Tumor-infiltrating B cells and T cells correlate with postoperative prognosis in triple-negative carcinoma of the breast.

BACKGROUND: In this study, we investigated CD20+ TILs in triple-negative breast cancer (TNBC) and their relationship with T lymphocyte subsets (CD4+, CD8+, CD25+, and FOXP3+), including their combined prognostic value using an immunohistochemical staining method. METHODS: We investigated 107 patients with TNBC for whom a full-face section stained by hematoxylin and eosin between 2006 and 2018 at Dokkyo Medical University Hospital was available. RESULTS: The strongest association of infiltrating CD20+ TILs was with CD4+ TILs. There was a significant relationship between CD20+ and CD4+ TILs (r = 0.177; p < 0.001), CD8+ TILs (r = 0.085; p = 0.002), and FOXP3+ TILs (r = 0.0043; p = 0.032). No significant relationships were observed between the CD20+ and CD25+ TILs (r = 0.012; p = 0.264). Multivariate analysis revealed that only the CD20+/FOXP3 ratio was an independent factor for relapse-free survival (p < 0.001) and overall survival (p < 0.001). Patients with tumors highly infiltrated by CD4+, CD8+, and CD20+ TILs had a good prognosis. In contrast, those with tumors weakly infiltrated by CD20+ TILs but highly infiltrated by CD25+ and FOXP3+ TILs had a poor prognosis. CONCLUSIONS: CD20+ TILs may support an increase in CD4+ and CD8+ TILs, which altered the anti-tumor response, resulting in a positive prognosis. CD20+ TILs correlated with FOXP3+ Treg lymphocytes, which were reported to be correlated with a poor prognosis. Our study suggested that TIL-B cells have dual and conflicting roles in TIL-T immune reactions in TNBC.

Clinical characteristics of 15 children with juvenile myelomonocytic leukaemia who developed blast crisis: MDS Committee of Japanese Society of Paediatric Haematology/Oncology.

Juvenile myelomonocytic leukaemia (JMML) is a rare haematopoietic stem cell disease of early childhood, which can progress to blast crisis in some children. A total of 153 children diagnosed with JMML were reported to the Myelodysplastic Syndrome Committee in Japan between 1989 and 2007; 15 of them (9·8%) had 20% or more blasts in the bone marrow (blast crisis) during the disease course. Blast crisis occurred during observation without therapy (n = 3) or with oral 6-mercaptopurine treatment (n = 9) and in relapse after haematopoietic stem cell transplantation (HSCT; n = 3). Six patients had a complex karyotype (5 including monosomy 7) and an additional three patients had isolated monosomy 7 at blast crisis. Seven patients received HSCT after blast crisis and four of them achieved remission. Eleven out of the 15 patients died; the cause of death was disease progression in 10 patients and transplant-related complication in one patient. In summary, patients with blast crisis have poor prognosis and can be cured only by HSCT. The emergence of monosomy 7 and complex karyotype may be characteristic of blast crisis in a substantial subset of children.

Clinical characteristics and treatment outcome in 65 cases with refractory cytopenia of childhood defined according to the WHO 2008 classification.

This study analysed 65 children who were prospectively registered between 1999 and 2008 and fulfilled the World Health Organization 2008 criteria of refractory cytopenia of childhood (RCC). First-line therapy was determined by the treating physicians: 25 patients received immunosuppressive therapy (IST), 12 patients received haematopoietic stem cell transplantation (HSCT) and one patient received intensive chemotherapy. The remaining 27 patients were followed without treatment for more than 2 years (watch and wait; WW). In the WW group, 18 patients had stable disease without further intervention. Thirteen of 29 patients (45%) who ended up receiving IST showed response. The combination of ciclosporin and antithymocyte globulin was not shown to be superior to ciclosporin alone with regard to response rate or survival. Of 28 patients who ended up undergoing HSCT, 17 patients are alive in complete remission, whereas nine patients died mostly due to transplantation-related mortality. The 5-year overall survival for all patients was 82 ± 5%. Eight patients suffered from disease progression. Patients with monosomy 7 or multilineage-dysplasia had a significantly higher incidence of disease progression. This analysis revealed heterogeneity in the clinical course of RCC, varying from those who remained stable for long periods to those who progressed to advanced disease.

Neuroendocrine carcinoma arising in a hepatitis C virus-infected liver: mechanism of the tumor development may be similar to that of development of pancreatic neuroendocrine cells.

We experienced a case of neuroendocrine carcinoma (NC). The tumor developed in the cirrhotic liver of a 62-year-old Japanese man who had been infected with hepatitis C virus. The tumor cells showed high N/C ratio, formed many rosettes, and expressed CD56, synaptophysin, HepPar1 and pancreatic and duodenal homeobox 1. MIB1 expression was 65%. Because both liver and pancreas are derived from a common endodermal layer during fetal development, we speculated that the tumor may have formed via the interaction of neurogenin 3, insulinoma-associated 1 gene and NeuroD/beta2, which are involved in the stage at which some pancreatic cells commit to becoming endocrine cells. Molecular analysis revealed that the NC had higher relative expression levels of mRNA of the three molecules than did the nontumorous liver. The results indicate that the NC in this patient may have formed via the same mechanism that acts in the development of pancreatic neuroendocrine cells.

A case of pulmonary papillary adenoma: possible relationship between tumor histogenesis/tumorigenesis and fibroblast growth factor receptor 2 IIIb.

Pulmonary papillary adenoma is a rare tumor. We analyzed a tumor which appeared in a 16-year-old Japanese woman. The tumor histologically showed papillary proliferation of one-layered tumor cells coating inflammatory fibrovascular cores. At the periphery of the tumor, the tumor cells grew in a lepidic fashion. The tumor cells were confirmed as type-II pneumocytes with electron-microscope. In this study, using immunohistochemistry, in situ hybridization and real-time reverse transcription polymerase chain reaction, we examined the expressions and quantities of fibroblast growth factor 10 (FGF10), keratinocyte growth factor (KGF) and fibroblast growth factor receptor 2 (FGFR2) IIIb, based on the extent of their abilities of proliferation and differentiation of type II pneumocytes. The tumor cells expressed FGFR 2 and produced 350 times more FGFR2IIIb messenger RNA (mRNA) than did the nontumorous lung. The quantity of KGF mRNA in the tumor tissue was twice that of the nontumorous lung. Moreover, there was dysregulation of FGFR2IIIb transcription in the tumor. According to these findings, we expect overexpression of FGFR2IIIb to play an important role in causing tumor. Because FGFR is suspected to be connected with lung carcinoma, we also treat similar tumorigenesis via FGFR as carcinoma; complete resection of adenoma might be indicated.

Autopsy cases of fulminant bacterial infection in adults: clinical onset depends on the virulence of bacteria and patient immune status.

To assist physicians in recognizing the potentially fatal onset of symptoms in cases of fulminant bacterial infection, we analyzed 11 autopsy cases of such infection (four caused by Streptococcus pneumoniae, four by S. pyogenes, one by S. dysgalactiae subsp. equisimilis, one by Staphylococcus aureus, and one by Vibrio vulnificus). Clinicohistopathologic features were evaluated. All patients experienced sudden onset of hypotension and multiple organ failure, leading to unexpected death. Blood culture confirmed bacteremia. The main chief complaints were gastrointestinal symptoms (45%) and limb pain (36%). All had an underlying chronic illness (82%), e.g., a hematologic disorder (36.3%) or liver cirrhosis (27.2%). Necrotizing fasciitis occurred in only 55% of cases, with none involving pneumococcal infection. Laboratory tests typically showed C-reactive protein elevation but without leukocytosis, indicating a high-level inflammatory state. In ten cases, death was attributed to circulatory collapse due to sepsis; severe pulmonary congestion and hemorrhage were present in these cases. The onset of fulminant bacterial infection depends on both virulence of the bacterium and status of the host defense system.

A case of granulocyte colony-stimulating factor and interleukin 6 receptor-producing mediastinal mature cystic teratoma with somatic-type malignancy.

Mediastinal germ cell tumor with somatic-type malignancy is a rare neoplasm. We describe one such case in a 49-year-old Japanese man who had shown an elevated serum concentration of granulocyte colony-stimulating factor (GCSF) and leukocytosis without a shift to the left. Histologically, the tumor formed a teratomatous cyst whose wall contained benign epithelial components, well-differentiated tubular and mucinous adenocarcinoma, and poorly-differentiated pleomorphic carcinoma. Immunohistochemically, both the well differentiated adenocarcinoma and poorly differentiated pleomorphic carcinoma expressed GCSF. Immunohistochemistry and molecular analysis revealed that both components also produced interleukin 6 receptor (IL6R). We diagnosed this tumor as a GCSF- and IL6R-producing mediastinal mature cystic teratoma with somatic-type malignancy. The tumor showed immunohistochemical expression of activated signal transducer and activator of transcription 3. The patient died 6 months after developing systemic symptoms. For a GCSF-producing tumor, complete resection appears to offer the best outcome at present. For any patient presenting with leukocytosis without a shift to the left, a thorough analysis should be conducted, and the tumor diagnosed as early as possible.

[Prognosis of 75 patients with juvenile myelomonocytic leukemia: prospective study by MDS committee in the Japanese Society of Pediatric Hematology].

Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic/myeloproliferative disorder of young children. Because the disease is rare and the diagnosis is difficult, a prospective registration of patients suspected of having JMML with a pathological central review have been conducted by the MDS Committee of the Japanese Society of Pediatric Hematology. Between 1999 and 2006, 75 children with JMML were enrolled and diagnosed through this system. Median age at diagnosis was 20 months (1∼85 months). Cytogenetic abnormalities were detected in 21 patients, including 11 with monosomy 7. The 5-year overall survival (OS) was 60%. Regarding the treatment, 61 of the 75 patients received stem cell transplantation (SCT). Conditioning regimen varied widely, and the source of grafts was bone marrow for 43 patients, peripheral blood for 5, and cord blood for 13. The 5-year OS after SCT was 61%. Notably, patients who received cord blood transplantation had inferior survival than those who received grafts from other sources (38 vs. 68%; P=0.03). Given better recognition of the disease, a multi-center protocol study on SCT, JMML11, is now being planned by the Japanese Pediatric Leukemia/Lymphoma Study Group.

Gastric Adenocarcinoma of the Fundic Gland Type: A Case Report.

BACKGROUND Gastric adenocarcinoma of the fundic gland type (GAFG) is an extremely rare neoplasm that consists of a mixed proliferation of oxyntic and chief cells. Differential diagnosis of GAFG is difficult in the absence of infiltration. Here, we report a case of GAFG and discuss the clinicopathological features. CASE REPORT A 78-year-old man was diagnosed with gastritis and reflux esophagitis, status after esophagectomy for carcinoma of the esophagus in 2015. The patient underwent repeated gastric biopsies in 2017 and an atypical epithelium was observed, but no diagnosis was confirmed. There was no evidence of tumor extension in the submucosa. The tumor was resected via endoscopic mucosal resection, and pathological examination was performed. Microscopic findings revealed an oxyntic-type gastric mucosa with atypical dense or dilated glands with abundant pale basophilic cytoplasm and round nuclei with prominent nucleoli. The majority of the tumor cells resembled chief cells, suggesting they were derived from gastric fundic glands. However, the tumor appeared to have no submucosal infiltration or focal stromal desmoplastic reaction. Sections stained positive for MUC6 and pepsinogen-I in chief cells, and H+/K+ ATPase and PDGFRa in parietal cells, but were mostly negative for CDX2, chromogranin A, synaptophysin, and CD10. Sections stained for mib-1 expressed very low proliferative activity, with an average of 10%. Staining for TP53 overexpression was negative. CONCLUSIONS Immunostaining markers are a supportive tool for histological diagnosis of GAFG. However, if there is no infiltration, as in our case, it is difficult to consider it as a malignant tumor. Further elucidation is needed in the future, including an officially accepted diagnostic name.

Prognostic value of tumor-infiltrating B lymphocytes and plasma cells in triple-negative breast cancer.

BACKGROUND: Recent investigations have demonstrated that the tumor microenvironment, including tumor-infiltrating lymphocytes (TILs), is an important factor in tumor growth and development. While the prognostic correlation of tumor-infiltrating T cells has been widely studied in breast cancer, that of tumor-infiltrating B cells and plasma cells has not received so much attention, especially in triple-negative breast cancer (TNBC). METHODS: We investigated 114 patients with TNBC who had surgery between 2006 and 2019 at Dokkyo Medical University Hospital. Intratumoral (i) TILs were considered to be lymphocytes within cancer cell nests and directly infiltrating tumor cells. Similarly, stromal (s) TILs were considered to be lymphocytes within the tumor stroma, but not directly infiltrating tumor cells. CD20 + , CD38 + and CD138 + staining was determined by estimating the number of positive B cells. RESULTS: sCD20 + TILs had prognostic significance for relapse-free survival (RFS) (p = 0.043) and overall survival (OS) (p = 0.027). The sCD38 + TILs were significantly related to favorable RFS (p = 0.042). iCD38, iCD138, and sCD138 was not significantly correlated with RFS (p = 0.065, p = 0.719, p = 0.074) or OS (p = 0.071, p = 0.689, p = 0.082). CONCLUSIONS: The present study demonstrated that a high density of sCD20 + TILs was significantly related to favorable prognosis in both RFS and OS. Increased sCD38 + TILs in TNBC were correlated with a significantly favorable prognosis in RFS. These results indicate that TILs-B may have a profound influence on the clinical outcome of TNBC.

Autopsy cases of fulminant-type bacterial infection with necrotizing fasciitis: group A (beta) hemolytic Streptococcus pyogenes versus Vibrio vulnificus infection.

Two autopsy cases of fulminant-type infection associated with necrotizing fasciitis were analyzed clinicopathologically. Both cases involved 57-year-old alcohol abusers. The former was a woman with group A (beta) hemolytic Streptococcus pyogenes infection, and the latter was a man with Vibrio vulnificus infection. The sudden onset of shock with high fever resulted in sepsis, decreased clotting, and hepatorenal symptoms, followed by death within a few days. Post-mortem examination showed widespread congestion and bleeding, and alcoholic liver cirrhosis was observed. Necrotizing fasciitis was identified in both cases. Bacteria from the pharynx or intestinal tract invaded the blood, and marked bacterial proliferation produced sepsis, resulting in necrotizing fasciitis. Despite the presence of sepsis, bilateral pulmonary congestion and bleeding were observed without pneumonia. Due to the rapid progression of sepsis, there was no time for granulocyte migration from the bone marrow. It seems that almost all mature granulocytes which had already existed in the bone marrow accumulated at the focus of necrotizing fasciitis because the bone marrow had few mature granulocytes and lacked hypercellularity. The cause of death in each case was circulatory collapse due to septic shock. It was difficult to distinguish the type of infection on histopathology. Cultures were necessary to determine the bacterial agents involved.

Thymic epithelial cells expressed unusual follicular dendritic cell markers: thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue.

Described herein is a case of thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Using immunohistochemical double staining it was found that most of the thymic lymphoid follicles in this case possessed cytokeratin-positive and follicular dendritic cell (FDC) marker-positive cells. Moreover, using immunoelectron microscopy it was confirmed that some of the double-positive cells were thymic epithelial cells. The candidate of cytokeratin subtype expressed on the double-positive cells was cytokeratin 1 (CK1), which was expressed only by the epithelium of Hassall's corpuscles in thymuses from age-matched patients with myasthenia gravis. The present case indicates a possibility that some thymic epithelial cells become FDC, although it was uncertain whether they were derived from the epithelia of Hassall's corpuscles or whether they were at the same differentiation stage as Hassall's corpuscles.

Possible relationship between fibrosis of IgG4-related thymitis and the profibrotic cytokines, transforming growth factor beta 1, interleukin 1 beta and interferon gamma: a case report.

BACKGROUND: IgG4-related disease often forms a mass and the affected lesion is clinically removed because the mass cannot be differentiated from a neoplasm. Affected lesions commonly occur in the pancreas, hepatobiliary tract, kidney, and retroperitoneum. However, the lesion rarely occurs in the thymus. A histological worldwide consensus of IgG4-related disease proposed that pathological diagnosis of IgG4-related disease should meet more than two of three major features: 1) dense lymphoplasmacytic infiltration with greater than 40% IgG4+/IgG+ plasma cells, 2) storiform fibrosis; and 3) obliterative phlebitis. Currently, fibrosis of IgG4-related disease is thought to be induced by profibrotic cytokines such as transforming growth factor beta 1 (TGFB1), interleukin 1 beta (IL1B) and interferon gamma (IFNG), which are secreted by regulatory T cells (Tregs) and CD4-positive cytotoxic T cells. However, it is unclear whether profibrotic cytokines are associated with the fibrosis seen in IgG4-related thymitis. Here we examined whether cytokines in the mass were increased compared with those in the surrounding thymus, and whether Tregs were present in the mass, using reverse transcription absolute quantitative polymerase chain reaction (RT-ab-qPCR) and immunohistochemistry. CASE PRESENTATION: A 70-year-old Japanese man contracted IgG4-letated thymitis. Histological and immunohistochemical analyses demonstrated his mass had massive fibrosis with a focally storiform pattern and lymphoplasmacytic infiltration with 40% IgG4+/IgG+ plasma cells, but not obliterative phlebitis. The mass was surrounded by atrophic thymus. We diagnosed the mass as IgG4-related thymitis. Immunohistochemically, Tregs were scattered throughout the mass. RT-ab-qPCR showed that messenger RNA expressions of TGFB1, IL1B and IFNG in the mass were 270-, 158- and 5.5- fold higher than in the surrounding thymus. His serum IgG4 level after surgery was within the normal range (83.4 mg/dl soon after surgery, 89.3 mg/dl 2 weeks after surgery). CONCLUSIONS: Our results suggested the profibrotic cytokines TGFB1, IL1B and IFNG induce fibrosis and that Tregs might produce some of these cytokines in IgG4-related thymitis as well as in the other affected lesions of IgG4-related disease.

Loss of myelinated axons and astrocytosis in an autopsy case of acute encephalopathy with biphasic seizures and late reduced diffusion.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common pediatric encephalopathy in Japan, however, the exact neuropathology remains uncertain. The postmortem neuropathology in a patient with AESD revealed reduction of myelinated axons with early stage of astrocytosis in the absence of neuronal loss, which suggests the primary pathological damage in AESD involves myelinated axons and astrocytes rather than cortical neurons. An increased number of gemistocytic astrocytes at the corticomedullary junction may cause reduced diffusion, leading to the so-called bright tree appearance on magnetic resonance imaging, characteristic to AESD.

A surgical case of lung cancer with poor general status associated with parathyroid hormone-related protein.

Parathyroid hormone-related protein (PTHrP), which is released in the presence of malignant disease, is associated with hypercalcemia. Complete resection of the tumor in such patients is rarely performed because of their poor general condition. We herein report a case of lung cancer associated with PTHrP in a patient whose condition dramatically improved after surgery. We also review the literature on the benefits of various surgical options. Although only a few cases of complete resection in such patients have been reported, the mental and physical condition of the patients improved postoperatively and the median survival time was longer than 12 months. A poor general status is frequently considered a contraindication for surgery, even in a palliative setting; however, we conclude that resection of lung cancer may lead to improved symptom control and survival when the patient's condition is induced by hypercalcemia secondary to PTHrP secretion from the tumor.

Diffusion kurtosis imaging with the breath-hold technique for staging hepatic fibrosis: A preliminary study.

PURPOSE: To evaluate the potential of diffusion kurtosis imaging (DKI) analysis with the breath-hold technique to assess the stage or classify hepatic fibrosis. MATERIALS AND METHODS: Patients (n=67) suspected of having a disease of the hepatobiliary system examined by diffusion-weighted imaging (DWI) using a 3.0-T magnetic resonance imaging unit were enrolled in this study. To evaluate hepatic fibrosis, mean kurtosis, Mean apparent diffusion (MD) and apparent diffusion coefficient (ADC) values were compared between groups with varying fibrosis; F0-F1, F2-F3, and F4. The Steel-Dwass test was used for overall comparisons. Correlations between the fibrosis stage and mean kurtosis, MD or ADC values were assessed using Spearman's rank correlation. Discriminative capacities of DKI were evaluated using receiver operating characteristic (ROC) analysis. RESULTS: There were significant differences in ADC, MD and mean kurtosis values between non-cirrhosis and cirrhosis groups. Moreover, the mean kurtosis value was statistically different between the F0-F1 and F2-F3, F0-F1 and F4, and F2-F3 and F4 groups (all P<0.05). MD value was statistically different between the F0-F1 and F4 groups, and F2-F3 and F4 groups (all P<0.05). However, there was no significant difference in ADC values for all groups (all P>0.05). In addition, mean kurtosis and MD values significantly correlated with the extent of hepatic fibrosis staging (Spearman's rank correlation coefficient, ρ=0.851 and -0.672; P<0.0001). However, ADC values did not reveal a correlation with the extent of hepatic fibrosis staging (ρ=-0.227; P=0.078). According to the ROC analysis for the assessment of no fibrosis (F0), fibrosis (≥F1), and advanced fibrosis (≥F2) and liver cirrhosis, the DKI cut-off values were 0.923, 0.955, and 1.11, respectively. CONCLUSION: Using the DKI method with the breath-hold technique in the liver, the stage of hepatic fibrosis can be classified into normal and early hepatic fibrosis, substantial stages, and advanced hepatic fibrosis.

Acute myeloid leukemia with multilineage dysplasia in children.

We retrospectively surveyed pediatric acute myeloid leukemia (AML) patients with multilineage dysplasia treated with the AML 99 and the Children's Cancer and Leukemia Study Group (CCLSG) AML 9805 protocols. We found only 9 AML patients (2.6%) with multilineage dysplasia among the 341 patients with newly diagnosed de novo AML. Eight of the 9 patients obtained complete remission (CR) following the intensive AML-oriented treatments. Three of 7 patients who underwent stem cell transplantation were alive in CR for more than 4 years, and the 2 patients treated only with chemotherapy were alive in CR for more than 30 months. We did not identify any particular chromosomal abnormalities or differentiation according to the French-American-British classification in these 9 patients. No reports have described AML with multilineage dysplasia in children, and the incidence of the disease is expected to be very low. We plan to conduct a prospective pathologic review to select cases with this disease entity in the next Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma with squamous differentiation: a novel histological finding.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare neoplasm originating from the nasopharyngeal surface epithelium. Histopathologically, TL-LGNPPA is characterized by cuboidal/columnar tumor cells forming papillary fronds and thyroid transcription factor-1 (TTF-1) expression resembling papillary thyroid carcinoma. To date, the recorded histological features of TL-LGNPPA have been almost uniform, and the range of histological variations in this tumor type has not been sufficiently understood. Here, we report on a 68-year-old man with TL-LGNPPA. Microscopic examination of the resected tumor revealed findings typical of papillary adenocarcinoma of this type, and moreover, this case showed scattered squamous cell foci as a hitherto unreported finding. The squamous cells showed no obvious nuclear atypia or proliferating activity, and their presence was similar to the "squamous metaplasia" of papillary thyroid carcinoma. Immunohistochemically, p40 and TTF-1 coexpression was observed in the squamous cell nuclei, indicating their origin from the glandular tumor cells of TL-LGNPPA.