Megumu Fujihara

Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease

IgG4-related disease sometimes involves regional and/or systemic lymph nodes, and often clinically and/or histologically mimics multicentric Castlemans disease or malignant lymphoma. In this study, we examined clinical and pathologic findings of nine patients with systemic IgG4-related lymphadenopathy. None of these cases were associated with human herpes virus-8 or human immunodeficiency virus infection, and there was no T-cell receptor or immunoglobulin gene rearrangement. Histologically, systemic IgG4-related lymphadenopathy was classified into two types by the infiltration pattern of IgG4-positive cells: interfollicular plasmacytosis type and intra-germinal center plasmacytosis type. The interfollicular plasmacytosis type showed either Castlemans disease-like features or atypical lymphoplasmacytic and immunoblastic proliferation-like features. By contrast, the intra-germinal center plasmacytosis type showed marked follicular hyperplasia, and infiltration of IgG4-positive cells mainly into the germinal centers, and some cases exhibited features of progressively transformed germinal centers. Interestingly, eight of our nine (89%) cases showed eosinophil infiltration in the affected lymph nodes, and examined patients showed high elevation of serum IgE. Laboratory examinations revealed elevation of serum IgG4 and soluble interleukin-2 receptors. However, the levels of interleukin-6, C-reactive protein, and lactate dehydrogenase were within normal limits or only slightly elevated in almost all patients. One patient showed a high interleukin-6 level whereas C-reactive protein was within the normal limit. Autoantibodies were examined in five patients and detected in four. Compared with the previously reported cases of multicentric Castlemans disease, our patients with systemic IgG4-related lymphadenopathy were significantly older and had significantly lower C-reactive protein and interleukin-6 levels. In conclusion, in our systemic IgG4-related lymphadenopathy showed pathologic features only partially overlapping those of multicentric Castlemans disease, and serum data (especially C-reactive protein and interleukin-6) are useful for differentiating the two. Our findings of eosinophil infiltration in the affected tissue and elevation of serum IgE may suggest an allergic mechanism in the pathogenesis of systemic IgG4-related lymphadenopathy.

RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose

A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAF(V600E) point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAF(V600E) mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (P(trend) = 0.002). In contrast, BRAF(V600E) mutation was less frequent in cases exposed to higher radiation dose (P(trend) < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAF(V600E) mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis.

Hepatocellular Tumorigenicity of Butylated Hydroxytoluene Administered Orally to B6C3F1 Mice

Butylated hydroxytoluene (BHT), a preservative widely found in food as a food additive, was orally administered at concentrations of 1% and 2% of the diet to B6C3F1 mice for 104 consecutive weeks. Treated animals underwent a 16‐week recovery period prior to pathological examination. In male mice administered BHT, the incidence of mice with either a hepatocellular adenoma or a focus of cellular alteration in the liver was increased in a clear dose‐response relationship. The incidences of male mice with other tumors and the incidences of female mice with any tumor were not significantly increased as a consequence of BHT administration. The results of this study indicate BHT to be tumorigenic to the liver of the B6C3F1 male mouse.

Serum soluble interleukin‐2 receptor level and immunophenotype are prognostic factors for patients with diffuse large B‐cell lymphoma

Diffuse large B‐cell lymphoma is the most common form of non‐Hodgkin lymphoma. Although many studies have attempted to identify prognostic factors, most have focused on conventionally treated patients. The influence of anti‐CD20 antibody (rituximab) should be considered now. We evaluated the prognostic significance of serum soluble interleukin‐2 receptor levels and germinal center B‐cell‐like or non‐germinal center B‐cell like subgroups in 80 patients with diffuse large B‐cell lymphoma, who had been treated with rituximab. Serum soluble interleukin‐2 receptor levels ranged from 322 to 39900 U/mL (median 1365 U/mL). Sixteen (20%) were germinal center B‐cell‐like subgroups, and the remainder (80%) non‐germinal center B‐cell‐like. Survival analysis associated lower serum soluble interleukin‐2 receptor level and germinal center B‐cell‐like phenotype with better overall survival (P = 0.015), whereas multivariate analysis, including International Prognostic Index factors, revealed that only higher performance status score and higher serum lactate dehydrogenase levels significantly affected survival. However, serum soluble interleukin‐2 receptor levels were elevated in patients with higher International Prognostic Index scores as well as in the non‐germinal center B‐cell‐like subgroup. Serum soluble interleukin‐2 receptor levels, International Prognostic Index, and subphenotypes were strongly correlated with each other. Our study showed that soluble interleukin‐2 receptor is quite useful and may serve as a substitute for the International Prognostic Index, especially for patients undergoing treatment. Moreover, the differentiation between the germinal center B‐cell‐like and non‐germinal center B‐cell‐like phenotypes is also useful for predicting patients with diffuse large B‐cell lymphoma, even among those treated with rituximab. (Cancer Sci 2009; 100: 1255–1260)

EARLY CANCER AND RELATED LESIONS IN THE BRONCHIAL EPITHELIUM IN FORMER WORKERS OF MUSTARD GAS FACTORY

The bronchial epithelium in stepwise transverse sections was examined histologically in 66 male autopsy cases, composed of the groups of 19 mustard gas (MG) ex‐workers with lung cancer, 17 MG ex‐workers with non‐lung cancer, 10 non‐MG lung cancer cases, and 20 non‐MG non‐lung cancer cases. Foci of moderate or severe atypical cellular lesion or dysplasia, or of carcinoma in situ (CIS) in total slides of each group, were counted as 146 in 3,485, 72 in 2, 226, 70 in 3,797, and 18 in 4,611, respectively. The relative frequency of moderate or severe dysplasia and CIS in MG exposed non‐lung cancer cases resembled that found in lung cancer cases of both MG and non‐MG exposed. Seven CIS lesions were detected from among all MG‐exposed cases and one CIS was found in a non‐MG lung cancer case. Six out of eight CIS examples were adjoined by dysplasia. A multi‐variate analysis revealed a significant correlation between the incidence of atypical lesions and MG exposure, though the incidence of atypical lesions was also influenced significantly by age, smoking, and chronic bronchitis. The incidence of atypical lesions was significantly higher in cases of squamous cell lung cancer than those of other histological types, particularly small cell cancer.

Clinical Features of Gastrointestinal Follicular Lymphoma: Comparison with Nodal Follicular Lymphoma and Gastrointestinal MALT Lymphoma

We retrospectively compared the clinicopathological features of primary intestinal follicular lymphomas (FL-GIs), nodal follicular lymphomas (FL-LNs) and gastrointestinal MALT lymphomas (MALT-GIs), and investigated the distribution and the endoscopic appearances of FL-GI to evaluate the effectiveness of treatment modality. The subjects were 28 FL-GI patients, 135 FL-LN patients and 70 MALT-GI patients. In FL-LNs the clinical stage III–IV was 83%, while in FL-GIs clinical stage I–II was 68%. In MALT-GIs clinical stage I–II was 87%. The overall survival was significantly better in MALT-GI patients than in FL-LN patients. All FL-GI patients were alive at the time of evaluation. Regarding the histological grade (WHO), grade 1 was 81% in FL-GI, whereas in FL-LN grade 2 was 28% and grade 3 was 11%. The Follicular Lymphoma International Prognostic Index was low in 61% of FL-GIs, while in FL-LNs it was equally distributed to low, intermediate and high, suggesting that the prognosis is better in FL-GIs than in FL-LNs. The clinicopathological studies revealed the FL-GI has intermediate characteristics between FL-LN and MALT-GI. We recommend a ‘watch-and-wait’ policy or chemotherapy with rituximab for the therapy of FL-GIs because the lesions are often located in broader areas from the lower duodenum to the small intestine.

PREDICTIVE VALUE OF ENDOSCOPY AND ENDOSCOPIC ULTRASONOGRAPHY FOR REGRESSION OF GASTRIC DIFFUSE LARGE B-CELL LYMPHOMAS AFTER HELICOBACTER PYLORI ERADICATION

Background:  Some gastric diffuse large B‐cell lymphomas have been reported to regress completely after the successful eradication of Helicobacter pylori. The aim of this study was to investigate the clinical characteristics of gastric diffuse large B‐cell lymphomas without any detectable mucosa‐associated lymphoid tissue (MALT) lymphoma that went into complete remission after successful H. pylori eradication.

Hepatocellular carcinoma infiltrated with non-Hodgkin’s lymphoma: Report of a case

A 70-year-old woman diagnosed to have a hepatitis C virus (HCV) infection was referred to our hospital because of a solitary liver tumor. because of a solitary liver tumor. She underwent a partial hepatectomy, and the tumor was histologically diagnosed as a hepatocellular carcinoma (HCC). diagnosed as a hepatocellular carcinoma (HCC). In addition, a focal follicle consisting of atypical lymphoid cells was seen within the HCC. cells was seen within the HCC. Two months later, she was readmitted because of weakness and rapidly developing abdominal fullness. developing abdominal fullness. An abdominal computed tomography scan showed widespread tumors with ascites. with ascites. A cytological examination of the ascites showed large-sized atypical lymphoid cells. showed large-sized atypical lymphoid cells. An immunohistochemical stain confirmed that the atypical lymphoid cells within the HCC were positive for the CD 20 antigen. antigen. Taking these findings into account, the hepatic tumor was determined to be a HCC infiltrated with diffuse large B-cell lymphoma. diffuse large B-cell lymphoma. The coexistence of HCC and non-Hodgkin’s lymphoma (NHL) is extremely rare. and non-Hodgkin’s lymphoma (NHL) is extremely rare. We herein report a case of HCC infiltrated with NHL. We herein report a case of HCC infiltrated with NHL.

Lack of Tumorigenicity of Aminopyrine Orally Administered to B6C3F1 Mice

To test the tumorigenic potential of aminopyrine, an antipyretic analgesic, it was administered in drinking water at levels of 0 (control), 0.04 and 0.08% to 50 male and 50 female B6C3F1, mice for 100 weeks, and the mice were subsequently maintained without aminopyrine for a further 4 weeks. The most frequent types of tumor, in both treated and control groups, were hepatocellular tumor in male mice and malignant lymphoma/lymphoid leukemia in female mice. No statistically significant differences were observed in the incidences of these tumors between treated and control groups. The incidences of several other tumors in male and female mice also showed no statistically significant differences between treated and control groups. Therefore, no tumorigenic effect of orally administered aminopyrine in B6C3F1 mice was apparent in the present study.

Characteristic miR-24 Expression in Gastric Cancers among Atomic Bomb Survivors

Objective: To elucidate the mechanism of radiation-induced cancers, we analyzed the expression profiles of microRNAs extracted from formalin-fixed paraffin-embedded (FFPE) gastric cancer (GC) tissue samples from atomic bomb survivors. Methods: The expression levels of miR-21, miR-24, miR-34a, miR-106a, miR-143, and miR-145 were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: The expression of microRNAs was measured by qRT-PCR in a Hiroshima University Hospital cohort comprising 32 patients in the high-dose-exposed group and 18 patients in the low-dose-exposed group who developed GC after the bombing. The GC cases showing high expression of miR-24, miR-143, and miR-145 were more frequently found in the high-dose-exposed group than in the low-dose-exposed group. We next performed qRT-PCR of miR-24, miR-143, and miR-145 in a cohort from the Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital comprising 122 patients in the high-dose-exposed group and 48 patients in the low-dose-exposed group who developed GC after the bombing. High expressions of miR-24 and miR-143 were more frequently found in the high-dose-exposed group than in the low-dose-exposed group. Multivariate analysis demonstrated that only high expression of miR-24 was an independent predictor for the exposure status. Conclusion: These results suggest that the measurement of miR-24 expression from FFPE samples is useful to identify radiation-associated GC.