantly poorer prognosis than EBV(+) cHL (P < .001). The polymorphous subtype of aEBVLPD constitutes an aggressive group with an immune response distinct from EBV(+) cHL, and requires the development of innovative therapeutic strategies.

Age‐related Epstein–Barr virus‐associated B‐cell lymphoproliferative disorders: Special references to lymphomas surrounding this newly recognized clinicopathologic disease

Epstein–Barr virus (EBV) is associated with some disease entities of malignant lymphomas, including Burkitt lymphoma, Hodgkin lymphoma, immunodeficiency‐associated lymphoproliferative disorders (LPD), and a part of diffuse large B‐cell lymphoma. We have recently identified a series of elderly patients with EBV‐associated (or EBV+) B‐cell LPD (B‐LPD) showing similarities in many respects to immunodeficiency‐associated LPD, although no evidence of underlying immunodeficiency was found. Therefore, the nosological category of senile or age‐related EBV+ B‐LPD has been proposed for those patients. A larger series of patients with this disease revealed that the relative ratios of such EBV+ B‐LPD to all diffuse large B‐cell lymphoma cases were higher with increasing with age, reaching a peak (20–30%) at ≥90 years of age, with a median of 71 years, providing additional evidence for our assertion that this disease may be related to immunological deterioration as a result of the aging process. This new disease entity is characterized pathologically by centroblasts, immunoblasts, and Hodgkin and Reed–Sternberg‐like giant cells with a varying degree of reactive components, often posing therapeutic and diagnostic problems for hematologists and pathologists, respectively. The aim of the present review is to briefly summarize the overall clinicopathological profile of this newly recognized age‐related (also called ‘senile’) EBV+ B‐LPD and EBV+ Hodgkin lymphoma for a practical diagnostic approach. (Cancer Sci 2008; 99: 1085–1091)

Clinicopathologic study of cholangiocarcinoma with superficial spread.

Objective:To review our experience with cholangiocarcinoma with superficial spread, to clarify its clinical features, and to discuss treatment strategies. Summary Background Data:Most of the previous reports on cholangiocarcinoma with superficial spread were case reports. Little is known about this type of cholangiocarcinoma. Methods:The medical records of 471 patients with cholangiocarcinoma who underwent resection (351 perihilar and 120 distal cancers) were retrospectively reviewed, focusing on superficial spread, which was defined as noninvasive cancer extension of more than 20 mm. Results:Superficial spread was found in 69 (14.6%) of 471 patients, and its length was 54 ± 19 mm. Histologically, papillary and well differentiated adenocarcinomas were observed more frequently in cholangiocarcinomas with superficial spread (C+SS), compared with those without superficial spread (C−SS). Histologic indexes showing tumor aggressiveness, including lymphatic, venous, and perineural invasions, were lower in C+SS, and all factors of tumor staging (pT, pN, and pM) were less advanced in C+SS than in C−SS. Regarding surgical procedure, a combined hepatectomy and pancreatoduodenectomy was indicated in 26 (37.7%) of the 69 patients with C+SS, but in only 25 (6.2%) of the 402 patients with C−SS. Positivity of the proximal ductal margin was higher in C+SS than in C−SS (18.8% vs. 11.9%), although this was not statistically significant. All positive proximal ductal margins in C+SS were because of carcinoma in situ, whereas invasive cancer was the main reason for positivity in C−SS. Survival (excluding 29 in-hospital deaths) was significantly better in the patients with C+SS than in those with C−SS (5- and 10-year survival rates; 48.8% and 19.6% vs. 26.8% and 16.6%, P = 0.0009). Survival was comparable between the patients with a negative ductal margin and those with a positive margin with carcinoma in situ. On multivariate analysis, the presence or absence of superficial spread was not identified as a prognostic factor. Conclusions:C+SS is associated with less advanced, slower growing tumors and better survival compared with C−SS. In many cases of C+SS, the survival does not depend on the complete resection of all the superficial spread but on the stage of the main lesion.

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A- and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-alpha6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype.

Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer

BACKGROUND Pancreatic cancer has a dismal prognosis that is attributed to common local invasiveness and metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in cancer invasion and metastasis and is associated with early dissemination. The aim of this study was to evaluate the association between EMT and the prognoses for patients with pancreatic cancer. METHODS Immunohistochemistry of E-cadherin and vimentin was performed on surgical specimens from 174 patients who underwent resection of their pancreatic cancers. Tumoral stainings of E-cadherin and vimentin were graded, and EMT statuses were determined by calculating the ratio of vimentin to E-cadherin, whereby patients were categorized into 3 groups: epithelial, intermediate, and mesenchymal. The correlations between EMT statuses and clinicopathologic factors and prognoses were analyzed. RESULTS There was a significant correlation between EMT status and CA19-9 levels (P = .020); peritoneal washing cytology (P = .025); portal vein invasion (P = .038); and lymph node metastasis (P = .030). The median survival for patients with epithelial tumors was 40.2 months as compared to 13.7 months for patients with mesenchymal tumors. Multivariate analysis demonstrated that perineural invasion (P = .024); lymph node metastasis (P = .033); and EMT status (P < .0001) were significant prognostic factors. It is interesting that adjuvant chemotherapy (gemcitabine and/or S-1) improved the median survival time from 10.8 to 16.1 months in patients with mesenchymal tumors (P = .002); however, no significant difference was seen in patients with epithelial tumors. CONCLUSION EMT status is an important prognostic factor for pancreatic cancer and is associated with portal vein invasion and lymph node metastasis.

Age‐related EBV‐associated B‐cell lymphoproliferative disorders: Diagnostic approach to a newly recognized clinicopathological entity

EBV is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age‐related EBV‐associated B‐cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency‐associated ones, which may be associated with immune senescence in the elderly and which are now incorporated into the 2008 World Health Organization lymphoma classification as EBV‐positive diffuse large B‐cell lymphoma (DLBCL) of the elderly. This newly described disease is pathologically characterized by a proliferation of atypical large B cells including Reed–Sternberg‐like cells with reactive components, which pose a diagnostic problem for pathologists. Clinically, this disease may present with lymphadenopathy, and is often extranodal, frequently involving the skin, gastrointestinal tract, or lung. Onset is usually after the age of 50; the median patient age is 70–79 years, and incidence continues to increase with age, providing additional support to the nosological term of EBV+ DLBCL of the elderly. These patients have a worse prognosis than those with EBV‐negative DLBCL or EBV+ classical Hodgkin lymphoma (CHL). The aim of the present review was to summarize the clinicopathological profile of age‐related EBV+ LPD and EBV+ Hodgkin lymphoma to facilitate diagnostic approach.

Prognostic Significance of T-Cell or Cytotoxic Molecules Phenotype in Classical Hodgkin’s Lymphoma: A Clinicopathologic Study

PURPOSE Classical Hodgkins lymphoma (CHL) is characterized by Hodgkins and Reed-Sternberg (H-RS) cells, most of which are derived from germinal-center B cells. Nevertheless, one or more markers for T cells and follicular dendritic cells (FDC) may be expressed in a minority of H-RS cells in some CHL patients, although the clinical significance of this remains controversial. The aim of this study was to clarify the association between phenotypic expression and clinical outcome in CHL. PATIENTS AND METHODS Participants were 324 consecutive CHL patients, comprising 132 patients with nodular sclerosis (NS), 35 patients with NS grade 2 (NS2), and 157 patients with mixed cellularity (MC). We evaluated the presenting features and prognosis of patients on categorization into four phenotypically defined groups: B-cell (CD20+ and/or CD79a+; n = 63), T-cell and/or cytotoxic molecules (CD3+, CD4+, CD8+, CD45RO+, TIA-1+, and/or granzyme B+; n = 27), FDC (CD21+ without B-cell marker; n = 22), and null-cell types (n = 212). Other potential prognostic factors were examined. RESULTS The T-cell and/or cytotoxic molecules group showed a significantly poorer prognosis than the other three groups (P < .0001). This finding was seen consistently in multivariate analyses. Morphologic subtyping (NS/NS2/MC) and Epstein-Barr virus positivity were not identified as independent prognostic factors. CONCLUSION The presence of T-cell and/or cytotoxic antigens in H-RS cells may represent a poor prognostic factor in CHL, even if their expression is not regarded as lineage specific. Examination of T-cell and/or cytotoxic molecules phenotype in CHL patients is recommended as a routine pathologic practice.

Clinical Significance of Left Trisectionectomy for Perihilar Cholangiocarcinoma: An Appraisal and Comparison With Left Hepatectomy

Objective:To review our experiences with left-sided hepatectomy for perihilar cholangiocarcinoma, to compare left hepatectomy with left trisectionectomy, and to evaluate the clinical significance of left trisectionectomy from the viewpoint of surgical oncology. Background:Only 4 large case series have been reported on left trisectionectomy, with only a few patients diagnosed with perihilar cholangiocarcinoma. Therefore, the oncologic advantage of left trisectionectomy compared with left hepatectomy for perihilar cholangiocarcinoma is still unclear. Methods:This study involved 201 patients who underwent left-sided hepatectomy for perihilar cholangiocarcinoma (86 trisectionectomies and 115 hepatectomies). Surgical outcome and survival were compared between the 2 types of hepatectomy. The length of the resected right posterior bile duct was also measured. Results:Patients who underwent trisectionectomy had more advanced tumors, thus requiring combined vascular and/or other organ resection. Operative time and blood loss were significantly greater in trisectionectomy than in hepatectomy; therefore, overall morbidity was significantly higher in the former (59.3% vs 33.0%, P < 0.001). Mortality was similar (1.2% vs 0.9%) in both techniques. The length of the resected supraportal right posterior bile duct was significantly longer in trisectionectomy than in hepatectomy (20.7 ± 6.4 vs 13.6 ± 5.2 mm, P < 0.001). However, there was no difference in length of the infraportal type right posterior bile duct. The percentage of negative radial and distal common bile duct margins was similar, but the percentage of negative right posterior bile duct margins was significantly higher in trisectionectomy than in hepatectomy (97.7% vs 89.6%, P = 0.027). Overall, R0 resection was achieved in 84.9% of patients with trisectionectomy and in 70.4% of patients with hepatectomy (P = 0.019). Survival rates were similar between patients with trisectionectomy and those with hepatectomy (36.8% vs 34.0% at 5-year), despite the fact that the former had more advanced disease. Conclusions:Left trisectionectomy for perihilar cholangiocarcinoma, although technically demanding, can be performed with similar mortality rates as left hepatectomy. From an oncologic viewpoint, this operation can increase the number of negative proximal ductal margins, leading to a high proportion of R0 resection, and, in turn, to improved survival rates of patients with advanced left-sided perihilar cholangiocarcinoma.

A novel IL36RN/IL1F5 homozygous nonsense mutation, p.Arg10X, in a Japanese patient with adult‐onset generalized pustular psoriasis

homozygous, asymptomatic individual with porphyrin levels 10 times the upper limit of normal in the report by Ged et al. Simultaneous occurrence of thalassaemia and CEP due to a single trans-acting mutation has been previously reported. We herein report the occurrence of thalassaemia trait and CEP due to two independent mutations. Thalassaemia is endemic to our region and the co-occurrence is probably a coincidence; however, it allows us to examine the existence of any interaction. Despite reported exceptions, the S47P generally displays a severe phenotype, as is the case in our patient. Our patient is also heterozygous for a severe b-chain mutation and an interaction cannot be ruled out. Thalassaemia might increase the severity of the phenotype by increasing the demand for haem products through ineffective erythropoiesis. This remains unknown, but it is a theory that merits consideration.