Disordered Balance of T-Cell Subsets in Arterial Tertiary Lymphoid Organs in Immunoglobulin G4-Related Vascular Disease.

BACKGROUND: Arterial/aortic tertiary lymphoid organs (ATLOs), characterized by germinal centers, control local arterial immune responses. T follicular helper cells (Tfh), resident in germinal centers, regulate immunoglobulin production and germinal center development. They consist of Tfh1, Tfh2, and Tfh17 subsets. T follicular regulatory (Tfr) cells possess suppressive functions as regulatory T cells and migrate into germinal centers. Immunoglobulin G4 (IgG4)-related diseases manifest in vascular lesions as frequently formed inflammatory aneurysms (IgG4-related abdominal aortic aneurysm [IgG4-AAAs]). IgG4-AAAs contain several ATLOs. METHODS AND RESULTS: We performed whole-slide immunohistochemical image analysis in surgical specimens of IgG4-AAAs (n=21), non-IgG4-related inflammatory AAAs (n=17), atherosclerotic AAAs (n=10), and Takayasu arteritis (n=5). IgG4-AAA was characterized by numerous, large, irregular-shaped ATLOs, and higher numbers of Tfr and Tfh2 cells than Tfh1 cells were present compared with others. The morphologic abnormalities (in number, area, and form) of ATLOs in IgG4-AAAs and the increased number of Tfr cells are closely related to the activity of IgG4-related diseases. All T-cell subsets were more enriched within ATLOs than outside ATLOs. In particular, an increase in Tfr cells in IgG4-AAAs was associated with ATLO formation. Increased Tfh17 cells were found in Takayasu arteritis, and atherosclerotic AAA and non-IgG4-related inflammatory AAAs were characterized by increased Tfh1 cells. CONCLUSIONS: In the classification of vascular lesions, considering the imbalance in T-cell subsets, IgG4-AAA should be positioned as adventitial vasculitis with predominant Tfr and Tfh2 cells, accompanied by the abnormal appearance of ATLOs.

Epstein-Barr Virus-Positive Cutaneous and Systemic Plasmacytosis with TAFRO Syndrome-like Symptoms Successfully Treated with Rituximab.

Histopathologic findings in the lymph nodes of patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome are similar to those of idiopathic multicentric Castleman's disease (iMCD), but TAFRO syndrome is different from iMCD in how it can progress rapidly and be fatal. These patients present scarce lymphadenopathy and low immunoglobulin levels. We present a case of cutaneous and systemic plasmacytosis (C/SP) that caused TAFRO syndrome-like symptoms which were successfully treated with rituximab. A 67-year-old woman presented with fever and a pruritic skin rash. Numerous plasma cells were observed in the peripheral blood and imaging revealed organomegaly, anasarca, and generalized lymphadenopathy. Subsequently, she rapidly developed thrombocytopenia as well as renal and heart failure. She tested positive for the Epstein-Barr virus (EBV), elevated immunoglobulins, and C/SP, which are also atypical for TAFRO syndrome, thereby complicating the diagnosis. However, after using the Japanese TAFRO Syndrome Research Group diagnostic criteria, we promptly administered rituximab to treat the C/SP with TAFRO-like symptoms and saved her life. Finally, histopathological observations of the lymph node biopsy helped confirm EBV-positive hypervascular-type iMCD. Therefore, diagnosing TAFRO-like syndromes based on the Japanese diagnostic criteria and following the associated treatment even without a confirmed diagnosis is crucial to improving the patient outcomes.

The disturbance of the distribution of T helper cell subsets in the mantle area surrounding germinal centers in immunoglobulin G4-related sclerosing sialadenitis.

The function of germinal centers (GCs) is an important factor in the pathogenesis of immunoglobulin G4 (IgG4)-related disease, in which inflammatory and fibrotic processes are controlled by type 2 helper T (Th) cells and regulatory T cells. T follicular helper cells (Tfh), which are present in GCs, regulate GC development, and they consist of Tfh1, Tfh2, and Tfh17 subsets. This study examined the association of Th cell subsets in IgG4-RD and pathogenesis of the disease using whole-slide image analysis for immunohistochemistry. IgG4-related sclerosing sialadenitis (IgG4-SS, n = 19) was characterized by higher numbers of Tfh2 and Tfh17 cells than Tfh1 cells compared to the findings in patients with chronic sialadenitis (n = 18) or Sjögren syndrome (n = 17). The number of Tfh2 cells was significantly associated with all parameters of GC structures and the number of IgG4 + plasmacytes, whereas the number of Tfh1 cells was inversely associated with the aforementioned parameters. Concerning extrafollicular helper T (Teh) cells, among three groups, the Tfh2/Teh2 ratio was highest and the Tfh1/Teh1 ratio was lowest in the IgG4-SS group, which exhibited a characteristically regional distribution of Tfh and Teh subsets, especially higher numbers of Teh2 cells and lower numbers of Teh1 cells in the mantle areas surrounding GCs. Mantle Teh2 cells and central Tfh17 cells were significantly correlated with morphological abnormalities of GCs. Our results indicated that the peculiar regional distribution and altered balance of Tfh and Teh subsets are novel hallmarks of IgG4-SS that are associated with GC formation in IgG4-SS.

Regional disturbance of the distribution of T regulatory cells and T helper cells associated with irregular-shaped germinal centers in immunoglobulin G4-related sialadenitis.

Although many germinal centers (GCs) have been reported in immunoglobulin (Ig) G4-related disease, the significance of GCs in IgG4-related disease has not received attention. Both T follicular regulatory cells (Tfr), which are regulatory T cells (Treg) in GCs, and T follicular helper cells (Tfh) produce the cytokine interleukin (IL)-10 and regulate GC development. In whole-slide image analysis in surgical specimens using immunohistochemistry, IgG4-related sclerosing sialadenitis (IgG4-SS, n = 17) was characterized by markedly numerous, large, and irregular-shaped GCs with increased IL-10 + cells and Tfr and Tfh in the total area of the salivary gland compared with controls, including patients with chronic sialadenitis (n = 17) and Sjögren syndrome (n = 15). In particular, the central area of GC in IgG4-SS showed a higher Tfr number and Tfr/Tfh ratio than controls. The number of Tfr in the central area was significantly correlated with the number of IgG4 + plasmacytes and the number, size, and irregularity of GCs. In the mantle area, which surrounds GCs, IgG4-SS showed a higher Treg number and Treg/T helper cells (Th) ratio than controls. In IgG4-SS, the Treg/Th ratio was highest in the mantle area outside GCs and the Tfr/Tfh ratio was highest in the central area inside GCs. However, in controls, the Treg/Th ratio gradually decreased from outside to inside GCs. Our findings reveal that the morphological abnormality of GCs and the characteristic localization and altered balance of Treg and Th in the different compartments of inside and outside GCs would be the novel hallmarks of IgG4-SS.

HPV Genotyping by Molecular Mapping of Tissue Samples in Vaginal Squamous Intraepithelial Neoplasia (VaIN) and Vaginal Squamous Cell Carcinoma (VaSCC).

HPV genotypes were determined in 63 vaginal squamous intraepithelial neoplasia (VaIN) and 7 vaginal squamous cell carcinomas (VaSCC). Of these, 37 cases had VaIN alone, and 26 cases had both VaIN and cervical intraepithelial neoplasia (CIN) or condyloma. HPV typing was performed in scraped cells by Genosearch-31 (GS-31) and in the archived tissues by uniplex E6/E7 PCR. In a total of 49 VaIN1, 17 VaIN2/3, and 7 VaSCC tissues, the prevalence of HPV was 91.2% in VaIN (VaIN1: 87.8%, VaIN2/3: 100%) and 85.7% in VaSCC. Comparing HPV results in scraped cell and tissue, 46.2% of high-risk (HR) types and 68.1% of any HPV types that had been identified in cell samples were not present in corresponding tissues. HPV types in VaIN and CIN lesions differed in 92.3% (24/26) of cases with multiple lesions. These results suggest that there are many preclinical HPV infections in the vagina or the cervix, and VaIN and CIN are independently developed. The manual microdissection procedure of tissue revealed one HPV type in one lesion. Seventeen HPV types, including high-risk (HR), possible high-risk (pHR), and low-risk (LR), were identified in 43 VaIN1 lesions. In higher grade lesions, six HR (HPV16, 18, 51, 52, 56, 58), one pHR (HPV66), and one LR (HPV42) HPV types were identified in 17 VaIN2/3, and six HPV types, including HPV16, 45, 58, and 68 (HR), and HPV53 and 67 (pHR), were detected in each case of VaSCC. The vagina appears to be the reservoir for any mucosal HPV type, and HR- or pHR-HPV types are causative agents for vaginal malignancies.

The role of axillary reverse mapping in intraoperative nodal palpation during sentinel lymph node biopsy.

Intraoperative nodal palpation in the axilla is a mandatory part of sentinel lymph node biopsy. However, there is no consensus regarding the definition of suspicious palpable node. The sampling rate and involvement rate of suspicious palpable nodes are inconsistent. We hypothesized that axillary reverse mapping is helpful to select suspicious palpable sentinel lymph nodes more accurately. Patients with clinically negative nodes underwent sentinel lymph node biopsy with intraoperative nodal palpation and axillary reverse mapping. Blue and hot nodes were removed as sentinel lymph nodes. Suspicious palpable nodes that were neither blue nor hot were removed as palpable sentinel lymph nodes. Nodes around blue and hot sentinel lymph node were incidentally removed as para-sentinel lymph nodes. Fluorescent nodes were considered axillary reverse mapping nodes. Patients with positive sentinel lymph node underwent axillary lymph node dissection. Palpable sentinel lymph nodes and para-sentinel lymph nodes were removed in 130 (15%) of 850 patients with clinically negative nodes. Although palpable sentinel lymph nodes and para-sentinel lymph nodes were involved in 19 (15%) of 130 patients, fluorescent palpable sentinel lymph nodes were involved only in 2 patients and fluorescent para-sentinel lymph nodes were not involved. When excluding fluorescent palpable sentinel lymph nodes and para-sentinel lymph nodes, the sampling rate of suspicious palpable nodes significantly decreased (15% vs. 5%, p < 0.01) and the involvement rate of palpable sentinel lymph nodes significantly increased (15% vs. 31%, p < 0.05). Axillary reverse mapping is helpful to avoid an unnecessary removal of palpable nodes without metastases.

Pancreatic acinar cell carcinoma with extension into the main pancreatic duct: a case report.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare exocrine malignant tumor. Its widespread intraductal extension into the main pancreatic duct (MPD) is also rare. CASE PRESENTATION: We report the case of a 71-year-old man with PACC with MPD extension. The patient was assessed with laboratory and radiographic investigations that facilitated a preoperative diagnosis. Endoscopic ultrasonography (EUS) and dynamic thin-slice multi-detector row computed tomography (MDCT) were useful for determining the resection line of the pancreas. EUS-guided fine needle aspiration (EUS-FNA) was also helpful in determining the tumor biology and treatment strategy. Distal pancreatectomy was performed. The MPD was occupied by the tumor 35 mm downstream and 5 mm upstream. Histopathologically, the pancreatic tail tumor extended continuously into the MPD. The tumor was solid with cells showing eosinophilic and granular cytoplasm, indicating the diagnosis of PACC. This is an interesting case of PACC with intraductal extension into the MPD. We discuss the possible mechanisms of tumor extension in this rare case together with a review of the literature. CONCLUSIONS: We describe a rare pancreatic acinar cell carcinoma that could be adequately treated using preoperative precise imaging and histopathological evaluations. When an intraductal tumor extension in the MPD is encountered, the diagnosis of a rare pancreatic tumor should be considered, as in our case.

The potential role of follicular helper T cells and helper T cells type 1 in Warthin tumour.

Warthin tumour (WT) is a benign tumour of the salivary gland that proliferates in both glandular epithelial and lymphoid tissue components, and rarely exhibits cystic changes. T follicular helper cells (Tfh) are involved in the formation and maintenance of germinal centres, the differentiation of B cells into plasma cells, and the maintenance of helper T cell type 2 (Th2)-dominant humoral immune responses. T-bet induces differentiation into helper T cell type 1 (Th1) by suppressing differentiation into Tfh and enhances cellular immune responses. The objective of this study was to enhance our understanding of the immune responses and relationship between Tfh and Th1 cells in patients with WTs. In this study, we classified WTs (n = 64) into solid-type (n = 25) and cyst-type (n = 39). We also performed immunostaining of the Tfh markers CXCR5 and CD40 L, and the Th1 marker T-bet for statistical analysis. The cyst-type exhibited significant atrophy of the germinal centre area (P = 0.0019), significantly fewer Tfh-positive lymphocytes in germinal centres (P < 0.0001), and significantly more T-bet-positive lymphocytes in the epithelium (P = 0.0017). We observed that Tfh were involved in the formation and maintenance of lymphoid follicles in WTs. In the cyst-type, Th2-dominant humoral immune responses were suppressed, and Th1-dominant cellular immune responses may have caused damage to tumour tissue.

Optimal treatments for TAFRO syndrome: a retrospective surveillance study in Japan.

TAFRO syndrome is a systemic inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. Mortality in patients with this syndrome is high; however, an optimal treatment strategy has not been established. To explore the strategy, we retrospectively analyzed 81 patients with TAFRO syndrome registered in the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome in Japan by December 2019. Sixty-eight patients received corticosteroid therapy as the first-line treatment, and as the second-line treatment, 21 received tocilizumab (Toc), 14 received cyclosporine A (CsA), and 8 received rituximab (Rit) in addition to corticosteroids. We compared these second-line treatment groups by setting the primary endpoint as time to next treatment or death (TTNT). Kaplan-Meier analysis showed that the median TTNT in the Toc, CsA, and Rit groups were 2.8 months, 9.2 months, and not reached, respectively. The TTNT of the Rit group was significantly longer than that of the Toc group. In contrast, there were no significant differences in overall survival between groups, indicating that subsequent salvage therapies rescued a large proportion of patients who failed the second-line treatments. Further studies are warranted to establish the optimal treatment strategies for this syndrome.

Early-stage multi-differentiated gastric carcinosarcoma and post-resection local recurrence: a case report.

BACKGROUND: Carcinosarcoma is a rare neoplasm with a poor prognosis that is most often discovered at an advanced stage; a gastric carcinosarcoma is even rarer than carcinosarcomas originating in other organs, such as the uterus. We report our experience with an early-stage multi-differentiated gastric carcinosarcoma. CASE PRESENTATION: A 68-year-old male patient presented with anemia, and his fecal occult blood test was positive. An endoscopic examination was conducted which revealed a hemorrhagic, irregular, protruding lesion in the stomach. The lesion was diagnosed as an adenocarcinoma by histopathological examination of the biopsy specimen, and a segmental gastrectomy was performed. A 41 × 29 × 18 mm3 protruding lesion was observed in the resection specimen, and histologically confirmed to be a gastric carcinosarcoma with mixed adenocarcinomatous and sarcomatous composition. Tumor invasion was limited to the submucosa. Besides the adenocarcinomatous portion, neuroendocrine differentiation and AFP-positive gastric carcinoma were present in the carcinomatous portion of the tumor; in the sarcomatous portion, chondrosarcomatous, leiomyosarcomatous, and rhabdomyosarcomatous components were observed in addition to the undifferentiated sarcomatous component. Furthermore, the tumor included SALL4-positive germ cell-like cells. Despite early-stage detection, the cancer recurred locally 14 months after tumor resection, which necessitated a total gastrectomy. At the 2-month follow-up after the total gastrectomy, the patient was alive. This patient had developed an esophageal squamous cell carcinoma and primary lung adenosquamous carcinoma, both of which were resected. CONCLUSIONS: Few cases of early-stage gastric carcinosarcoma have been reported, but there are no reports of recurrence to date. Local recurrence as in this patient, and even in early-stage cases, requires cautious surveillance to check for post-resection recurrence and metastasis. The etiopathogenesis of carcinosarcoma has not yet been elucidated; however, in the present case, despite the tumor's relatively small size, it exhibited various types of differentiation in both the carcinomatous and sarcomatous components and a proliferative germ cell-like portion, which suggests that the monoclonal origin hypothesis may be a valid theory for the carcinosarcoma.

Interleukin-6-producing Intravascular Large B-cell Lymphoma with Lymphadenopathy Mimicking the Histology of Multicentric Castleman Disease.

An inguinal lymph node biopsy of a woman with a one-month history of a progressive fever, fatigue, dyspnea, skin rash, and lymphadenopathy revealed a well-preserved basic structure, hyperplastic germinal centers, and an interfollicular region containing polyclonal plasma cell sheets, suggesting plasma cell-type multicentric Castleman disease (MCD). We initiated prednisolone and anti-interleukin (IL)-6 antibody (tocilizumab), without success. A biopsy specimen re-evaluation detected CD20-positive atypical large B cells infiltrating the small vessels within and around the lymph node and its capsule. We diagnosed her with intravascular large B-cell lymphoma (IVLBCL). Lymphoma cells were weakly positive for IL-6 by immunohistochemical staining. IL-6 from lymphoma cells may have caused the MCD-like presentation as a paraneoplastic etiology. Malignant lymphoma should be excluded before diagnosing MCD.

Peroxiredoxin 4 promotes embryonal hepatoblastoma cell migration but induces fetal cell differentiation.

Hepatoblastoma (HB) is the leading primary hepatic malignancy in children and likely emerges due to failure of hepatic progenitor cells to properly differentiate. The peroxiredoxin (PRDX) family is frequently linked to cancer. In our previous study, we demonstrated that expression of the only secreted family member, PRDX4, was correlated with hepatocellular carcinoma. The aim of this new study was to investigate PRDX4's role in HB. We collected 87 HB specimens and performed PRDX4 immunohistochemistry staining. Clinical analysis was conducted and the effect of PRDX4 overexpression on two HB cell lines (Huh6 and HepG2) was also examined. Clinical data revealed elevated PRDX4 expression in embryonal component was correlated with advanced stage (IV) and metastasis. In comparison, increased PRDX4 expression in fetal component was associated with well differentiation. In vitro experiments showed PRDX4 overexpression enhanced migration in embryonal-like HB cells (Huh6), which was accompanied by epithelial-mesenchymal transition (EMT). By contrast, PRDX4 overexpression inhibited proliferation, decreased stemness markers, and increased hepatic markers in fetal-like HB cells (HepG2), which indicated induction of tumor cell differentiation. In conclusion, PRDX4 promotes embryonal hepatoblastoma cell migration but induces fetal cell differentiation. It can be adopted as an important marker for HB prognosis and a potential treatment target.

Case report of large malignant pericardial effusion in a post-surgical setting of endometrial mixed carcinoma: A description of unique cytological, histological, and immunohistochemical findings.

Appearance of endometrial carcinoma in pericardial effusion is extremely rare. Its major etiological factors include lung cancer, breast cancer, lymphoma, and leukemia. We herein report a case of a large malignant pericardial effusion 7 years after surgery for endometrial carcinoma. A 66-year-old woman who underwent modified radical hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection for endometrial carcinoma 7 years ago and who had self-interrupted subsequent chemotherapy was presented with vertigo and vomiting. Chest computed tomography revealed pericardial effusion. Cytological examination diagnosed it as adenocarcinoma with psammoma bodies and mitoses. Immunohistochemistry analysis revealed that adenocarcinoma cells were positive for p53, p16, and insulin-like growth factor II mRNA-binding protein-3, but negative for estrogen receptor. Adenocarcinoma cells in pericardial effusion were morphologically and immunohistochemically similar to the serous carcinoma component of the surgical specimen. The appearance of psammoma bodies in cytological examination triggered the diagnosis.

Arteriovenous malformation that caused prolapse of the colon and was treated surgically in an infant: a case report.

BACKGROUND: Various terms have been used to describe vascular lesions in the intestine, including angiodysplasia, arteriovenous malformation, and telangiectasia. Such lesions are common in adults and are typified by angiodysplasia, a type of arteriovenous malformation. In contrast, these lesions are rarely seen in the pediatric population. Angiodysplasia may cause gastrointestinal bleeding, which is sometimes an indication for treatment. Considering the high rate of recurrence after surgical treatment, conservative treatments are mainly chosen. We herein report an extremely rare case of a prolapsed colon due to an arteriovenous malformation successfully treated by resection in a 1-year-old girl. We also highlight the differences between pediatric and adult cases. CASE PRESENTATION: A girl developed bloody stools at 7 months of age. She visited another hospital at 1 year of age because of continuing moderate hematochezia and recent onset of rectal prolapse. Colonoscopy showed a protruding lesion located 15 cm from the anal verge, suggesting a submucosal vascular abnormality. Contrast-enhanced computed tomography and magnetic resonance imaging at our hospital revealed the localized lesion with dilated blood vessels in part of the sigmoid colon; no other lesions were present in the gastrointestinal tract. Laparoscopic-assisted sigmoidectomy was performed. A subserosal vascular lesion was visualized and resected using end-to-end anastomosis. Pathologic examination of the 2.2 × 2.7-cm segment revealed several abnormally enlarged and ectatic blood vessels in the submucosa extending into the subserosa. The lesion was diagnosed as an arteriovenous malformation. The patient had a good clinical course without recurrence at the 2-year follow-up. CONCLUSIONS: An arteriovenous malformation in the sigmoid colon may rarely cause intussusception and prolapse of the colon. Complete resection is a radical and potentially effective treatment. Computed tomography and colonoscopy were useful for evaluation of the lesion in the present case.

Intracytoplasmic Lumen in Urine Cytology Predicts Worse Prognosis in Non-Muscle-Invasive Bladder Cancers.

BACKGROUND: Intracytoplasmic lumina (ICL) are observed in several cancers, including urothelial carcinoma (UC). We have reported that ICL in urine cytology (cICL) is more frequent in high-grade UCs than in low-grade UCs; however, the correlation between the presence of ICL and prognosis is unclear. OBJECTIVES: The aim of this work was to determine the association between cICL and prognosis in bladder cancer. METHOD: We retrospectively investigated 87 patients with bladder cancer who received a histological diagnosis within 3 months of urine cytology at Kanazawa Medical University between 2003 and 2007. The cytological diagnosis and the number of cICL, histological diagnosis, tumor grade or variant, pT stage, ICL in histological specimens, and immunohistochemistry for mucins were evaluated. Data on the treatment type, recurrence, survival, cause of death, and length of follow-up were collected from electronic medical records. RESULTS: Muscle invasion, high-grade UC, lymph node metastasis, distant metastasis, adjuvant therapy, and disease-related mortality were more frequent in patients with cICL-positive bladder cancer than in those without cICL-positive bladder cancer. Immunohistochemistry revealed the expression of Muc-1 and Muc-4 in patients with cICL-positive bladder cancer. Univariate analysis revealed that cytological diagnosis by the Paris system and the 2015 version of the Japanese reporting system, muscle invasion, high-grade UC, lymph node metastasis, distant metastasis, and adjuvant chemotherapy and/or radiotherapy were significant factors associated with prognosis. Furthermore, survival was shorter in patients with cICL-positive non-muscle-invasive bladder cancer than in those with cICL-negative non-muscle-invasive bladder cancer. In the multivariate analysis, only distant metastasis was significantly associated with survival. CONCLUSIONS: cICL predicted shorter survival in patients with non-muscle-invasive bladder cancer, suggesting that ICL is one of the important diagnostic features of high-grade UC with a worse prognosis in urine cytology.

Epidemiological analysis of multicentric and unicentric Castleman disease and TAFRO syndrome in Japan.

Castleman disease is a polyclonal lymphoproliferative disease which is clinically classified into unicentric (UCD) and multicentric (MCD). TAFRO syndrome is a relatively new concept that partly overlaps with MCD. Due to their rarity, their incidence remains unknown. This study investigated the incidence and prevalence of UCD, MCD, and TAFRO syndrome in Japan using a fixed-point observation method based on their incidence in Ishikawa prefecture. The annual incidences of MCD, UCD, and TAFRO syndrome in Japan were 309-731, 71-542, and 110-502, respectively, yielding annual incidence rates per million individuals of 2.4-5.8, 0.6-4.3, and 0.9-4.9, respectively, and nationwide prevalence of 4,180-14,900, 1,350-10,300, and 860-7,240, respectively. In conclusion, MCD, UCD and TAFRO syndrome may not be as rare as previously estimated in Japan.

The impact of PRDX4 and the EGFR mutation status on cellular proliferation in lung adenocarcinoma.

Background: Oxidative stress plays key roles in the progression of lung adenocarcinoma. Recently, we reported that peroxiredoxin 4 (PRDX4), an antioxidant enzyme, can be a prognostic marker of lung adenocarcinoma (LUAD). In the present study, we aimed to further investigate the relationship among the PRDX4 expression, epidermal growth factor receptor (EGFR) mutations and cell proliferation in LUAD. Methods: The expression of PRDX4 was immunohistochemically analyzed and the EGFR mutation status was examined in 127 paraffin-embedded human surgical specimens from patients with stage I LUAD. The PRDX4 expression was considered to be high when >40% of the adenocarcinoma cells were positively stained. In vitro, using plasmid transfection methods, PRDX4 plasmid DNAs were transfected into human lung adenocarcinoma cell lines, A549 (EGFR-wild) or PC-9 (EGFR mutant). The viability of these cells was analyzed using a Cell Counting Kit-8 kit. Results: The number of cases with high PRDX4 expression levels among patients with LUAD with EGFR mutations was significantly larger than that in patients with EGFR wild-type. The combination of the PRDX4 expression level with the EGFR mutation status was closely associated with the prognosis of patients with stage I LUAD. Viability assays showed that the proliferation of A549 cells was significantly suppressed after PRDX4 plasmid transfection, while the overexpression of PRDX4 had no effect on the proliferation of EGFR-mutant PC-9 cells. Conclusions: The PRDX4 expression and EGFR mutation status were significantly associated with the prognosis of patients with stage I LUAD, and EGFR mutations affected the role of PRDX4 in the proliferation of LUAD cells.

Rhabdomyosarcoma arising from retroperitoneal teratoma in an infantile neurofibromatosis type 1 patient.

We herein report the case of a 2-year-old girl with neurofibromatosis type 1 (NF1), who presented with a 12-cm mass in the right retroperitoneum and underwent tumor resection. Histologically, the tumor was composed of two distinct components: one was teratoma, showing mature morphology; and the other was embryonal rhabdomyosarcoma. An interphase fluorescence in situ hybridization (FISH) analysis of the rhabdomyosarcoma component revealed the absence of isochromosome 12p. Although it is well known that rhabdomyosarcoma occurs in infantile NF1, and that rhabdomyosarcoma can arise from teratoma as a somatic-type malignancy, to the best of our knowledge, this is the first case of an infantile NF1 patient, who developed rhabdomyosarcoma within a retroperitoneal teratoma. The absence of chromosome 12p alteration suggests a possibility that the rhabdomyosarcoma occurred due to the NF1 background, not as a somatic-type malignancy of germ cell tumor.

The potential role of follicular helper T cells in idiopathic multicentric Castleman disease with and without TAFRO syndrome.

Idiopathic multicentric Castleman disease (iMCD) is a systemic inflammatory disease of unknown etiology caused by hypercytokinemia. Recently, TAFRO (thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly) syndrome has been reported, which shows similar histopathological findings to iMCD and factors associated with a poor prognosis. iMCD shows no plasma cell infiltration in the germinal center (GC), but CD38-positive (CD38+)-plasma cells are observed in the interfollicular area. Our previous report revealed that atrophic change of GC, glomeruloid vascular proliferation, and abnormal proliferation of follicular dendritic cells are more prominent in iMCD with TAFRO (TAFRO+) in comparison to iMCD without TAFRO (TAFRO-). In addition, the numbers of CD38+ and immunoglobulin G4-positive (IgG4+) plasma cells were decreased in the interfollicular area. The roles of T follicular helper cells (Tfh) are well-known to assist B-cell proliferation, maturation, and differentiation．It maintains the formation of GC and is also related in the class switching of IgG isotypes, including IgG4. Thus, we immunohistochemically examined the number of Tfh in GCs in both TAFRO- and TAFRO+ iMCD. The number of Tfh was significantly decreased in TAFRO- iMCD (n = 9) and was further decreased in TAFRO+ iMCD (n = 18) in comparison to non-specific lymphadenopathy (n = 6) and IgG4-related disease (n = 4). These results suggest that decreased Tfh may be one etiology of iMCD.