Grading Histopathology Features of Graft-versus-host Disease in Animal Models; A Systematic Review.

Graft-versus-host disease (GvHD), a frequent and severe complication following allogeneic hematopoietic stem cell transplantation, presents substantial morbidity and mortality risks. The crucial role of histopathological examination in diagnosing and grading GvHD, particularly within animal models, is pivotal for elucidating disease mechanisms and assessing emerging therapies. This systematic review aims to critically evaluate the various grading systems for GvHD in animal models, emphasizing histopathological characteristics. In this endeavor, we meticulously examined original research articles sourced from PubMed, Scopus, Web of Science, and Google Scholar. Our findings reveal a diverse array of grading systems, each differing in the tissues examined, criteria evaluated, severity scoring scales, and the granularity of the information provided. Predominantly, skin, liver, and gut tissues are assessed, though some systems also incorporate lung and thymus evaluations. This review will delve into the alignment between clinical and histological grading in animal models of GvHD, also casting light on prospective advancements and the impact of technological progress. In conclusion, our analysis underscores the imperative need for uniform criteria and consistent application of grading systems. Such standardization is essential to foster comparability across studies and enhance the translation of preclinical discoveries into clinical applications.

Expression and Clinical Significance of Ki-67, CD10, BCL6, MUM1, c-MYC, and EBV in Diffuse Large B Cell Lymphoma Patients.

INTRODUCTION: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in adults. Although studies regarding the association between the expression of Ki-67, CD10, BCL6, and MUM1 proteins, as well as c-MYC amplification and EBV status with clinicopathologic characteristics have rapidly progressed, their co-expression and prognostic role remain unsatisfactory. Therefore, this study aimed to investigate the association between the expression of all markers and clinicopathologic features and their prognostic value in DLBCL. Also, the co-expression of markers was investigated. METHODS: The protein expression levels and prognostic significance of Ki-67, CD10, BCL6, and MUM1 were investigated with clinical follow-up in a total of 53 DLBCL specimens (including germinal center B [GCB] and activated B cell [ABC] subtypes) as well as adjacent normal samples using immunohistochemistry (IHC). Besides, the clinical significance and prognostic value of c-MYC and EBV status were also evaluated through chromogenic in situ hybridization (CISH), and their correlation with other markers was also assessed. RESULTS: The results demonstrated a positive correlation between CD10 and BCL6 expression, with both markers being associated with the GCB subtype ( P< 0.001 and P =0.001, respectively). Besides, we observe a statistically significant association between MUM1 protein expression and clinicopathologic type ( P< 0.005) as well as a positive association between c-MYC and recurrence ( P =0.028). Our survival analysis showed that patients who had responded to R-CHOP treatment had better overall survival (OS) and progression-free survival (PFS) than those who did not. CONCLUSION: Collectively, this study's results add these markers' value to the existing clinical understanding of DLBCL. However, further investigations are needed to explore markers' prognostic and biological roles in DLBCL patients.

The Confounding Role of Graft-Versus-Host Disease in Animal Models of Cancer Immunotherapy: A Systematic Review.

BACKGROUND: Cancer immunotherapy has emerged as a transformative approach for treating various malignancies, including melanoma, lung cancer, breast cancer, and leukemia. Animal models have been instrumental in elucidating the mechanisms and potential of these therapies. However, graft-versus-host disease (GVHD) is an inherent challenge in these studies, primarily because the introduction of foreign immune cells or tissues often triggers immune responses. METHODS: A detailed systematic search was conducted across various scientific databases, including PubMed, Scopus, Embase, and Web of Science. The search aimed to identify peer-reviewed articles published in English from January 2000 to September 2023. Keywords and phrases used in the search included "Graft-versus-Host Disease", "GVHD", "animal models", "cancer immunotherapy", and combinations thereof. Boolean operators (AND/OR) were employed to refine the search. Finally, 6 articles were included in this systematic review, which is registered on PROSPERO (ID number CRD42024488544). RESULTS: Our systematic review identified several mechanisms employed in animal studies to mitigate the confounding effects of GVHD. These included genetically modified mouse models, immunosuppressive drugs, and humanized mice. Furthermore, the review highlights innovative approaches such as selective T-cell depletion and the use of specific cytokine inhibitors. CONCLUSION: By systematically identifying and mitigating the confounding effects of GVHD, we can significantly improve the predictive validity of preclinical trials, obtain broadly applicable findings, improve the efficiency of drugs, enhance safety profiling, and develop better therapeutic strategies. This approach is crucial in ensuring that the immunotherapeutic strategies developed in the laboratory are reflective of the human physiological response, thereby bridging a critical translational gap in oncological research.

Stiff-person syndrome revealing an occult gray zone lymphoma: A diagnostic challenge.

Key Clinical Message: Stiff-Person Syndrome (SPS) can be associated with various malignancies, including lymphomas. Therefore, clinicians should always remain vigilant for the presence of an underlying malignancy, especially in older patients presenting with SPS. Abstract: Stiff-person syndrome (SPS) is a rare neurological disorder characterized by painful muscle spasms. It can occur as a paraneoplastic syndrome associated with various malignancies. We present a case of an older male adult with a history of recurrent fever episodes and elevated inflammatory markers for 1 year who subsequently developed neurological symptoms. The presence of positive amphiphysin antibodies led to the diagnosis of SPS, which prompted further investigations revealing an underlying Gray Zone lymphoma (GZL). This case highlights the challenges in diagnosing lymphoma and emphasizes the importance of considering SPS as a paraneoplastic syndrome in guiding toward the final diagnosis. The diagnostic challenge in our case is summarized in Chart 1.

Mediastinal gray zone lymphoma in a pregnant woman presenting with cardiac tamponade.

BACKGROUND: Mediastinal gray zone lymphoma is a newly recognized rare B cell neoplasm, which is challenging in diagnosis and treatment. CASE PRESENTATION: In the current study, we aimed to report a 25-year-old pregnant woman at 25 weeks of gestation who presented with chronic cough and progressive shortness of breath, hypotension, tachycardia, and tachypnea. A large circumferential pericardial effusion with compressive effect on the right atrium and right ventricle and a large extracardiac mass with external pressure to mediastinal structures were seen on trans thoracic echocardiography. The emergency pericardiocentesis was performed with the diagnosis of cardiac tamponade. Also, CMR revealed a huge heterogeneous anterior mediastinal mass, and the pathology and the immunohistochemistry of the mass biopsy revealed gray zone lymphoma with positive CD3, CD20, CD30, CD45, PAX5, and negative CD15 expression. Three courses of chemotherapy with the CHOP regimen were performed with an acceptable response every three weeks before delivery. A caesarian section was performed at 37 weeks without any problem for the patient and fetus, and chemotherapy will be started three weeks after delivery. CONCLUSION: Cardiac tamponade as an emergency condition occurred in this pregnant patient by malignant pericardial effusion and mediastinal mass pressure. Accurate diagnosis and on time interventions caused a significant improvement and a successful delivery.

New Presentation of CD27 Deficiency; Coronary Ectasia and COVID-19.

CD27 is a costimulatory receptor involved in the maturation of the innate and adaptive immunity. CD27, through interaction with CD70, plays a role in the control of Epstein-Barr virus (EBV) infection. CD27 deficiency leads to an immune dysregulation disease characterized by EBV susceptibility. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might put patients with primary immunodeficiency at risk for adverse outcomes. Chromogenic in situ hybridization (CISH) study was performed to detect EBV in the lymphoma tissue. Genetic analysis of the patient was done with Whole Exome Sequencing and detected variant was confirmed with PCR-Sanger sequencing. Here we report a 20-month-old boy with CD27 deficiency who developed lymphoma and coronary artery ectasia and had been infected with SARS-CoV-2. Clinical and laboratory findings were incompatible with atypical Kawasaki syndrome or multisystem inflammatory syndrome in children (MIS-C). As CD27 deficiency is a rare immune defect, publishing clinical data about the identified patient(s) can shed light on our knowledge about the related phenotype and the spectrum of clinical manifestations associated with CD27 deficiency. Thus, our findings expanded the spectrum of manifestations beyond EBV infection, highlighting this unusual cardiac sequela that could be related to EBV infection, lymphoma, or an underlying disease.

The utility of IMP3 immunohistochemical staining in differentiating nodular lymphocyte predominant Hodgkin Lymphoma from T-Cell/Histiocyte-Rich large B-Cell lymphoma.

INTRODUCTION: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have overlapping histological features that make their diagnosis challenging. Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a recently proposed diagnostic marker for Hodgkin's lymphoma. The aim of this study was to determine the ability of IMP3 in differentiating NLPHL from THRLBCL. METHODS: In this retrospective study, the formalin-fixed paraffin-embedded blocks from 56 patients (28 NLPHL and 28 large B cell lymphoma (LBCL, including 16 THRLBCL and 12 DLBCL, NOS) cases based on immunohistochemistry (IHC) were included. Sample sections were stained for IMP3 using IHC method. Moderate to strong staining in at least 10% of tumor cells was considered positive IMP3 expression. RESULTS: The mean age of the patients was 41.25 ± 16.08 years old. The majority of the patients were male. There was a significant age difference between NLPHL (34.61 ± 16.44 years old) and LBCL (47.89 ± 12.85 years) groups (p = 0.001). No significant difference was seen in gender and site between NLPHL and LBCL groups. The expression of IMP3 was mainly strong in LBCL group, while it was heterogeneously distributed among NLPHL samples ranging from weak to strong (p < 0.001). It was determined that strong IMP3 expression at 55.00% can differentiate LBCL from NLPHL with 71.4% sensitivity and 71.4% specificity. CONCLUSION: Our findings showed that IMP3 may be a good complement in differentiating NLPHL cases from THRLBCL.

Expression of PD1 and PDL1 as immune-checkpoint inhibitors in mantle cell lymphoma.

BACKGROUND: Mantle cell lymphoma (MCL) has remained incurable in most patients. The expression of PD-L1 as a prognostic and predictive marker has not been fully evaluated in MCL. The current study aimed to determine PD-1/PD-L1 expression in MCL specimens and its significance as an immune check point inhibitor. METHODS: This retrospective study was conducted on the formalin-fixed paraffin-embedded blocks of 79 confirmed MCL patients based on immunohistochemistry (IHC). The IHC method was used to stain patient samples for PD1 and PDL1. Positive PD-1/PD-L1 expression was defined as moderate to strong or memberanous or memberanous/cytoplasmic staining in at least 5% of tumor and/or 20% of associated immune cells. Tumor aggressiveness was determined based on Ki67 and variant. RESULTS: The mean age of the patients was 60.08 ± 10.78 years old. Majority of the patients were male. The prevalence of aggressive tumor was 25%. Positive PD1 and PDL1 expression were identified in 12 (15.0%) and 3 (3.8%) of tumor cells, respectively. PD1 and PDL1 were positive in zero (0%) and 7 (8.9%) of background cells, respectively. There was no significant difference in terms of study parameters between positive and negative groups for both PD1 and PDL1 proteins. PD1 tumor cell percentage was negatively correlated with age (r = -0.254, p = 0.046). CONCLUSION: Our results suggest that neither PD-1 nor its ligands represent relevant targets for MCL treatment. Age may impact the efficiency of immune checkpoint inhibitors and could be related to the increased incidence of MCL with age.

The utility of PAX8 in comparison with PAX5 immunohistochemical staining in the diagnosis of Hodgkin lymphoma.

BACKGROUND: Hodgkin's lymphoma (HL) is among the most prevalent lymphomas worldwide. PAX5 has a great value in separating this entity from other T cell lymphoma; however, it is weakly expressed in neoplastic cells. Polyclonal PAX8 was positive in a variety of lymphoid neoplasms in several previous studies and the staining paralleled that of PAX5 but monoclonal PAX8 was negative in the same neoplasms. The aim of this study was to compare immunohistochemical patterns of monoclonal PAX8 with PAX5 in Classical and NLPHL samples. MATERIAL AND METHODS: This retrospective study was conducted on 89 formalin-fixed paraffin embedded blocks from HL patients (69 Classical and 20 NLPHL) admitted to Imam Khomeini and Dr. Shariati hospitals, Tehran, Iran during 2016-2020. Diagnoses were confirmed by reviewing previous immunohistochemistry (IHC) studies, including PAX5. All samples were stained for PAX8 (clone MRQ-50). Expression intensity scoring was made for both antibodies in neoplastic and background cells based on nuclear staining percentage. RESULTS: PAX8 was positive in neoplastic and background B lymphocytes of all classical and NLPHL samples. PAX8 Expression intensity was significantly higher in neoplastic and background cells compared to PAX5 in classical HL samples (P = 0.001). PAX5 expression intensity in neoplastic cells was significantly higher in NLPHL samples compared to classical HL (P = 0.040); however, no significant difference in PAX8 expression between neoplastic cells of NLPHL and HL was seen. PAX8 expression intensity was not significantly correlated with gender, histologic subtype, tumor location, and relapse. CONCLUSIONS: PAX8 monoclonal antibody (clone MRQ-50) showed strong nuclear reactivity in neoplastic and background cells of classical HL and NLPHL samples. Therefore, this marker can be utilized as a valuable alternative for PAX5 in differentiating HL from other T cell lymphoma in challenging cases.

Subcutaneous panniculitis-like T-cell lymphoma in a young girl presenting with periorbital edema and fever: A case report.

Subcutaneous panniculitis-like T-cell lymphoma is a rare and highly malignant extra-nodal lymphoma. It has a wide range of clinical presentations (such as periorbital swelling as in our case) and should be considered in the differential diagnosis of systemic lupus erythematosus, especially in children.

Myofibroblastoma of the Breast: A Morphologic and Immunohistochemical Study of Three Cases.

Myofibroblastoma (MFB) of the breast is an uncommon entity of benign spindle neoplasms of the breast. This tumour possesses a broad spectrum of histomorphological patterns. Distinguishing of myofibroblastoma variants from malignant mimics of this benign neoplasm is essential for pathologists to avoid further invasive surgical procedures. In this article, we report the clinical, morphological, and immunohistochemical features of three cases, including two females and one male patient with mammary myofibroblastoma with emphasis on the histomorphological findings. As there is not yet enough information about MFB, more reports of MFB are still required to more clarify the pathogenesis and potential predisposing factors of this rare type of breast tumours.

A misdiagnosed case of blastic plasmacytoid dendritic cell neoplasm experiencing multiple recurrences who underwent allogeneic stem cell transplantation: a case report.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm represents a rare type of hematologic malignancy that often manifests itself through various skin lesions. It commonly affects the elderly male population. Lymph nodes, peripheral blood, and bone marrow involvement are the typical findings that justify its aggressive nature and dismal prognosis. On histopathological assessment, malignant cells share some similarities with blastic cells from the myeloid lineage that make immunohistochemistry staining mandatory for blastic plasmacytoid dendritic cell neoplasm diagnosis. CASE PRESENTATION: A 35-year-old Asian man presented with cervical lymphadenopathy followed by an erythematous lesion on his left upper back. At first, the lesion was misdiagnosed as an infectious disease and made the patient receive two ineffective courses of azithromycin and clarithromycin. Six months later, besides persistent skin manifestations, he felt a cervical mass, which was misdiagnosed as follicular center cell lymphoma. Tumor recurrence following the chemoradiation questioned the diagnosis, and further pathologic assessments confirmed blastic plasmacytoid dendritic cell neoplasm. The second recurrence occurred 3 months after chemotherapy. Eventually, he received a bone marrow transplant after complete remission. However, the patient expired 3 months after transplant owing to the third recurrence and gastrointestinal graft versus host disease complications. CONCLUSIONS: Early clinical suspicion and true pathologic diagnosis play a crucial role in patients' prognosis. Moreover, allogenic bone marrow transplant should be performed with more caution in aggressive forms of blastic plasmacytoid dendritic cell neoplasm because of transplant side effects and high risk of cancer recurrence.

Metastasis of a prostate adenocarcinoma to mandible: A case report and review of literature.

Dentists and physicians should include oral metastases originating from prostate adenocarcinoma as a rare differential diagnosis of jaw lesions that can produce periosteal reactions in the radiographic features such as osteosarcoma.

The Correlation between Serum Zinc Level and Liver Histology in Non-Alcoholic Steatohepatitis.

BACKGROUND & OBJECTIVE: The aim of this present study was to assess the relationship between serum zinc levels and liver histopathological findings in non-alcoholic steatohepatitis (NASH) patients. METHODS: This case-control study was performed in consecutively selected NASH patients who had been referred to a general hospital. The control group consisted of age and sex-matched individuals with normal physical examinations, laboratory findings, and liver ultrasounds. Serum zinc level was measured using atomic absorption spectrophotometry. Liver histopathological findings were determined based on non-alcoholic fatty liver activity score. RESULTS: A cohort of eighty biopsy-proven NASH patients and eighty controls were enrolled in the study. The mean serum zinc level was significantly lower in the NASH group compared with the controls. The mean serum zinc concen- tration was significantly lower in moderate and severe lobular inflammation groups than the mild group. After multiple adjustments for potential contributing variables, serum zinc level was associated with the severity of lobular inflam- mation. Nonetheless, it was not associated with liver steatosis and fibrosis. A serum zinc value of 89 (µg/dl) yielded a sensitivity and specificity of 93% and 86%, respectively, characterizing patients with lobular inflammation of less than two inflammatory foci per high-power field (HPF) from more advanced groups. Furthermore, a value of 79.55 (µg/dl) yielded a sensitivity and specificity of 87% and 100%, respectively, distinguishing those with a lobular inflammation grade of less than four foci per HPF from more advanced cases. CONCLUSION: Serum zinc level might be associated with the severity of lobular inflammation in NASH.

MIR196A2 rs11614913 contributes to susceptibility to colorectal cancer in Iranian population: A multi-center case-control study and meta-analysis.

Maturation of MIR196A2 as a gene regulator with a high potential for targeted cancer therapy can be modulated by the rs11614913 polymorphism. Several studies evaluating the association between this variant and pathogenesis of colorectal cancer (CRC) found significant results in various ethnic groups. This study aimed at investigating this relationship in a large sample size of Iranians as well as in a systematic review and meta-analysis of the pooled data of the current study with previous reports from Iran and other populations. After extraction of genomic DNA from the formalin-fixed paraffin-embedded tissues and whole blood of 2150 subjects (42% CRC patients), the rs11614913 was genotyped in both cases and controls. Furthermore, we conducted a meta-analysis of the present case-control study together with a previous report from Iranian population. The results of case-control study identified significant association between the rs11614913 and susceptibility to CRC [TT vs. CC: 1.58 (1.26-1.98), p < 0.01; TT vs. CT: 3.94 (3.07-5.05), p < 0.01; TT vs. CC + CT: 0.70 (0.59-0.83), p < 0.01; and CT + TT vs. CC: 1.43 (1.21-1.70), p < 0.01]. After correction of the meta-analysis results by using Bonferroni protocol, no significant association was observed in overall and in Asians [T vs. C: 1.19 (1.00-1.43), p = 0.05 and 1.14 (0.83-1.56), p = 0.43, respectively], whereas association was significant in Caucasians [T vs. C: 1.14 (1.04-1.25), p = 0.004] influenced by the data from Iran [T vs. C: 1.15 (1.03-1.29), p = 0.02 and TT vs. CC + CT: 0.73 (0.60-0.87), p = 0.003]. In conclusion, MIR196A2 rs11614913 might play a potential role in the pathogenesis of CRC in Iranian population.

The Comparison Between Microwave and Autoclave as Antigen Retrieval Methods for Immunohistochemical Detection of CD15 and CD30 in Hodgkin's Lymphoma.

BACKGROUND AND OBJECTIVE: Hodgkin's lymphoma is a potentially curable hematologic malignancy with difficulty in its diagnosis especially in atypical cases even in expert hands. Today, immunohistochemistry plays a significant role in the diagnosis of it especially applying the anti-CD15 and anti-CD30 antibodies. The negativity of CD15 can be reduced by antigen retrieval for methods. In this study, the effect of autoclave was compared with microwave as heating sources of antigen retrieval in immunohistochemical staining. METHODS: Sections prepared from 50 formalin-fixed paraffin-embedded tissue blocks of Classic Hodgkin's lymphomas stained for CD15 and CD30 using autoclave and microwave, were randomly and blindly reviewed by an expert hematopathologist, mostly focusing on Reed-Sternberg cells; the intensities were scored from 0 to +4 and analyzed by SPSS software. RESULTS: Fifty eight percent of patients were male. The mean age was 32 years (range: 7 to 77). Nodular sclerosis was the most prevalent subtype. CD15 positivity in microwave treatment was 92% compared to 50% in autoclave. Negative CD30 decreased from 20% in autoclave to 2% in microwave. Intensity of staining in both markers was at least +1 greater in microwave treatment. No background staining was seen in microwave method. CONCLUSION: There was bimodal age distribution in Hodgkin's lymphoma patients with the predominant male and Nodular Sclerosis as the most common type. Comparing autoclave and microwave, higher rate of the positivity was detected using microwave treatment, especially in CD15 staining. Improvement in staining intensity was also noticeable in both markers. There was no background or non-specific staining in microwave method. No disturbance of cells or nuclear morphology was also reported.

Assessment of Micro-vessel Density in Brain Gliomaby CD105 Expression.

BACKGROUND & OBJECTIVE: Micro-vascular proliferation is an important histological feature of brain glioma with more vascular proliferation is present in higher grades of glioma. CD 105 is expressed in new actively proliferating and immature endothelial cells in tumor environment and appears to be capable to distinguish between malignant neo-vasculature and normal vessels. METHODS: This study was designed to evaluate the Micro-Vessel Density(MVD) in different grades of brain glioma based on CD 105 expression byImmunohistochemistry method to determine whether it can be a helpful marker for rumor grading or not.Paraffin blocks of formalin fixed samples of brain astrocyticglioma were retrieved and IHC was performed using anti-CD105 monoclonal mouse antibody. RESULTS: Total number of 48cases of low and high grade astrocyticgliomas were evaluated.We noted that there was a positive correlation between MVD evaluated by CD105 and tumor grade, meaning that expression was significantly greater in tumors with higher grade (P=0.019). CONCLUSION: We concluded that MVD quantified by CD 105 has positive correlation with tumor grade. Also we think that expression of CD 105 specially in low-grade glioma can serve as a basis for selective treatment option in combination with current standard care.

Lack of association of CASC8 rs1447295 with colorectal cancer in Iranian population: A multicenter case-control study.

Several studies reported the potential role of the rs1447295 polymorphism in susceptibility to cancer. This variant located in the cancer susceptibility candidate 8 (CASC8) is a long noncoding RNA (lnRNA) gene and does not code protein. LnRNA transcripts play a potential regulatory role in the expression of key genes involved in multiple cellular pathways, including cell cycle, pluripotency, and immune response. The aim of this study is to evaluate this association with colorectal cancer (CRC) in a large case-control study of the Iranian population. After extraction of genomic DNA by the standard protocols, the rs1447295 was genotyped in 2416 subjects (46% patients). Results of this case-control demonstrated no significant association between the rs1447295 polymorphism and risk of CRC or its characteristics under allele or alternative genotype models. In conclusion, it is unlikely that the rs1447295 polymorphism is a risk variant for the development of CRC in Iranian population.

The Correlation Between Liver Fat Content and Ulcerative Colitis Disease Severity.

To evaluate the association between disease severity and hepatic steatosis in patients with ulcerative colitis (UC) and non-alcoholic steatohepatitis (NASH). Consecutively selected UC patients admitted to the gastroenterology clinic were enrolled in the study. UC severity was assessed by Truelove and Witts classification. Patients with severe UC were excluded from the study. NASH was determined based on persistently elevated serum aminotransferase levels and detection of fatty liver ultrasound. Patients with other etiologies for elevated aminotransferase levels were excluded. Liver fat content (LFC) was assessed by measuring liver fat score (LFS). One hundred patients (42% male) were included in the study. According to liver ultrasound examination, 62 (%) patients were identified with grade 1 fatty liver disease, and 38 (%) patients were classified as advanced (grade 2 and 3) fatty liver disease. Sixty-one patients had left-sided UC and (46%) had mild UC disease severity index. LFS was significantly higher in UC patients with the moderate disease than patients with mild disease (3.53±2.68 vs. 5.89±2.85, respectively; P<0.01). Nevertheless, no significant difference was observed in LFS regarding UC extension. There was no significant difference between NASH ultrasound grades in view of UC severity and extension. LFC might be associated with UC severity.