Application of Mass Spectrometry for Determining the Geographic Production Area of Wagyu Beef.

Japanese Black cattle (Japanese Wagyu) beef is attracting attention for its aroma and marbling, and its handling is increasing worldwide. Here, we focused on the origin discrimination of Wagyu beef and analyzed the nutritional components of Japanese Wagyu (produced in multiple prefectures of Japan), Hybrid Wagyu (a cross between Angus and Wagyu cattle born in Australia and transported to Japan), and Australian Wagyu beef using mass spectrometry (MS). Triple-quadrupole liquid chromatography-MS was used to clarify the molecular species of lipids in Wagyu beef. Fourteen classes of lipids were separated, and 128 different triacylglycerides (TGs) were detected. A simple comparative analysis of these TGs using high-performance liquid chromatography revealed significantly higher levels of triolein (C18:1/C18:1/C18:1; abbreviated OOO) and C18:1/C18:1/C16:1 (OOPo) in Japanese Wagyu. Wagyu elements beef were comprehensively analyzed using inductively coupled plasma (ICP)-MS and ICP-optical emission spectrometry. We found significant differences in the rubidium, cesium, and lithium levels of Japanese and Australian Wagyu beef. On comparing metabolites using gas chromatography-MS, we identified significant differences in the levels of amino acids and other components of the Japanese and Australian Wagyu beef. These results suggest the possibility of determining the origin of Wagyu cattle breeds using MS and genetic discrimination.

Gastrointestinal stromal tumors in the duodenum show increased contrast enhancement compared with those in the stomach on computed tomography.

Duodenal gastrointestinal stromal tumors (D-GISTs) are a rare and relatively small subset of GISTs whose imaging features are not well known. The present study aimed to evaluate the enhancement pattern of D-GISTs compared with that of gastric GISTs (G-GISTs) using dynamic computed tomography. This single-center, retrospective, clinicopathological analysis was conducted on 10 patients with D-GISTs who underwent surgery between June 2006 and October 2018. In the same period, 25 patients with G-GISTs underwent surgery and were enrolled. The contrast ratio was defined as the ratio between Hounsfield units in contrast enhanced and unenhanced images in different phases, and these ratios were compared between the D-GIST and G-GIST groups. Furthermore, microvessel density, analyzed by immunohistochemical staining for CD31, was compared between the D-GIST and G-GIST groups. The contrast ratio of D-GIST was significantly higher than that of G-GIST in the arterial, portal and delayed phases (P<0.01, P<0.01 and P=0.02, respectively). The microvessel density of the D-GISTs was significantly higher than that of the G-GISTs (P<0.0001). D-GISTs were more hypervascular than G-GISTs on both imaging and pathological analyses.

Comprehensive Analysis of Lipid Composition in Human Foremilk and Hindmilk.

Precision nutrition, also referred to as personalized nutrition, focuses on the individual to determine the individual's most effective eating plan to prevent or treat disease. A precision nutrition for infants requires the determination of the profile of human milk. We compared the lipid profiles of the foremilk (i.e., the initial milk of a breastfeed) and hindmilk (the last milk) of six Japanese subjects and evaluated whether a human milk lipid profile is useful for precision nutrition even though the fat concentration fluctuates during lactation. We detected and quantified 527 species with a lipidome analysis by liquid chromatography-tandem mass spectrometry. The fat concentration in hindmilk (120.6 ± 66.7 µmol/mL) was significantly higher than that in foremilk (68.6 ± 33.3 µmol/mL). While the total carbon number of fatty acids in triglyceride (TG) was highest in C52 for all subjects, the second or third number differed among the subjects. Both the distribution of total carbon number of fatty acids included in TG and the distribution of fatty acids in TG classified by the number of double bonds were almost the same in the foremilk and hindmilk in each subject. The lipids levels containing docosahexaenoic acid and arachidonic acid in total lipids of the foremilk and the hindmilk were almost the same in each subject. Among the sphingolipids and glycerophospholipids, the level of sphingomyelin was the highest in four subjects' milk, and phosphatidylcholine was the highest in the other two subjects' milk. The order of their major species was the same in each foremilk and hindmilk. A clustering heatmap revealed the differences between foremilk and hindmilk in the same subject were smaller than the differences among individuals. Our analyses indicate that a human-milk lipid profile reflects individual characteristics and is a worthwhile focus for precision nutrition.

A case of ectopic hamartomatous thymoma: controversy over the designation.

BACKGROUND: Ectopic hamartomatous thymoma, which usually occurs in the lower neck, is a rare benign tumor containing spindle cells, epithelial nests, and adipose tissue. Although the origin of this tumor is still unknown, recent reports suggest that the designation of this tumor is inappropriate. CASE PRESENTATION: A 38-year-old with an anterior cervical mass in the suprasternal region of her neck was referred to our hospital. An ultrasound examination showed that the well-defined oval mass was 31 × 23 × 17 mm in size. A non-enhanced computed tomography scan of the neck revealed that the distinct neck mass in the subcutaneous tissue had a mixture of soft tissue and fatty components. The cervical tumor was clinically diagnosed to be an unusual lipoma with degeneration. The patient underwent the neck mass extirpation. During the surgery, the cervical mass was well demarcated and did not adhere to the surrounding tissues. The postoperative course was uneventful. The gross pathology report showed that the neck mass measured 3.0 × 2.5 × 2.0 cm. Microscopically, the tumor was composed of spindle cells, epithelial nests, and mature adipose tissue. Immunohistochemical examination revealed that both spindle cells and epithelial nests were positive for cytokeratin AE1/AE3. These histopathological findings were consistent with the features of ectopic hamartomatous thymoma. Over a follow-up period of 30 months, this patient exhibited no evidence of recurrence. CONCLUSIONS: Ectopic hamartomatous thymoma should be considered in the differential diagnosis of subcutaneous tumors in the lower neck, when the CT shows the tumor has the mixed components of fat and soft tissues.

Frequent MYD88 L265P and CD79B Mutations in Primary Breast Diffuse Large B-Cell Lymphoma.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare disease comprising <3% of extranodal lymphomas. It frequently reveals an activated B-cell (ABC)-like phenotype. ABC-like DLBCL was reported to have gain-of-function mutations in MYD88, CD79B, CARD11, and TNFAIP3, resulting in constitutive activation of the NFκB pathway. Because of the rare occurrence of PB-DLBCL, the frequency of MYD88 and CD79B mutations is still unknown. We used Sanger sequencing to study these mutations from 46 breast DLBCL cases and also investigated the associated clinicopathologic factors. MYD88 L265P was confirmed by allele-specific polymerase chain reaction and compared with the Sanger sequencing results. MYD88 L265P and CD79B mutations were detected in 27/46 (58.7%) and 11/33 (33.3%) cases, respectively. Twenty-eight of 46 cases met the criteria for PB-DLBCL, and the latter 18 cases were further classified as clinical breast DLBCL (CLB-DLBCL). The frequency of MYD88 L265P and CD79B mutations was 16/28 (57.1%) and 9/23 (39.1%), respectively, in PB-DLBCL and 11/18 (61.1%) and 2/10 (20%), respectively, in CLB-DLBCL. When the cutoff value was set at ΔCt≤1, the result of allele-specific polymerase chain reaction for MYD88 corresponded to those of the Sanger sequence at 92.6% sensitivity and 100% specificity. According to Choi's algorithm, 16/27 (59.3%) demonstrated an ABC-like phenotype in PB-DLBCL, and 15/18 (83.3%) demonstrated an ABC-like phenotype in CLB-DLBCL. In conclusion, MYD88 L265P and CD79B mutations were frequently detected in PB-DLBCL, and they may be key molecules associated with PB-DLBCL lymphomagenesis. Further analysis will be required to clarify the mechanism of its pathogenesis.

Effects of causeway construction on environment and biota of subtropical tidal flats in Okinawa, Japan.

Okinawa, Japan is known for its high marine biodiversity, yet little work has been performed on examining impacts of numerous large-scale coastal development projects on its marine ecosystems. Here, we examine apparent impacts of the construction of the Kaichu-Doro causeway, which was built over 40 years ago. The causeway is a 4.75 km long embankment that divides a large tidal flat and has only two points of water exchange along its entire length. We employed quadrats, transects, sampling, visual surveys, and microbial community analyses combined with environmental, water quality data, and 1m cores, at five stations of two paired sites each (one on each side of Kaichu-Doro) to investigate how the environment and biota have changed since the Kaichu-Doro was built. Results indicate reduction in water flow, and site S1 was particularly heavily impacted by poor water quality, with low diversity and disturbed biotic communities.

Low-grade B-cell lymphoma presenting primarily in the bone marrow.

Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma.

Germinal center B-cell-like diffuse large B-cell lymphoma of the duodenum is associated with t(14;18) translocation.

Diffuse large B-cell lymphoma (DLBCL) rarely involves the duodenum, and its clinicopathological characteristics have not been well elucidated. We performed clinicopathological examinations and identified 15 patients with duodenal DLBCL using 18 gastric or colonic DLBCL as a control. Eleven of the 15 patients (73%) were subclassified by immunohistochemical analysis according to the Choi algorithm as germinal center B-cell-like (GCB) type, whereas the 18 control gastric and colonic DLBCL were predominantly subclassified as activated B-cell-like (ABC) type. The classifications according to organ involvement were statistically significant (P= 0.011 and P= 0.035). Macroscopically, the GCB lesions were varied, while all ABC lesions were ulcerative. Fluorescence in situ hybridization analysis revealed a higher frequency of t(14;18) translocation in patients with duodenal DLBCL (3 of 13) as compared with non-duodenal gastrointestinal tract DLBCL (0 of 18), however, the difference was not significant (P = 0.064). Furthermore, the three patients with t(14;18) translocations were classified as GCB. In addition, overall survival of patients was statistically different between those with and without t(14;18) translocation (P= 0.040). In conclusion, duodenal DLBCL predominantly exhibits GCB-type tumors and the frequency of t(14;18) translocation appears to be higher in duodenal GCB-type DLBCL compared to non-duodenal tumors.

Cyclin D2 is overexpressed in proliferation centers of chronic lymphocytic leukemia/small lymphocytic lymphoma.

The D cyclins are important cell cycle regulatory proteins involved in the pathogenesis of some lymphomas. Cyclin D1 overexpression is a hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 have not been shown to be closely associated with any particular subtype of lymphoma. In the present study, we found that cyclin D2 was specifically overexpressed in the proliferation centers (PC) of all cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) examined (19/19). To examine the molecular mechanisms underlying this overexpression, we immunohistochemically examined the expression of nuclear factor (NF)-κB, p15, p16, p18, and p27 in the PC of six patients. Five cases showed upregulation of NF-κB expression, which is known to directly induce cyclin D2 by binding to the promoter region of CCND2. All six PC examined demonstrated downregulation of p27 expression. In contrast, upregulation of p15 expression was detected in five of six PC examined. This discrepancy suggests that unknown cell cycle regulatory mechanisms involving NF-κB-related pathways are also involved, because NF-κB upregulates cyclin D2 not only directly, but also indirectly through c-Myc, which is believed to downregulate both p27 and p15. In conclusion, cyclin D2 is overexpressed in the PC of CLL/SLL and this overexpression is due, in part, to the upregulation of NF-κB-related pathways.

Gastric adenocarcinoma of fundic gland type (chief cell predominant type) treated with endoscopic aspiration mucosectomy.

Upper endoscopy screening in an asymptomatic 56-year-old man showed a small, yellowish elevated lesion with a central depression on the posterior wall in the gastric cardia. Biopsy specimens from this lesion were suspicious of carcinoid tumor. We suspected this lesion to be a sporadic gastric carcinoid tumor with a diameter of 5 mm, limited to the mucosal layer. We then performed an endoscopic aspiration mucosectomy with a cap-fitted endoscope. Microscopically, the lesion obtained from the resected specimen was minimally invasive to the submucosa and showed highly differentiated columnar cells in irregularly anastomosing glands. Immunohistology was positive for pepsinogen-I, and MUC6, partially positive for H(+)/K(+)-ATPase, and negative for MUC5AC. In addition, it was positive for synaptophysin and CD56, and negative for chromogranin A. We finally diagnosed the patient as having gastric adenocarcinoma of fundic gland type (chief cell predominant type) with minimal invasion (100 µm) to the submucosa. Surveillance endoscopy with biopsy specimens and abdominal computed tomography at 1 year revealed no evidence of tumor recurrence. We herein report this rare case of gastric adenocarcinoma of fundic gland type (chief cell predominant type).

Downregulation of the B-cell receptor signaling component CD79b in plasma cell myeloma: a possible post transcriptional regulation.

The CD79 molecule, encoded by the CD79a and CD79b genes, is a signaling unit of the B-cell receptor complex, which transmits signals of B-cell activation, growth, and differentiation. They are B-cell-specific and expressed at most stages of B-cell development. Although plasma cells have been believed to lack these gene products, the regulation of CD79 expression in plasma cells is still controversial. In particular, the regulation of CD79b expression remains unclear. We sought to examine CD79b expression in normal and neoplastic plasma cells by immunohistochemical analysis. Out of the 23 clinical samples and 11 cell lines of plasma cell myeloma (PCM), none of the clinical samples and only 1 of 11 cell lines expressed CD79b immunohistologically, whereas non-neoplastic plasma cells in reactive hyperplastic lymph nodes exhibited loss of CD79b protein expression. This finding is quite different from our previous report on CD79a. Not only immunocytochemistry, but also RT-PCR and Western blot analysis of PCM cell lines gave identical results. Interestingly, we detected mRNA transcripts of CD79b in PCM cell lines, although protein translation was lacking. These findings suggest that expression of CD79b is downregulated in both plasma cells and plasma cell myeloma, and this process is possibly under post transcriptional regulation.

Diversity of oligotrichia and choreotrichia ciliates in coastal marine sediments and in overlying plankton.

Elucidating the relationship between ciliate communities in the benthos and the plankton is critical to understanding ciliate diversity in marine systems. Although data for many lineages are sparse, at least some members of the dominant marine ciliate clades Oligotrichia and Choreotrichia can be found in both plankton and benthos, in the latter either as cysts or active forms. In this study, we developed a molecular approach to address the relationship between the diversity of ciliates in the plankton and those of the underlying benthos in the same locations. Samples from plankton and sediments were compared across three sites along the New England coast, and additional subsamples were analyzed to assess reproducibility of methods. We found that sediment and plankton subsamples differed in their robustness to repeated subsampling. Sediment subsamples (i.e., 1-g aliquots from a single approximately 20-g sample) gave variable estimates of diversity, while plankton subsamples produced consistent results. These results indicate the need for additional study to determine the spatial scale over which diversity varies in marine sediments. Clustering of phylogenetic types indicates that benthic assemblages of oligotrichs and choreotrichs appear to be more like those from spatially remote benthic communities than the ciliate communities sampled in the water above them.

Ciliate diversity and distribution across an environmental and depth gradient in Long Island Sound, USA.

The nature and extent of microbial biodiversity remain controversial with persistent debates over patterns of distributions (i.e. cosmopolitanism versus endemism) and the processes that structure these patterns (neutrality versus selection). We used culture-independent approaches to address these issues focusing on two groups of ciliates, the Oligotrichia (Spirotrichea) and Choreotrichia (Spirotrichea) across an environmental gradient. We assessed SSU rDNA diversity in ciliate communities at six stations in Long Island Sound spanning the frontal region that separates the fresher Connecticut River outflow plume from the open Sound. As in previous studies, we find one abundant cosmopolitan species (Strombidium biarmatum), a few moderately abundant sequences, and a long list of rare sequences. Furthermore, neither ciliate diversity nor species composition showed any clear relationship to measured environmental parameters (temperature, salinity, accessory pigment composition and chorophyll). Overall, we observed that diversity decreased moving from nearshore to offshore. We also conducted analyses to detect clustering among the sampled communities using the software Unifrac. This approach revealed three significant clusters grouping samples from nearshore, surface and deep/well mixed stations. We find no strong fit of our communities to log series, geometric or log normal distributions, though one of the 3 clusters is most consistent with a log series distribution. However, when we remove the abundant cosmopolitan species S. biarmatum, all three clusters fit to a log series distribution. These analyses suggest that, with the exception of one cosmopolitan species, the oligotrich and choreotrich communities at these stations may be distributed in a neutral manner.

Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma.

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.

Frequent downregulation or loss of CD79a expression in plasma cell myelomas: potential clue for diagnosis.

Plasma cell myeloma is a frequent hematogeneous disorder that occurs mainly in older people. Not only bone marrow smears but also clots and/or biopsied specimens are often taken for confirmation of pathological diagnosis. Some specimens show sheet-like plasma cell proliferation associated with immunoglobulin monotype on immunohistology, which readily leads to diagnosis, but many samples do not clearly show light-chain restriction. The aim of the present study was therefore to examine CD79a expression because some samples had reduced expression or none at all. The immunoreactivity of CD79a was categorized into three groups: positive, weakly positive and negative, compared with scattering non-neoplastic plasma cells in the same specimen. Out of 100 specimens of plasma cell myeloma, 48% were positive for CD79a, 15% were weakly positive, and 37% were negative. In contrast, overexpression of cyclinD1 was detected in 26% of examined samples. CD79a-negative cases had a significantly lower percentage of positive staining for cyclinD1 than CD79a-positive or weakly positive cases. Clinicopathological data showed that CD79a-negative expression was associated with decreased platelet numbers in patients. The present study indicates that downregulation or loss of CD79a and/or overexpression of cyclin D1, observed in 59% of neoplastic plasma cell samples, could provide a strong diagnostic clue without regard to the results of immunoglobulin light-chain restriction.

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.

Duodenal and nodal follicular lymphomas are distinct: the former lacks activation-induced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations.

Although most follicular lymphomas are believed to be of nodal origin, they sometimes originate from the duodenum. We have reported that the latter differ from nodal follicular lymphomas in having lower clinical stages and uniformly low histological grades, along with variable region of immunoglobulin heavy chain gene (VH) usage that is more similar to mucosa-associated lymphoid tissue (MALT) lymphomas. Little is known, however, about whether they possess other characteristics of nodal follicular lymphomas, particularly ongoing mutations with follicular dendritic cells. We examined 17 cases for which PCR identified the monoclonal bands of the immunoglobulin gene. The duodenal cases showed ongoing mutations, but they lacked activation-induced cytidine deaminase (AID) expression, a statistically significant difference from the nodal cases (P<0.001), and their follicular dendritic cell networks were disrupted. Moreover, not only were VH deviations observed but also they used very restricted VH genes. Although the mechanisms of ongoing mutation without AID and follicular dendritic cell were not clarified, restricted VH usage strongly suggested that antigen stimulation was involved, and that was similar to MALT lymphomas. In conclusion, duodenal follicular lymphomas were shown to be unique, in that they had ongoing hypermutations such as nodal cases, but the mechanisms involved in the hypermutation were quite different; furthermore, restricted VH usage suggested a strong similarity to the antigen-dependent origin of MALT lymphomas.

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 Castleman's 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 Castleman's 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 Castleman's 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 Castleman's 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.

Patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma exhibit favorable prognosis despite a non-germinal center B-cell-like phenotype.

Diffuse large B-cell lymphomas are detected frequently in the oral cavity. Although tonsillar lymphomas have been rather well characterized, lymphomas originating from non-tonsillar regions, such as the gingiva, palate, and tongue, have not been well studied. We examined the pathology of clinical samples obtained from 21 patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma. Immunohistological examination of CD10, Bcl-6, and MUM1 determined that 17 of 21 (81%) samples exhibited non-germinal center B-cell type, an increased proportion of non-germinal center B-cell type compared with previous reports in samples of tonsillar origin (P<0.05). The four remaining samples exhibited germinal center B-cell type, although one sample expressed MUM1. Follow-up clinical survival data were obtained from the 17 patients over a range from 4 to 173 months (mean 52 months). All patients were treated with chemotherapies, irradiation, or surgical resection. Sixteen patients achieved complete remission and two patients relapsed, but no patient has died of disease. Extranodal diffuse large B-cell lymphomas of non-germinal center B-cell type are generally characterized by poor prognosis, regardless of localized disease. Interestingly, our results indicate that, unlike similar lymphomas of tonsillar origin, localized primary non-tonsillar oral diffuse large B-cell lymphomas exhibit favorable prognosis, suggesting that these lymphomas may be clinicopathologically distinct.

IgG4-producing marginal zone B-cell lymphoma.

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. Little is known about lymphomagenesis in the context of IgG4-related disease, we recently first reported the ocular adnexal marginal zone B-cell lymphomas arising from IgG4-related disease. To the best of our knowledge, no existing study has ever established the neoplastic potential of IgG4-producing cells. In the present report, we describe the first IgG4-producing lymphoma. The patient was a 72-year-old male who was being followed for an asbestos-related pleural plaque. During follow-up, computed tomography revealed bilateral renal masses and multiple swollen retroperitoneal lymph nodes. A retroperitoneal lymph node biopsy was performed. Histologically, the interfollicular areas were expanded by medium to large plasmacytoid cells. These plasmacytoid cells showed nuclear pleomorphism and had prominent Russell bodies. Immunohistochemistry and double immunofluorescence staining of these cells revealed IgG4 positivity and monotypic lambda-light chain predominance. A portion of these cells were partially positive for CD20, negative for CD3, and somewhat faintly positive for CD138. In addition, serum IgG4 was elevated. Southern blot analysis of the lymph node specimen detected immunoglobulin heavy chain gene rearrangement. The present study indicates that, not only can malignant lymphomas occur in the setting of IgG4-related disease, but IgG4-producing cells can also be neoplastic.