Pediatric and elderly polymorphous low-grade neuroepithelial tumor of the young: Typical and unusual case reports and literature review.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY), one of the pediatric-type diffuse low-grade gliomas, is characterized by a diffuse infiltrating pattern of oligodendroglioma-like tumor cells showing CD34 positivity and harbors mitogen-activated protein kinase (MAPK) alteration, such as vRAF murine sarcoma viral oncogene homolog B1 (BRAF) p.V600E or fibroblast growth factor fusion genetically. It occurs mainly in pediatric and adolescents with seizures due to the dominant location of the temporal lobe. However, there have been a few cases of PLNTY in adult patients, suggesting the wide range of this tumor spectrum. Here, we describe two cases of PLNTY, one in a 14-year-old female and the other in a 66-year-old female. The pediatric tumor showed typical clinical course and histopathology with BRAF p.V600E mutation, whereas the elderly tumor was unusual because of non-epileptic onset clinically and ependymal differentiation histopathologically harboring KIAA1549-BRAF fusion. There might be unusual but possible PLNTY, as in our elderly case. We also compared typical pediatric and unusual elderly tumors by reviewing the literature.

Deep learning shows the capability of high-level computer-aided diagnosis in malignant lymphoma.

A pathological evaluation is one of the most important methods for the diagnosis of malignant lymphoma. A standardized diagnosis is occasionally difficult to achieve even by experienced hematopathologists. Therefore, established procedures including a computer-aided diagnosis are desired. This study aims to classify histopathological images of malignant lymphomas through deep learning, which is a computer algorithm and type of artificial intelligence (AI) technology. We prepared hematoxylin and eosin (H&E) slides of a lesion area from 388 sections, namely, 259 with diffuse large B-cell lymphoma, 89 with follicular lymphoma, and 40 with reactive lymphoid hyperplasia, and created whole slide images (WSIs) using a whole slide system. WSI was annotated in the lesion area by experienced hematopathologists. Image patches were cropped from the WSI to train and evaluate the classifiers. Image patches at magnifications of ×5, ×20, and ×40 were randomly divided into a test set and a training and evaluation set. The classifier was assessed using the test set through a cross-validation after training. The classifier achieved the highest levels of accuracy of 94.0%, 93.0%, and 92.0% for image patches with magnifications of ×5, ×20, and ×40, respectively, in comparison to diffuse large B-cell lymphoma, follicular lymphoma, and reactive lymphoid hyperplasia. Comparing the diagnostic accuracies between the proposed classifier and seven pathologists, including experienced hematopathologists, using the test set made up of image patches with magnifications of ×5, ×20, and ×40, the best accuracy demonstrated by the classifier was 97.0%, whereas the average accuracy achieved by the pathologists using WSIs was 76.0%, with the highest accuracy reaching 83.3%. In conclusion, the neural classifier can outperform pathologists in a morphological evaluation. These results suggest that the AI system can potentially support the diagnosis of malignant lymphoma.

Comprehensive immunohistochemical analysis of immune checkpoint molecules in adult T cell leukemia/lymphoma.

Acute or lymphomatous type adult T cell leukemia/lymphoma (ATLL) is an aggressive hematopoietic malignancy with poor prognosis. We previously reported that programmed cell death ligand 1 (PD-L1) expression could predict ATLL outcomes. However, the roles of other immune checkpoint molecules remain largely unknown in ATLL. Our aim in this study was to explore the clinicopathological impacts of immune checkpoint molecules in ATLL. Immunohistochemistry was performed in 69 ATLL patients with antibodies against the following: PD-L1, programmed cell death ligand 2 (PD-L2), OX40, OX40 ligand (OX40L), CD137, CD137 ligand (CD137L), Galectin-9, T cell immunoglobulin mucin-3 (Tim-3), cytotoxic T lymphocyte associated protein-4 (CTLA-4), lymphocyte activating-3 (LAG-3), CD80, CD86, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), GITR ligand (GITRL), and programmed death-1 (PD-1). Immune checkpoint molecules were variably expressed on neoplastic and/or microenvironmental cells. Expression of PD-1, OX40L, Galectin-9, and PD-L1 was nearly mutually exclusive on neoplastic cells, suggesting that immune checkpoint pathways differ in patients. Microenvironmental expression of PD-L1, OX40L, and Tim-3 was significantly associated with better overall survival (log-rank test; P =0.0004, 0.0394, and 0.0279, respectively). Univariate and multivariate analyses with clinical prognostic factors identified microenvironmental expression of PD-L1 and OX40L, and age (> 70 years) as significant prognostic factors. This is the first comprehensive analysis of ATLL immune checkpoint molecules. Our results may provide information on new therapeutic strategies in ATLL.

Expression of the ghrelin/growth hormone secretagogue receptor axis and its functional role in promoting tumor growth in primary central nervous system lymphomas.

Ghrelin and its receptor, growth hormone secretagogue receptor (GHS-R), have been found in a variety of malignant tumor tissues, suggesting a biological function of the ghrelin/GHS-R axis in tumor growth and progression. Among central nervous system tumors, primary central nervous system lymphomas (PCNSLs) are relatively rare and characterized by a rapid progression and poor prognosis. In order to clarify ghrelin expression and its functional role in promoting tumor growth and progression in PCNSLs, we undertook an immunohistochemical investigation for ghrelin and GHS-R expression in 43 patients and tested the effect of ghrelin inhibition on lymphoma cells. Furthermore, we investigated the expression of CD105, a marker for tumor angiogenesis, to explore its association with the ghrelin/GHS-R axis. The Kaplan-Meier method and Cox's proportional hazards regression model were used to determine the association of ghrelin/GHS-R expression with overall survival rate. The immunohistochemical study showed moderate/strong immunostaining of cells for ghrelin and GHS-R in 40 patients (93.0%) and 39 patients (90.7%), respectively. A ghrelin inhibitor did not affect tumor cell proliferation in vitro. Expression levels of ghrelin and GHS-R were divided into high and low groups by the rate of moderate-strong staining cells to tumor cells. The survival rate was significantly lower in patients with high GHS-R expression (P = 0.0368 by log-rank test; P = 0.0219 by Wilcoxon test). In addition, multivariate analysis of overall survival using Cox's proportional hazards regression model indicated that GHS-R was a significant independent prognostic factor (P = 0.0426). CD105 expression on tumor vessels was positive in 33 patients (33/37, 89.2%). There was a positive correlation between the moderate-strong staining rate of ghrelin and CD105-positive vessel count. These results indicated that the ghrelin/GHS-R axis plays a potential role in promoting tumor growth and progression through neoangiogenesis, rather than the proliferation of tumor cells.

Human leukocyte antigen class II expression is a good prognostic factor in adult T-cell leukemia/lymphoma.

Attenuated human leukocyte antigen (HLA) class I expression is implicated as a major immune escape mechanism in several types of tumor. We previously reported that HLA class I/ß2 microglobulin and programmed death ligand-1 expression are prognostic factors in adult T-cell leukemia/lymphoma. A recent report suggested that HLA class II expression is also an important prognostic factor for the clinical outcome of programmed death-1 blockade therapy in recurrent/refractory Hodgkin lymphoma. This prompted us to evaluate HLA class II expression in adult T-cell leukemia/lymphoma and to compare the findings with the patients' clinicopathological features. Of the 132 biopsy specimens examined from newly diagnosed patients, lymphoma cells were positive for HLA class II expression in 44 patients (33.3%), whereas programmed death ligand-1 expression was observed on neoplastic cells from nine patients (6.9%) and on stromal cells in the tumor microenvironment in 83 cases (62.9%). HLA class II-positive cases showed a significantly better overall survival compared to the HLA class II-negative cases (P<0.0001). Patients positive for HLA class II and programmed death ligand-1 microenvironmental expression had significantly better prognosis than the other groups (P<0.0001). HLA class II-positive and HLA class II-negative groups also showed a significant difference in complete remission rate (P=0.0421), HLA class I/ß2 microglobulin expression (P=0.0165), and the number of programmed death-1-positive tumor infiltrating cells (P=0.0020). HLA class II expression was a prognostic factor for overall survival both in univariate and multivariate analyses (P<0.0001 and P=0.0007, respectively). Our study reveals that HLA class II is a novel prognostic factor in adult T-cell leukemia/lymphoma.

Primary malignant pericardial sarcomatoid mesothelioma: An autopsy report.

Primary malignant pericardial sarcomatoid mesothelioma (PMPSM) is an extremely rare tumor with poor prognosis. We present an autopsy case in an 80-year-old man admitted for heart failure after one month of treatment at an outpatient clinic. He died three months after symptom onset. A complete autopsy revealed localization of the tumor to the pericardium without other lesions. Histologically, mainly spindle-shaped atypical cells with hyperchromatic nuclei and nucleoli were observed. Immunohistochemical markers for mesothelioma were positive for calretinin, cytokeratin AE1/AE3, and cytokeratin CAM5.2. Thus, we diagnosed primary sarcomatoid malignant mesothelioma of the pericardium. To our knowledge, only four PMPSM cases have been reported in the English literature in the past 30 years. Although PMPSM is rare, clinicians and pathologists should recognize it as a possible diagnosis of pericardial tumors. It is necessary to accumulate clinical and pathological diagnostic findings to establish early detection methods for this extremely rare disease.

Composite lymphoma of peripheral T-cell lymphoma and Hodgkin lymphoma, mixed cellularity type; pathological and molecular analysis.

Composite lymphomas (CLs) are defined as two unrelated lymphomas occurring at the same time within the same tissue. The incidence of these tumors is low. Of all possible combinations between lymphomas, the least frequent are the ones combining peripheral T-cell lymphoma (PTCL) and Hodgkin lymphoma (HL). We recently identified five cases of CL composed of PTCL and classical HL, mixed cellularity type. We investigated histological and clinical features of these cases. Immunostaining was performed on paraffin sections. PTCL cells were positive for CD8 and TIA-1 in four of the five cases. Hodgkin and Reed-Sternberg (HRS) cells were positive for CD30 and weakly positive for PAX5 in all cases, positive for CD15 in three of five cases, positive for CD20 in one of five cases, and negative for EBER. Monoclonal rearrangement of the T-cell receptor (TCR) and immunoglobulin heavy chain (IGH) genes was confirmed by polymerase chain reaction (PCR) using whole paraffin sections. We concluded more precisely the monoclonality of the IGH rearrangement of HRS cells based on single-cell PCR for IGH and DNA sequencing analysis after laser microdissection of single cells in one case. HL can occur in CD8-positive and TIA-1-positive PTCL. Clinicians should recognize the possibility of these CL.

Endothelin B receptor expression in malignant gliomas: the perivascular immune escape mechanism of gliomas.

In order to clarify the role of endothelin B receptors (ETBRs) in gliomas, we analyzed cell cultures and surgical specimens of gliomas using RT-PCR and immunohistochemistry. RT-PCR measured the absolute expression of ETBR mRNA in twelve samples, which included gliomas that were classified using the World Health Organization (WHO) classification system Grade I-IV, as well as two glioblastoma cell lines (CCF-STTG1 and U87-MG). Using immunohistochemistry, 77 glioma specimens were evaluated for their expression of ETBR and infiltrating T lymphocytes, including an analysis of cytotoxic T cells (CTLs) and regulatory T lymphocytes (Tregs). The number of ETBR-positive vessels in the glioblastomas (Grade IV) was significantly higher than in other grades of gliomas (comparisons to Grade IV, Grade I: p = 0.0323, Grade II: p = 0.0009, Grade III: p = 0.0273). The ETBR expression rate (defined as the number of ETBR-positive blood vessels divided by the total number of blood vessels) in the glioblastomas was higher than the ETBR expression rate in the low-grade gliomas (compared to Grade IV, Grade I: p = 0.0132, Grade II: p = 0.0018, Grade III: p = 0.0745). In addition, the cases which had an ETBR expression rate of 50 % or higher exhibited fewer infiltrating CTLs and more infiltrating Tregs compared to the cases with an ETBR expression rate <50 % (CTLs: p = 0.0342; Tregs: p = 0.0175). Isocitrate dehydrogenase 1 (IDH-1) mutations were identified in 21 cases, but there was no correlation between ETBR expression and IDH-1 mutations for any WHO grade. These results suggest that ETBR expression during neo-angiogenesis may interfere with the homing of CTLs around the tumor and be involved in the immune escape mechanism of gliomas.

Primary central nervous system lymphomas and related diseases: Pathological characteristics and discussion of the differential diagnosis.

Although primary diffuse large B-cell lymphomas of the CNS are designated as primary CNS lymphomas according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue in 2008, a variety of other lymphomas (Burkitt lymphomas, EBV-positive diffuse large B-cell lymphoma of the elderly) and related diseases (lymphomatoid granulomatosis) that are also found in the CNS have been spotlighted in recent years. The histopathology of primary CNS Burkitt lymphomas mimics that of primary diffuse large B-cell lymphomas of the CNS after steroid administration. Therefore, for correct diagnosis of the involved lymphoma, comprehensive fluorescent in situ hybridization analysis for c-MYC and BCL2 is recommended in all primary CNS lymphoma cases with aggressive clinical course, multifocal involvement of the CNS, and a high proliferation index. The pathological characteristics of primary CNS EBV-positive diffuse large B-cell lymphoma of the elderly have similarities with those of the latency phenotype III, EBV lymphoproliferative disorders that arise in the setting of immunodeficiency. These age-related lymphomas usually occur in elderly immunocompetent patients, and the incidence of this disease was estimated to range from 4.0% to 13.6% of all primary CNS lymphomas. Shorter overall survival has been reported for patients with this disease. Lymphomatoid granulomatosis (LYG) is a systemic, EBV-driven, angiocentric and angiodestructive lymphoproliferative disorder. Primary LYG that shows distinct clinicopathological features compared with systemic LYG was recently reported. Finally, this review focuses on the relationship between primary CNS lymphomas and demyelinating diseases, and the concomitant use of intraoperative cytology and frozen sections that are helpful in rapid intraoperative diagnosis.

Central nervous system neuroblastic tumor with FOXR2 activation presenting both neuronal and glial differentiation: a case report.

A subset of central nervous system neuroblastomas (CNS NB), rare primary embryonal CNS tumors, has been encompassed in CNS NB with FOXR2 activation (CNS NB-FOXR2) and usually shows the primitive neuronal architecture and occasional neurocytic differentiation. Here, we report a rare case of 3-year-old female with uncommon morphology of CNS embryonal tumor with FOXR2 activation presenting bidirectional differentiation to neurocytic small primitive cells and astrocytic spindle cells both of which are positive for synaptophysin and GFAP. Ultrastructural study also showed that there were presynaptic structure and intermediate filament in the tumor cells, suggesting glioneuronal differentiation. This case indicates the possibility of CNS neuroblastic tumor to differentiate neuronal and glial lineages.

TACC3 expression as a prognostic factor in aggressive types of adult T-cell leukemia/lymphoma patients.

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is a malignant peripheral T-cell neoplasm associated with human T-cell leukemia virus type-1 (HTLV-1). The acute and lymphoma subtypes are regarded as aggressive ATLLs, and the overall survival (OS) of patients remains poor. Transforming acidic coiled-coil-containing protein 3 (TACC3) regulates microtubules, which are associated with cancer-related proteins overexpressed in various cancers. Such a relationship has not been reported in hematopoietic tumors, including ATLL. METHODS: We examined tissue microarrays of histological samples from 92 cases of aggressive ATLL and assessed clinical features, including TACC3 protein expression levels. RESULTS: Compared with TACC3-low, TACC3-high ATLL patients were significantly older (P < .001), with a tendency toward pleomorphic variant over other morphological classifications (P = .019). TACC3-high patients (median survival time [MST] 10.6 months, confidence interval [CI] [6.27-15.6]) had poorer OS compared to TACC3-low patients (MST 20 months, CI [9.43-38.5]) (P = .0168). Moreover, multivariate analysis on TACC3 expression levels suggests that TACC3-high is an independent significant prognostic factor (HR, 1.700; 95% CI, 1.037-2.753; P = .0355). CONCLUSION: Certain drugs that inhibit TACC3-overexpressing neoplastic cells are used clinically. Further studies might highlight a key role for TACC3 in the oncogenesis and progression of ATLL.

Benign mesenteric lipomatous tumor in a child: a case report and literature review.

BACKGROUND: Lipomatous tumors are the most common type of soft-tissue tumors. Benign lipomatous tumors are lipomas and lipoblastoma. We herein report a case of benign mesenteric lipomatous tumor and the largest collection of known benign mesenteric lipomatous tumors in children in the literature. CASE PRESENTATION: A 3-year-old girl presented with repeated dull abdominal pain and left abdominal mass swelling. On a physical examination, the child had a soft, moderately distended left abdomen that was not tender when palpated. Computed tomography and magnetic resonance imaging demonstrated a large fatty mass within the mesentery, measuring approximately 8 × 6 cm. The mass extended from the right upper quadrant to the lower pole of the kidneys. Laparotomy with resection of the mesenteric tumor was performed under general anesthesia. A well-capsuled tumor was a soft, yellow mass and found loosely attached to the mesenterium of the ileum. A histopathological examination demonstrated the lobular proliferation of mature adipocytes. Atypical lipoblasts were not seen. These features are compatible with benign lipomatous tumor, such as lipoma or lipoblastoma with maturation. CONCLUSION: In conclusion, benign mesenteric lipomatous tumors tend to be large in size over 10 cm in longitudinal length. However, resection is well tolerated in the vast majority of cases with benign post-operative courses.

Epidemiology and secular trends of malignant lymphoma in Japan: Analysis of 9426 cases according to the World Health Organization classification.

This study provides an overview of the epidemiology and secular trends of malignant lymphoma in Japan. Using data from clinics and hospitals throughout Japan, we analyzed 9426 cases of malignant lymphoma diagnosed in 2007-2014. We show that the proportion of follicular lymphoma and methotrexate-associated lymphoproliferative disorder increased during this time, as did the onset age for follicular lymphoma and diffuse large B-cell lymphoma. Significant increases in onset age for follicular lymphoma and diffuse large B-cell lymphoma were observed in both men and women (all P values <0.0001 except for P = 0.0448 for the latter disease in women). Further studies are required to determine the reasons for the higher proportion of and onset age for these lymphomas. Additionally, we believe that continued observation of these trends is necessary.

Detection of Tax-specific CTLs in lymph nodes of adult T-cell leukemia/lymphoma patients and its association with Foxp3 positivity of regulatory T-cell function.

Human T-cell lymphotropic virus type (HTLV)-1 Tax is a viral protein that has been reported to be important in the proliferation of adult T-cell leukemia/lymphoma (ATLL) cells and to be a target of HTLV-1-specific cytotoxic T lymphocytes (CTLs). However, it is not clear how Tax-specific CTLs behave in lymph nodes of ATLL patients. The present study analyzed the immunostaining of Tax-specific CTLs. Furthermore, ATLL tumor cells are known to be positive for forkhead box P3 (Foxp3)and to have a regulatory T (Treg)-cell-like function. The association between T-reg function and number and activity of Tax-specific CTLs was also investigated. A total of 15 ATLL lymphoma cases with human leukocyte antigen (HLA)-A24, for which Tax has a high affinity, were selected from the files of the Department of Pathology, School of Medicine, Kurume University (Kurume, Japan) using a polymerase chain reaction (PCR) method. Immunostaining was performed for cluster of differentiation (CD) 20, CD3, CD4, CD8, T-cell intracellular antigen-1 and Foxp3 in paraffin sections, and for Tax, interferon γ and HLA-A24 in frozen sections. In addition, the staining of Tax-specific CTLs (HLA-A24-restricted) was analyzed by MHC Dextramer® assay in frozen sections. In addition, the messenger RNA expression of Tax and HTLV-1 basic leucine zipper factor were also evaluated by reverse transcription-PCR. Immunohistochemical staining of Tax protein in lymphoma tissue revealed the presence of positive lymphoma cells ranging from 5 to 80%, and immunohistochemical staining of HLA-A24 revealed the presence of positive lymphoma cells ranging from 1 to 95%. The expression of Tax and HLA-A24 was downregulated by viral function. Foxp3, a marker for Treg cells, was expressed in 0-90% of cells. Several cases exhibited Tax-specific CTL (HLA-A24-restricted)-positive cells, and there was an inverse correlation between Tax-specific CTLs and Foxp3. However, neither Tax nor HLA-A24 expression was associated with CTL or Foxp3. Our study indicated the possibility that ATLL cells, which expressed Tax, target of CTL, evade the CTL-mediated immune control by expression of Foxp3 as a Treg function.

Methotrexate-associated orbital lymphoproliferative disorder in a patient with rheumatoid arthritis: a case report.

PURPOSE: Lymphoproliferative disorders (LPDs) can develop in patients treated with methotrexate (MTX) and usually respond well to MTX withdrawal. Mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare type of MTX-LPD. The development of MTX-LPD in the orbit has not been previously described. We here report a case of orbital MALT lymphoma that disappeared after MTX withdrawal in a patient treated with MTX for rheumatoid arthritis. CASE: A 78-year-old woman who complained of swelling of the left upper eyelid had been treated with MTX for >8 years for rheumatoid arthritis. Slit-lamp examination revealed a temporal subconjunctival mass, salmon pink in color, in the left eye. Fundus photographs also suggested the presence of a temporal tumor in the left orbit. [(18)F]Fluorodeoxyglucose positron emission tomography-computed tomography revealed highly integrated lesions in the left inferotemporal orbit and a left external iliac lymph node, a left obturator lymph node, and an inguinal lymph node. Pathologic analysis of a tumor biopsy specimen showed small- and medium-sized lymphocytes positive for CD20, MIB-1, and bcl-2 and negative for CD10, CD3, bcl-1, IgG4, and EBV-ISH. On the basis of these findings, we diagnosed the tumor as MTX-induced MALT lymphoma. The subconjunctival and orbital masses disappeared gradually over 10 months after MTX withdrawal and did not recur within 2 years. CONCLUSION: This case of orbital MTX-LPD suggests that the possibility of MTX-LPD should be considered even for ocular tumors in patients treated with MTX.

Bone status assessment in Japanese subjects using speed of sound along the tibia.

OBJECTIVES: To explore the potential use of ultrasound measurement (SoundScan 2000 Compact, Myriad Ultrasound Systems Ltd., Rehovot, Israel), and to assess both quantitative and qualitative properties of bone. METHODS: The speed of sound waves (SOS; m/s) propagating along the cortical bone was determined at the tibial shaft. The performance, reliability, validity, and clinical application of this system were evaluated in Japanese subjects. RESULTS: In phantom experiments, validity of this system was 0.04 (%), coefficient variation (CV: %) in same-day tests was 0.12, in five-separate-day tests was 0.13, and in independent operators was 0.11, respectively. In experiments with Japanese subjects, CV in same-day tests was 0.38, in five-separate-day tests was 0.99, and in independent operators was 0.90, respectively. In addition, cortical bone status of 1176 Japanese subjects (372 males, 804 females) was clinically evaluated by SoundScan 2000 Compact. SOS was negatively correlated with body fat percentage (%), body fat (kg) and waist hip ratio in females and subjects with higher weight bearing index (leg strength/body weight; WBI) have higher SOS in females under the age of forty. CONCLUSIONS: These findings indicate that the SoundScan 2000 Compact is a highly reliable and valid method for determining cortical bone status and body composition and WBI are closely related to cortical bone status in Japanese females.