Global, regional, and national time trends in myocarditis-related mortality, 1990-2019: An age-period-cohort analysis.

OBJECTIVE: The aim of this study was to analyze the tendency of myocarditis mortality in 204 countries and areas during the last three decades and its connection with age, epoch, and birth cohort. MATERIALS AND METHODS: The Global Burden of Disease 2019 Study acquired a cause-specific myocarditis mortality estimate. The net drift, as well as the influence caused by age, period, and birth cohort, were evaluated by the age-period-cohort model. Additionally, we analyzed the tendency in research intensity and international collaboration across countries using 3,983 myocarditis-related publications from four periods during 1990-2019. RESULTS: During the last three decades, 101 of 204 countries and areas experienced an increase (net drifts ≥0.0%) or stagnant declines (≥-0.5%) in the death rate. In particular, increasing death rate was generally discovered in most countries whose Socio-demographic indexes (SDIs) are high and middle-high, such as the United States [net drift=2.11% (95% CI 1.71-2.51)] and Italy [2.65% (1.24-4.08)]. Countries with a higher number of deaths were more active in this field of study, such as the United States (237 publications), China (120), and Italy (73). The United States and Italy, whose total link strengths were 209 and 135, respectively, were more active in international collaborative studies. CONCLUSIONS: Despite the global decrease in myocarditis death rate during the last three decades, negative period and cohort effects and elevated mortality were discovered in numerous countries, especially in those whose SDIs were high, and the age distribution of deaths shifted from adolescent to middle-aged and older populations. We also observed a decline in myocarditis research in some countries with increased mortality.

[Nodal T-follicular helper cell lymphoma, angioimmunoblastic-type associated with diffuse large B-cell lymphoma: a clinicopathological study].

Objective: To investigate the clinicopathological features and molecular genetics of diffuse large B-cell lymphomas (DLBCL) with concurrent or secondary to nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (nTFHL-AI). Methods: The clinicopathological features and molecular genetics of DLBCL associated with nTFHL-AI diagnosed between January 2015 and October 2022 at the First Affiliated Hospital of Zhengzhou University were analyzed using histology, immunohistochemistry, PCR, EBV-encoded RNA in situ hybridization and fluorescence in situ hybridization (FISH). Clinical information was collected and analyzed. Results: A total of 6 cases including 3 nTFHL-AI with secondary DLBCL and 3 composite lymphomas were reviewed. There were 4 male and 2 female patients, whose ages ranged from 40 to 74 years (median 57 years). All patients presented with nodal lesions at an advanced Ann Arbor stage Ⅲ/Ⅳ (6/6). Bone marrow involvement was detected in 4 patients. All cases showed typical histologic and immunophenotypic characteristics of nTFHL-AI. Among them, 5 cases of DLBCL with concurrent nTFHL-AI exhibited numerous large atypical lymphoid cells and the tumor cells were CD20 and CD79α positive. The only case of DLBCL secondary to nTFHL-AI showed plasma cell differentiation and reduced expression of CD20. All of cases were activated B-cell (ABC)/non-germinal center B-cell (non-GCB) subtype. Three of the 6 cases were EBV positive with>100 positive cells/high power field, meeting the diagnostic criteria of EBV+DLBCL. The expression of MYC and CD30 protein in the DLBCL region was higher than that in the nTFHL-AI region (n=5). C-MYC, bcl-6 and bcl-2 translocations were not detected in the 4 cases that were subject to FISH. Four of the 6 patients received chemotherapy after diagnosis. For the DLBCL cases of nTFHL-AI with secondary DLBCL, the interval was between 2-20 months. During the follow-up period ranging from 3-29 months, 3 of the 6 patients died of the disease. Conclusions: DLBCL associated with nTFHL-AI is very rare. The expansion of EBV-infected B cells in nTFHL-AI may progress to secondary EBV+DLBCL. However, EBV-negative cases have also been reported, suggesting possible other mechanisms. The up-regulation of MYC expression in these cases suggests a possible role in B-cell lymphomagenesis. Clinicians should be aware that another biopsy is still necessary to rule out concurrent or secondary DLBCL when nodal and extranodal lesions are noted after nTFHL-AI treatment.

[Mammary myofibroblastoma: a clinicopathological analysis of fifteen cases].

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of breast myofibroblastoma. Methods: The clinicopathological data and prognostic information of 15 patients with breast myofibroblastoma diagnosed at the Department of Pathology of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China from 2014 to 2022 were collected. Their clinical characteristics, histological subtypes, immunophenotypes and molecular characteristics were analyzed. Results: There were 12 female and 3 male patients, ranging in age from 18 to 78 years, with a median and average age of 52 years. There were 6 cases in the left breast and 9 cases in the right breast, including 12 cases in outer upper quadrant, 2 cases in inner upper quadrant and 1 case in outer lower quadrant. Most of the cases showed a well-defined nodule grossly, including pushing growth under the microscope in 13 cases, being completely separated from the surrounding breast tissue in 1 case, and infiltrating growth in 1 case. Among them, 12 cases were classic subtype and composed of occasional spindle cells with varying intervals of collagen fiber bundles; eight cases had a small amount of fat; one case had focal cartilage differentiation; one case was epithelioid subtype, in which epithelioid tumor cells were scattered in single filing or small clusters; one case was schwannoma-like subtype, and the tumor cells were arranged in a significant palisade shape, resembling schwannoma, and one case was invasive leiomyoma-like subtype, in which the tumor cells had eosinophilic cytoplasm and were arranged in bundles, and infiltrating into the surrounding mammary lobules like leiomyoma. Immunohistochemical studies showed that the tumor cells expressed desmin (14/15) and CD34 (14/15), as well as ER (15/15) and PR (15/15). Three cases with histologic subtypes of epithelioid subtype, schwannoma-like subtype and infiltrating leiomyoma-like subtype showed RB1 negative immunohistochemistry. Then FISH was performed to detect RB1/13q14 gene deletion, and identified RB1 gene deletion in all three cases. Fifteen cases were followed up for 2-100 months, and no recurrence was noted. Conclusions: Myofibroblastoma is a rare benign mesenchymal tumor of the breast. In addition to the classic type, there are many histological variants, among which the epithelioid subtype is easily confused with invasive lobular carcinoma. The schwannoma-like subtype is similar to schwannoma, while the invasive subtype is easily misdiagnosed as fibromatosis-like or spindle cell metaplastic carcinoma. Therefore, it is important to recognize the various histological subtypes and clinicopathological features of the tumor for making correct pathological diagnosis and rational clinical treatment.

[Primary central nervous system T-cell lymphoma in children and adolescents: a clinicopathological analysis of five cases].

Objective: To study the clinicopathological characteristics, and further understand primary central nervous system T-cell lymphoma (PCNSTCL) in children and adolescents. Methods: Five cases of PCNSTCL in children and adolescents were collected from December 2016 to December 2021 at the First Affiliated Hospital of Zhengzhou University. The clinicopathological characteristics, immunophenotypic, and molecular pathologic features were analyzed, and relevant literatures reviewed. Results: There were two male and three female patients with a median age of 14 years (range 11 to 18 years). There were two peripheral T-cell lymphomas, not otherwise specified, two anaplastic large cell lymphoma, ALK-positive and one NK/T cell lymphoma. Pathologically, the tumor cells showed a variable histomorphologic spectrum, including small, medium and large cells with diffuse growth pattern and perivascular accentuation. Immunohistochemistry and in situ hybridization showed CD3 expression in four cases, and CD3 was lost in one case. CD5 expression was lost in four cases and retained in one case. ALK and CD30 were expressed in two cases. One tumor expressed CD56 and Epstein-Barr virus-encoded RNA. All cases showed a cytotoxic phenotype with expression of TIA1 and granzyme B. Three cases had a high Ki-67 index (>50%). T-cell receptor (TCR) gene rearrangement was clonal in two cases. Conclusions: PCNSTCL is rare, especially in children and adolescents. The morphology of PCNSTCL is diverse. Immunohistochemistry and TCR gene rearrangement play important roles in the diagnosis.

Human health impact due to arsenic contaminated rice and vegetables consumption in naturally arsenic endemic regions.

Rice and vegetables cultivated in naturally arsenic (As) endemic areas are the substantial source of As body loading for persons using safe drinking water. However, tracing As intake, particularly from rice and vegetables by biomarker analysis, has been poorly addressed. This field investigation was conducted to trace the As transfer pathway and measure health risk associated with consuming As enriched rice and vegetables. Purposively selected 100 farmers from five sub-districts of Chandpur, Bangladesh fulfilling specific requirements constituted the subjects of this study. A total of 100 Irrigation water, soils, rice, and vegetable samples were collected from those farmers' who donated scalp hair. Socio-demographic and food consumption data were collected face to face through questionnaire administration. The mean As level in irrigation water, soils, rice, vegetables, and scalp hairs exceeded the acceptable limit, while As content was significant at 0.1%, 5%, 0.1%, 1%, and 0.1% probability levels, respectively, in all five locations. Arsenic in scalp hair is significantly (p ≤ 0.01) correlated with that in rice and vegetables. The bioconcentration factor (BCF) for rice and vegetables is less than one and significant at a 1% probability level. The average daily intake (ADI) is higher than the RfD limit for As. Both grains and vegetables have an HQ (hazard quotient) > 1. Maximum incremental lifetime cancer risk (ILCR) showed 2.8 per 100 people and 1.6 per 1000 people are at considerable and threshold risk, respectively. However, proteinaceous and nutritious food consumption might have kept the participants asymptomatic. The PCA analysis showed that the first principle component (PC1) explains 91.1% of the total variance dominated by As in irrigation water, grain, and vegetables. The dendrogram shows greater variations in similarity in rice and vegetables As, while the latter has been found to contribute more to human body loading compared to grain As.

[Malignant solitary fibrous tumors: a clinicopathological and molecular genetic analysis].

Objective: To explore the clinicopathological features, immunophenotype and molecular genetic characteristics of malignant solitary fibrous tumor (MSFT). Methods: Seven cases of MSFT were collected from the First Affiliated Hospital of Zhengzhou University from July 2018 to December 2020. Immunohistochemistry, RNA-based NGS and DNA-based NGS were performed. Results Among the 7 patients, there were 5 males and 2 females with a median age of 53 years (37-69 years). Two tumors located at skull base, and one in the tentorium of cerebellum, parietal occipital region, occipital area, chest and buttock respectively. The maximum diameter of the tumor was 2.5-20.0 cm. Microscopically, typical hemangiopericomatoid structures were noted; the tumor was cellular, fusiform or oval, very pleomorphic, with necrosis and high mitotic figures (>4/10 HPF). In some cases, classical solitary fibrous tumor morphology and dedifferentiated region were observed. Immunohistochemically, the tumor was positive for CD34 (6/7), STAT6 (7/7), bcl-2 (7/7), but negative for S-100 (7/7); CKpan or EMA was positive to varying degrees; mutated p53 was noted (3/7); Ki-67 positive index was more than 10%. NAB2-STAT6 gene fusion was typically detected in all the 7 cases. In 4 cases, ZNF415-FGFR1, COPG1-MET, IPO11-LRRC70_ncRNA-PLAG1 and Clorf198-CD274 (PD-L1) gene fusions were also detected. NOTCH1 mutation was found in 7 cases and TP53 mutation in 4 cases. TERT promoter mutations were not detected in all the cases. Conclusions: MSFT is rare and needs to be differentiated from many other spindle cell tumors. Especially when tumors express epithelial markers, they are easily misdiagnosed as sarcomatoid carcinoma and synovial sarcoma, etc. Immunohistochemistry and molecular detection of NAB2-STAT6 gene fusion have important diagnostic values. NOTCH1 and TP53 mutations may be associated with the progression of MSFT. Some patients have FGFR1 gene fusion and MET gene fusion, which may be potential therapeutic targets.

[Clinicopathological and molecular genetic features of cyclin D1-negative mantle cell lymphoma].

Objective: To investigate the clinicopathological features and molecular genetics of cyclin D1-negative mantle cell lymphoma (MCL). Methods: The clinicopathological features and molecular genetics of CyclinD1-negative MCL diagnosed between January 2016 and July 2021 at the First Affiliated Hospital of Zhengzhou University were analyzed using immunohistochemistry and fluorescence in situ hybridization. Clinical information was collected and analyzed. Results: A total of five Cyclin D1-negative MCL cases from all 212 MCL patients (5/212, 2.4%)were included. There were three male and two female patients,age ranged from 59 to 70 years (median 64 years). All patients presented with nodal lesions. None of the patients had B symptoms but four had bone marrow involvement. Histopathologically, four cases were classic MCL and one case was pleomorphic variant type. All five cases were negative for Cyclin D1 but SOX-11 were positive in all cases. CD5 was positive in four cases and one case was weakly positive for CD23. CD10 and bcl-6 were negative in all cases. CCND1 translocation was identified in three cases and CCND2 translocation in one case by FISH analysis. However,CCND3 translocations were not found in the five cases. Conclusions: Cyclin D1-negative MCL are uncommon, its accurate diagnosis needs combined analysis with morphologic and immunophenotypic characteristics and genetic changes. It may be particularly difficult to distinguish from other small cell type B cell lymphomas. FISH analyses for CCND1/CCND2/CCND3 translocations and immunohistochemistry for SOX-11 are helpful to resolve such a difficult distinction.

[Clinicopathological characteristics of natural killer cell enteropathy: report of two cases and review of literature].

Objective: To study the clinicopathological and genetic features of natural killer (NK)-cell enteropathy for better understanding of this rare disease and prevention of its misdiagnosis. Methods: Two cases of NK-cell enteropathy were diagnosed in the First Affiliated Hospital of Zhengzhou University, China from October 2017 to February 2021. The clinical characteristics, morphology, immunohistochemistry, Epstein-Barr virus-encoded RNA (EBER) in situ hybridization and T cell receptor gene rearrangement were analyzed. The patients were followed up by a telephone interview. Results: The patients were both male, aged 40 and 28 years, respectively. Both patients were admitted to the hospital for an annual checkup without obvious gastrointestinal symptoms. The endoscopy showed that the gastric body of case 1 had a mucosal bulge, small area of congestion and erosion, while the rectum of case 2 had congestion and erosion. Microscopically, the lesions of the 2 cases were relatively limited. Many lymphoid cells infiltrated within the lamina propria of the mucosa and into the muscularis mucosa in case 2. In case 1, the glands were reduced in the lesion, and the glandular cavity was slightly compressed and deformed. There was no infiltration or destruction of the glands in either case. Lymphoid cells were atypical, with medium-to-large cell sizes. Their cytoplasm was medium-to-slightly abundant and appeared eosinophilic or translucent. In case 2, characteristic eosinophilic granules were seen in the cytoplasm of a few cells. The nuclei in both cases were round, oval and irregular, with fine chromatin, inconspicuous nucleoli, and no mitotic figures were noted. Necrosis was seen in case 1 while both cases had no central growth or destruction of blood vessels. Immunophenotyping showed that CD56, granzyme B and TIA-1 were positive in both cases, part of the cells was CD3-positive, and some cells were weakly CD4-positive in case 2. The CD5, CD8, CD30, ALK and B-lineage markers (CD20, CD79α) were all negative. The Ki-67 proliferation index was about 60% and 30%, respectively. Both cases were EBER negative. TCR gene rearrangement was polyclonal. Follow-up showed that none of the 2 patients had any special treatments and stayed well. Conclusions: NK-cell enteropathy is rare, with biological behaviors similar to benign tumors, and occasional recurrence. Its histology and immunophenotype are easily confused with NK/T cell-derived lymphomas. Combination of its unique endoscopic features, EBER negativity, polyclonal TCR gene rearrangement and good prognosis can confirm the diagnosis and avoid misdiagnosis and overtreatment.

[Nodal lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia: a clinicopathological and prognostical study].

Objective: To study the clinicopathological features and prognosis of nodal lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (n-LPL/WM). Methods: A total of 19 cases of n-LPL/WM were collected from May 2009 to January 2020 at First Affiliated Hospital of Zhengzhou University. The clinicopathologic features, immunophenotype, Ig gene rearrangement (BIOMED-2), MYD88 L265P mutation status (by Sanger sequencing) and follow-up data (by telephone) were analyzed. Results: There were 15 males and 4 females with a median age of 61 years (range 43 to 82 years). There were 14 WM and five LPL. The most common symptoms were weakness, fatigue (9/19) and B symptoms (11/19). Majority of the patients (16/18) presented with systemic multiple lymphadenopathies. Eighteen patients presented at advanced stages (Ⅲ/Ⅳ stage). Serum M protein status was IgM (15 cases), IgG (1 case), IgA (1 case) and no-secretory type (2 cases). Seventeen patients had bone marrow involvement. Morphologically, all 19 cases were divided into two groups: typical group (9 cases) or atypical group (10 cases). In the typical group, the structures of the lymph nodes were preserved; the neoplastic cells were predominantly plasmacytoid lymphocytes or mixed small lymphocytes, plasmacytoid lymphocytes and plasma cells, without proliferation of FDC network and follicular implantation. In the atypical group, the tumor showed effaced nodal architecture (5 cases), mainly proliferation of small lymphocytes (6 cases), FDC proliferation and/or follicular implantation (6 cases), marginal zone B cell differentiation (4 cases) and diffuse amyloidosis (1 case). Hemosiderin deposition (19 cases), infiltration of fatty tissue (19 cases) and interstitial sclerosis (9 cases) were commonly seen in both groups. Immunohistochemically, the neoplastic B cells expressed CD20 and CD79α, and the neoplastic plasma cells were positive for CD38, CD138 and MUM-1; eight cases showed light chain restriction; of the seven detected cases, five expressed IgM and the other two expressed IgG and IgA respectively; four cases expressed CD23 weakly, Ki-67 index was 10%-30%. MYD88 L265P mutation was seen in 18/18 cases. There was no significant difference in clinicopathologic features and prognosis between the two groups (P>0.05). The median follow-up time was 61 months, 11 patients were alive, while eight died; the 5-year survival rate was 21.1%. Conclusions: n-LPL/WM is rare, but patients usually present in advanced stages. It is easily confused with other small B-cell lymphomas with plasma cell differentiation, especially basing on morphologic features alone; thus the accurate diagnosis of n-LPL/WM requires a combination of clinical features, serum M protein, immunohistochemistry, bone marrow morphology,flow cytometry and MYD88 L265P mutation status etc. The prognosis of n-LPL/WM may be not very good, and further studies with more cases are needed.

[Clinicopathological and molecular genetic features of Burkitt-like lymphoma with 11q aberration].

Objective: To investigate the clinicopathological features, molecular genetics, treatment and prognosis of Burkitt-like lymphoma with 11q aberration (BLL-11q). Methods: Six cases of BLL-11q diagnosed at the First Affiliated Hospital of Zhengzhou University, from January 2016 to January 2020 were reviewed and analyzed using hematoxylin-eosin staining, immunohistochemistry, EBER in situ hybridization and fluorescence in situ hybridization. Clinical information including follow-up data was collected and analyzed. Results: The median age of the six immunocompetent patients was 29 years (range 20-38 years) and the male to female ratio was 5∶1. All patients had nodal disease in the head and neck region. Five patients had Ann Arbor stage Ⅰ-Ⅱ disease, while one patient had stage Ⅳ disease. Lymph nodes showed partial or total architectural effacement by a diffuse proliferation of monomorphic lymphocytes. Four cases were morphologically similar to Burkitt lymphoma, and two cases were unclassified with histological features between Burkitt lymphoma and diffuse large B-cell lymphoma. Mitotic figures, apoptosis and necrosis were conspicuous. Five cases exhibited the"starry sky"pattern. CD20, CD10 and bcl-6 were diffusely and strongly positive. The Ki-67 index was more than 95%. The follicular-dendritic-cell meshwork was noted in one case using CD21 stain. C-MYC was expressed variably. CD3, bcl-2, MUM-1, CD30 and TDT were negative in all cases. EBER in situ hybridization was also all negative. FISH analyses using C-MYC, bcl-2 and bcl-6 break-apart probes were all negative. All cases had the 11q23.3 gain/11q24.3 loss pattern, and 11q23.3 amplification was found in one case. IgH and IRF4 break-apart probes analysis was also negative. All patients were alive with no disease after a follow-up of 4 to 19 months. Conclusion: BLL-11q is a rare lymphoma that resembles Burkitt lymphoma morphologically and phenotypically, but lacks C-MYC gene rearrangements. Instead, it has a chromosome-11q alteration characterized by proximal gains and telomeric losses. It's necessary to improve our understanding of BLL-11q to avoid misdiagnosis and missed diagnosis.

[Characteristics of primary cutaneous rare nasal extranodal NK/T cell lymphoma: a clinicopathological study of 15 cases].

Objective: To investigate the clinicopathological features and differential diagnosis of primary cutaneous nasal extranodal NK/T cell lymphoma (pcENKTCL-NT). Methods: Fifteen cases of pcENKTCL-NT were collected at the First Affiliated Hospital of Zhengzhou University from January 2016 to December 2019. The clinical characteristics, morphological features, immunophenotypes, and results of in situ hybridization and gene detection were analyzed. Results: Among the 15 patients, 7 were male and 8 were female, with a male to female ratio of 1.0∶1.1. Their ages ranged from 29 to 86 years, and the median age was 59.3 years. All patients were hospitalized for skin lesions, including skin ulcers, scattered patchy red papules, and local blisters. The skin lesion might be a hard nodular mass, and part of it was a confluent patchy erythema; it could be manifested as multiple scattered nodules of different sizes, and some lesions were like round ulceration. There were 8 cases of lower limbs, 4 cases of chest (1 case with upper limb lesions), 2 cases of trunk and 1 case of neck. Most of the patients were sensitive to GGDP regimen (cisplatin, dexamethasone, gemcitabine and pemostatin). Histologically, most lesions showed tumor cells invading the epidermis and skin appendages, dermal infiltration, diffuse distribution, vascular and peritubular destruction, and some subcutaneous adipose tissue involvement. Morphologically, most of the tumor cells were mixed with small-to medium-size lymphocytes, and some were large cells, mixed cells or small cells. Immunohistochemistry showed that CD3, CD3 ε and TIA-1 were expressed in all cases, but not CD20 and CD8. CD56 and granzyme B were expressed in most of the cases, and CD5 was not expressed. Ki-67 positive index was about 50%-90%. EBV in situ hybridization was positive in all cases. The clonal rearrangement of T cell receptor gene was found in some CD56 negative cases. The 15 patients were followed up for 5-45 months, and one of them was lost to follow-up. Five patients died within 5-13 months after the diagnosis, accounting for 35.7% (5/14) of the 14 patients. The average survival time of the deceased patients was 8.6 months. Conclusions: The incidence rate of pcENKTCL-NT is relatively low, but its biological behavior is aggressive and its prognosis is overall poor. Its skin lesions and histopathological features are relatively diverse. The diagnosis should be determined with using clinical data, histological morphology, immunophenotype and EB virus in situ hybridization. At the same time, attention should be paid to differential diagnosis from other cutaneous lymphoma with cytotoxic phenotype to avoid missed diagnosis and misdiagnosis.