Naoe Goto

Clinicopathologic analysis of IgG4-related skin disease

IgG4-related disease is a recently recognized systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration, increase in the number of IgG4+ cells in affected tissues and elevation of serum IgG4 levels. In 2009, we were the first to report skin lesions in patients with IgG4-related disease, but no large case series has been reported and clinicopathological findings remain unclear. To clarify these features, we herein report 10 patients (9 men and 1 woman; median age, 64 years; age range, 46–81 years) with IgG4-related skin disease. All patients had erythematous and itchy plaques or subcutaneous nodules on the skin of the head and neck, particularly in the periauricular, cheek, and mandible regions, except for one patient, whose forearm and waist skin were affected. In addition, eight patients had extracutaneous lesions: these were found on the lymph nodes in six patients, the lacrimal glands in three patients, the parotid glands in three patients, and the kidney in one patient. Histologically examined extracutaneous lesions were consistent with IgG4-related disease; five of six lymph node lesions showed progressively transformed germinal centers-type IgG4-related lymphadenopathy. Cases of IgG4-related skin disease were classified into two histological patterns: those exhibiting a nodular dermatitis pattern and those with a subcutaneous nodule pattern. The infiltrate was rich in plasma cells, small lymphocytes, and eosinophils; the majority of the plasma cells were IgG4+. The IgG4+ cell count was 49–396 per high-power field (mean±s.d., 172±129), with an IgG4+/IgG+ cell ratio ranging from 62 to 92%. Serum IgG4 levels were elevated in all examined patients. In conclusion, patients with IgG4-related skin disease had uniform clinicopathology. Lesions were frequently present on the skin of the periauricular, cheek, and mandible regions, and were frequently accompanied by IgG4-related lymphadenopathy.

Endoscopic Ultrasound-Guided Fine Needle Aspiration Biopsy for Diagnosis of Lymphoproliferative Disorders: Feasibility of Immunohistological, Flow Cytometric, and Cytogenetic Assessments

OBJECTIVES:In addition to morphology, immunophenotype and genetic abnormalities should be assessed during diagnosis and subclassification of lymphoproliferative disorders. The objective of this study was to evaluate the yield of endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) using a standard 19-gauge needle for diagnosis and subclassification of lymphoma, assessing the feasibility of immunohistological, flow cytometric, and cytogenetic assessments.METHODS:Two hundred forty patients with suspected lymphoma were referred for EUS-FNAB to our quaternary EUS center between June 2005 and December 2010. EUS-FNAB using a conventional 19-gauge needle was attempted for all patients, followed by histological assessments including immunohistological staining, flow cytometry, and cytogenetic analysis (G-band karyotyping). Among the patients, 152 were ultimately diagnosed with lymphoma. The primary outcome measure of this study was the sensitivity of histological assessment, including immunohistological staining, flow cytometry, and G-band karyotyping, for diagnosis and subclassification of lymphoma.RESULTS:Among the 152 patients ultimately diagnosed with lymphoma, 147 patients (96.7%) were diagnosed by EUS-FNAB, and classification in accordance with the WHO (World Health Organization) system was also possible for 135 patients (88.8%) on the basis of histological findings, including immunohistological staining. Flow cytometry showed abnormal or unusual cell populations in 121 (79.6%) of the 152 patients diagnosed with lymphoma, and in 114 (90.5%) of the 126 patients diagnosed with B-cell lymphoma. Specific cytogenetic abnormalities were detected in 21 (13.8%) of the lymphoma patients.CONCLUSIONS:EUS-FNAB using a standard 19-gauge needle has high diagnostic value for lymphoma. Immunophenotyping is usually possible, while cytogenetic abnormalities can be identified in a relatively limited number of patients.

Serum concentration of L-kynurenine predicts the clinical outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP

Purpose: Introduction of rituximab has largely improved the prognosis of patients with diffuse large B‐cell lymphoma(DLBCL). Such change in therapeutic outcome necessitates the identification of additional prognostic factors to conventional indexes that have been validated for CHOP without rituximab. Indoleamine 2,3‐dioxygenase (IDO) exerts intense immunomodulatory effects because of enzymatic activities that catalyze the breakdown of the essential amino acid L‐tryptophan. The activity of IDO can be estimated by measuring the serum concentration of L‐kynurenine. Here, we investigated the role of L‐kynurenine as a prognostic marker in R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy. Experimental design: Data from 73 consecutive patients treated with eight cycles of R‐CHOP or R‐THP (tetrahydropyranyl adriamycin)‐COP between December 2002 and March 2007 were analyzed. L‐kynurenine concentrations in serum samples obtained at admission were measured by high‐performance liquid chromatography. Results: The median serum L‐kynurenine level was 1.575 μm (range 0.537–9.588). The complete response (CR) rates of patients with L‐kynurenine <1.5 and ≥1.5 μm were 83% and 61%, respectively (P < 0.05). The three‐yr overall survival (OS) rates for patients with L‐kynurenine <1.5 and ≥1.5 μm were 89% and 58%, respectively (P < 0.005). In addition, higher age, poor performance status, elevated serum lactate dehydrogenase, and unfavorable as well as revised International Prognosis Index were significantly worse factors for CR rate and OS. Multivariate analyses revealed only L‐kynurenine as an independent prognostic factor for OS. Conclusions: Serum L‐kynurenine might be a novel prognostic factor to determine the treatment outcome of DLBCL with the R‐CHOP regimen.

Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP

Indoleamine 2,3-dioxygenase (IDO) exerts immunomodulatory effects due to enzymatic activities catalyzing the essential amino acid l-tryptophan. IDO activity might play an important role in regulating immune responses exerted by antigen-presenting cells as a potent tool to help escape from assault by the immune system. In this study, we performed immunohistochemical analysis for IDO expression using mouse anti-human IDO monoclonal antibody in 119 tissue samples of diffuse large B-cell lymphoma (DLBCL) obtained before treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Not only the lymphoma cells themselves but also dendritic cells (DCs) expressed IDO. Positive IDO expression in lymphoma cells was found in 38 cases (32%). Complete remission rates in patients with IDO-positive DLBCL and IDO-negative DLBCL were 55.3% and 79.0% (p = 0.008), while 3-year overall survival rates were 49.8% and 78.8%, respectively (p = 0.0003). IDO activity might thus play an important role in DLBCL and cells that express IDO appear important for determining outcomes after R-CHOP treatment. IDO might represent a candidate therapeutic target for DLBCL patients who show resistance to chemotherapy.

Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation

A 52-year-old woman was found to have a liver tumor during treatment for a liver abscess. The tumor was diagnosed as intrahepatic cholangiocarcinoma by closer examinations, including a percutaneous needle biopsy. Ten years previously, she had undergone excision of a choledochal cyst, with reconstruction by Roux-en-Y hepaticojejunostomy, as treatment for Todanis type Ia congenital biliary dilation, which had been confined only to the extrahepatic bile duct. The significant association between congenital biliary dilation and hepatobiliary malignancies is well known. Some patients have been reported to develop biliary cancer long after the excision of the entire extrahepatic bile duct and hepaticoenterostomy. However, in these patients, the development mostly took place in the remnant choledochal cyst, the anastomotic site, or in the dilated intrahepatic bile duct of Todanis type IV-A congenital biliary dilation. The development of intrahepatic cholangiocarcinoma after operation has not been reported previously in a patient with Todanis type I congenital biliary dilation. This case suggests that the entire biliary tree may have a high risk of field cancerization, even in extrahepatic congenital biliary dilation.

Expression of survivin and of antigen detected by a novel monoclonal antibody, T332, is associated with outcome of diffuse large B-cell lymphoma and its subtypes

Although diffuse large B‐cell lymphoma (DLBCL) is the most common type of non‐Hodgkin lymphoma, it is both clinically and morphologically heterogenous. The present study investigates the significance of survivin and a novel monoclonal antibody (MAb), T332, immunohistochemically for predicting the prognoses of DLBCL and its subtypes classified as germinal center B‐cell‐like type (GCB) and non‐GCB type (NGCB) based on the expression profiles of CD10, bcl‐6, and MUM1. A total of 60 cases of DLBCL (GCB, n = 22; NGCB, n = 38) were examined for the expression of survivin and T332 antigen. Survivin+ DLBCL had a significantly worse prognosis (P = 0.01) than survivin– cases, as already reported, while survivin+ GCB or NGCB tended to have poor prognoses (P = 0.06 and 0.07, respectively). However, T332+ DLBCL and NGCB had significantly more unfavorable prognoses than T332– cases (P = 0.01 and 0.02, respectively) while there was no significant survival difference between the T332+ and T332– groups of GCB (P = 0.11). Interestingly DLBCL coexpressing survivin and T332 (n = 13) had a significantly worse prognosis (P = 0.009) than the remaining single positive and double negative cases (n = 31). In conclusion, survivin and the novel MAb, T332, might be a good predictor of DLBCL and its subtypes.

Serum‐soluble tumor necrosis factor receptor 2 (sTNF‐R2) level determines clinical outcome in patients with aggressive non‐Hodgkin's lymphoma

Abstract:  Background: Recently investigators have worked to identify prognostic factors in non‐Hodgkins lymphoma (NHL) so an appropriate therapeutic plan can be put in action. The aim of the present study was to assess the prognostic significance of serum soluble tumor necrosis factor receptor (sTNF‐R) 2 in aggressive NHL. Methods: One hundred and ten consecutive patients with aggressive NHL who were previously untreated (diffuse large B‐cell lymphoma; 94, peripheral T‐cell lymphoma; 16) were prospectively enrolled in this study between 1997 and 2002. The patients were treated with 6–8 cycles of CHOP or THP‐COP regimens. Results: High serum sTNF‐Rs level was associated with some poor prognostic factors and low complete remission rate. Patients with high sTNF‐R1 (4 ng/mL and over) and sTNF‐R2 (15 ng/mL and over) at onset had significantly lower survival rates (5 yr: 19%, 19%) than those with low sTNF‐R1 (under 4 ng/mL) and sTNF‐R2 (under 15 ng/mL) (62% and 69%), respectively (P < 0.0005 and 0.0001). Multivariate analysis employing sTNF‐R2 and some conventional prognostic factors demonstrated that a combination of sTNF‐R2 and performance status, and that of sTNF‐R2, sIL‐2R, and LDH were significant prognostic factors for poor overall survival and for poor event‐free survival, respectively. In addition, we attempted to use sTNF‐R2 in combination with the international prognostic index (IPI). The patients in the high risk group and those with high sTNF‐R2 in the low‐intermediate (LI)/high‐intermediate (HI) risk group had significantly lower survival rates than the patients in the low risk group and those with low sTNF‐R2 in LI/HI risk group (P < 0.0001). Conclusions: The results suggest that a high serum sTNF‐R2 level predicts a poor prognosis in aggressive NHL and may be a useful biomarker for selecting appropriate treatment when used in combination with the IPI.

Efficacy and safety of micafungin for treating febrile neutropenia in hematological malignancies

Less toxic antifungal drugs are required for empirical antifungal therapy. Micafungin is an echinocandin drug that is effective against both Candida and Aspergillus, and preliminary clinical studies have shown good antifungal activity. We prospectively examined the effect and safety of micafungin against febrile neutropenia with suspected fungal infection in 53 patients (median age, 56 years) who had undergone chemotherapy. The administered dose of micafungin was 150 mg/day, and its effect was evaluated as fever resolution as well as the results of chest imaging and serum fungal tests. Micafungin levels were measured on day 4 after the first administration using high‐performance liquid chromatography. We also measured trough levels of micafungin. Underlying diseases comprised acute lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 20), multiple myeloma (n = 3), and non‐Hodgkins lymphoma (n = 26). The overall efficacy of micafungin was 70%. Breakthrough fungal infections were documented in two (3.8%) patients, both of whom died of invasive mycosis. None of the patients were switched to other antifungal drugs due to events unrelated to adverse effects. Plasma levels of micafungin and the degree of hepatic or renal dysfunction did not correlate. Micafungin is safe and effective for the empirical antifungal therapy of febrile neutropenia in patients with hematological malignancies. Am. J. Hematol., 2010.

Phase II study of the tetrahydropyranyl adriamycin–cyclophosphamide, vincristine, and prednisolone regimen combined with rituximab as first-line treatment for elderly patients with diffuse large B-cell lymphoma

The anthracycline drug pirarubicin (tetrahydropyranyl adriamycin; THP) apparently has fewer cardiotoxic effects than doxorubicin. We previously described the benefit of the THP-COP regimen comprising cyclophosphamide, THP, vincristine, and prednisolone for elderly patients with diffuse large B-cell lymphoma (DLBCL). However, that study was completed before rituximab (R) was introduced into clinical practice. Here we report a phase II study of the THP-COP regimen combined with R (R-THP-COP) every 3 weeks. The complete response and 3-year overall survival rates was 63% and 53%, respectively, and no deaths were related to the regimen. We conclude that the R-THP-COP regimen is safe and effective for patients with DLBCL. Based on these results, a randomized controlled trial of rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and R-THP-COP as a phase III study is ongoing.

Duodenal follicular lymphoma: comprehensive gene expression analysis with insights into pathogenesis.

Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B‐cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT‐PCR experiments and immunohistochemical analysis for 72 formalin‐fixed, paraffin‐embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM‐1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT‐PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co‐expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM‐1 and co‐expression of CCL20 and CCR6 may play an important role in tumorigenesis.