Augmentation of tumor expression of HLA-DR, CXCL9, and CXCL10 may improve olfactory neuroblastoma immunotherapeutic responses.

BACKGROUND: Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches. METHODS: Multispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed. RESULTS: A significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration. CONCLUSION: These data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses.

Post-transplant Lymphoproliferative Disorder of Naso-orbital Region in Adult Renal Transplant Recipients: A Case Report and Literature Review.

Post-transplant lymphoproliferative disorder (PTLD) is an uncommon but fatal complication following both solid organ and hematologic stem cell transplantations. Epstein-Barr virus (EBV) has been considered a main etiologic agent causing PTLD, especially in the first year after transplantation. Extranodal manifestations are frequently found in PTLD; however, naso-orbital involvement in adults is rare. We report a case of EBV-associated PTLD of the naso-orbital region in a 72-year-old patient that occurred 10 years after kidney transplant. Six additional adults with naso-orbital PTLD were identified after completing this literature review, including 2 cases with eyelid swelling, 3 cases with proptosis, and 1 case with facial numbness. The majority of cases occurred after 1 year of transplantation and were associated with EBV. This report emphasizes recognizing PTLD as differential diagnosis in transplant recipients who present with naso-orbital symptoms.

CD20-positive primary nasal peripheral T-cell lymphoma: An analysis of one case and review of the literature.

CD20-positive T-cell lymphoma (TCL) is a very rare disease entity that is associated with the co-expressions of a range of T cell lineage makers, such as, CD2, CD3, CD5, or CD7, and CD20. The biological and clinical significance of CD20 antigen expressed in TCL has been unclear. Here, we are reporting an unusual case of CD20-positive primary nasal peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in a 62-year-old female with both peripheral blood (PB) and bone marrow (BM) involvement. Flow cytometry (FC) analysis revealed CD20+ lymphoma cells in PB, BM, and lymph node (LN) and was consistent with pathological findings. FC immunophenotyping was proved of great diagnostic contribution.

Expression of Programmed Cell Death Ligand 1 and Associated Lymphocyte Infiltration in Olfactory Neuroblastoma.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) is a transmembrane glycoprotein that interacts with the receptor programmed cell death 1 (PD-1) to suppress T-cell activation, reduce adjacent tissue damage, and promote tolerance to self-antigens. Tumors may express PD-L1 as a mechanism to evade immune detection. Recent clinical trials have demonstrated the efficacy of PD-L1/PD-1 antagonists through activation of tumor-infiltrated CD8+ T cells. The aim of this study was to determine the expression pattern of PD-L1 and PD-1 in olfactory neuroblastoma (ONB) tumor cells and to determine the presence of PD-1+ and CD8+ lymphocytes in the ONB immune microenvironment. METHODS: Immunohistochemistry for expression of PD-L1, PD-1, and CD8 was performed on paraffin-embedded ONB tissue. RESULTS: Of the 10 primary site ONB samples, 4 demonstrated positive PD-L1 expression. Of PD-L1+ tumors, the 2 highest expressing samples were found to contain PD-1+ tumor cells. Of the 4 available metastatic samples, all of which arose from PD-L1- primary site ONB, 3 were positive for PD-L1 and contained PD-1+ tumor cells. PD-L1+ primary and metastatic tumors also demonstrated increased PD-1+ infiltrating lymphocytes in the tumor and stroma (11.6- and 4.62-fold increase) compared with PD-L1- samples (P < 0.05 and P = 0.068 respectively). PD-L1+ specimens demonstrated increased CD8+ lymphocytes in the tumor and stroma (7.46- and 2.14-fold increase) compared with PD-L1- tumors (P < 0.05 for both). CONCLUSIONS: These data demonstrate that a proportion of ONB primary and metastatic tumors express PD-L1 and possess an associated tumor and stromal infiltrate of PD-1+ and CD8+ lymphocytes.

Clinical significance of IgG4 in sinonasal and skull base inflammatory pseudotumor.

INTRODUCTION: Inflammatory pseudotumor (IPT) in the sinonasal cavity and skull base region is benign non-neoplastic inflammatory process. However, IPT can mimic malignant tumor or infectious disease and there are difficulties in confirmation of diagnosis. The aim of study is to evaluate the clinical significance of immunoglobulin G4 (IgG4) in IPT in terms of steroid response and differential diagnosis with other skull base infiltrative lesions. METHODS: Medical records were reviewed retrospectively from 1998 to 2016. Subjects diagnosed with IPT by surgical biopsy were enrolled. IgG4 positivity was defined as IgG4/IgG ratio > 0.4. Additionally, IgG4/IgG ratio was calculated in eight skull base osteomyelitis (SBO) patients. RESULTS: Twenty-six IPT patients were included and the average age was 52.3 years, and 57.7% were male and 42.3% were female. Most lesions were involved in the sinuses (88.5%) and the incidence of extension beyond the sinuses itself was as follows: the cheek/hard palate/parapharynx (15.4%), orbit (61.5%), skull base (57.7%), and dura or brain (23.1%). All IPT cases revealed IgG4 + plasma cells and IgG4/IgG ratio over 0.4 was detected in 42.3% (11/26) of cases. In case of SBO, no patients had IgG4/IgG ratio exceed 0.4. Main treatment modality was systemic steroids (61.5%) and other modalities were used: surgery (3.8%), immunosuppressant (7.7%), radiotherapy (30.8%), or a combination of these modalities (15.4%). Steroid responses were not significantly different, but IgG4-positive group tended to have better response to steroid therapy. CONCLUSIONS: IgG4-positive and IgG4-negative IPT patients revealed no differences in involvement sites, clinical course, and steroid responses. However, IgG4/IgG ratio and IgG4 + plasma cell count can provide a diagnostic clue for infiltrative skull base lesions such as IPT and a differential diagnosis of SBO.

High-risk mucosal HPV types associated with squamous cell carcinoma on the nose tip in an immunocompetent young man

Abstract: The oncogenic role of high-risk HPV in anogenital, head and neck, and cervical cancer is well recognized, but not in skin cancer in the general population. Some authors have demonstrated their appearance mainly on the hands and feet, particularly in the area of the nail bed, which could be due to contamination with HPV types from anogenital regions. Here, we describe a case of genital HPV associated with SCC on the nose tip in an immunocompetent young man, which was confirmed by histopathological findings and in situ hybridization. The importance of this report is to highlight the potential role of HPV in the etiology of skin cancer in an immunocompetent individual.

High-risk mucosal HPV types associated with squamous cell carcinoma on the nose tip in an immunocompetent young man.

The oncogenic role of high-risk HPV in anogenital, head and neck, and cervical cancer is well recognized, but not in skin cancer in the general population. Some authors have demonstrated their appearance mainly on the hands and feet, particularly in the area of the nail bed, which could be due to contamination with HPV types from anogenital regions. Here, we describe a case of genital HPV associated with SCC on the nose tip in an immunocompetent young man, which was confirmed by histopathological findings and in situ hybridization. The importance of this report is to highlight the potential role of HPV in the etiology of skin cancer in an immunocompetent individual.

Pure intravascular recurrence of CD5-positive diffuse large B-cell lymphoma primarily arising from the nasal cavities.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (DLBCL) and intravascular large B-cell lymphoma (IVL) are recognized as rare subsets of large B-cell lymphoma with poor prognosis. These two categories have similar clinicopathological features suggesting that they might overlap. CASE PRESENTATION: We present a case of a 72-year-old man with submental tumors. Positron emission tomography/computed tomography (PET/CT) showed tumors in the nasal and paranasal region and multiple submental and jugular swollen lymph nodes with abnormal uptake of 18F-fluorodeoxyglucose (FDG). Histology of biopsy from nasal tumors showed diffuse infiltration of large lymphoid cells, which showed positive expressions for CD20, CD79a, CD5 and negative for CD3 on immunohistochemistry. Thus, a CD5-positive DLBCL was diagnosed. After administration of 8 cycles of R-THPCOP (rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone), complete remission was achieved. Eight months after the first chemotherapy dose, local recurrence occurred. After salvage chemotherapy, nasal and paranasal tumors and lymph node swelling disappeared on PET/CT images, although the patient suffered from respiratory disturbance. A random skin biopsy revealed IVL, which was consistent with intravascular recurrence of CD5-positive DLBCL. Bone marrow smears showed hemophagocytosis. CONCLUSION: We present a rare case of primary CD5-positive DLBCL that relapsed as pure IVL after chemotherapy. Our case suggests that CD5-positive DLBCL is closely related to IVL.

Immunoglobulin G4-related disease of the paranasal sinuses.

Immunoglobulin G4-related disease (IgG4-RD) is becoming increasingly documented. It was first described in relation to autoimmune pancreatitis. Features of the disease include tissue infiltration by IgG4 plasma cells with associated fibrosis and the growth of pseudotumours. A 71-year-old woman presented with increasing right cheek swelling and mild proptosis. Ten years earlier, she had a similar presentation and was diagnosed with an inflammatory pseudotumour. Examination revealed a lesion in the right nasal cavity. CT and MRI confirmed a mass within the right maxillary antrum extending into the nasal cavity. Endoscopic biopsies showed florid plasma cell infiltrate with marked increase in IgG+ plasma cells. Immunostaining expressed IgG4 (70%). She was started on a course of prednisolone and her symptoms resolved. IgG4-RD is becoming an emerging disease entity. Its involvement in the paranasal sinuses can mimic nasal tumours. Major surgical resection should be avoided as patients can often be treated medically.

Efficacy of Tumor-Infiltrating Lymphocytes Combined with IFN-α in Chinese Resected Stage III Malignant Melanoma.

BACKGROUND: This study aims to explore the efficacy of tumor-infiltrating lymphocytes (TIL) along with interferon-α (IFN-α) to treat stage III malignant melanoma (MM) patients in China. METHODS: Between May 2010 and October 2014, 77 patients of stage III MM who underwent surgery were collected in this study. These patients were divided into two groups: patients who received TIL + IFN-α ± RetroNectin-activated cytokine-induced killer cells (R-CIK) in Arm 1 (n = 27) and IFN-α ± R-CIK in Arm 2 (n = 50) as adjuvant therapy. The primary endpoints were disease-free survival (DFS) time and DFS rates measured at time points of 1, 2, and 3 years. The secondary endpoints were overall survival (OS) rates measured at time points of 1, 2, 3, and 5 years as well as OS as evaluated by Kaplan-Meier. RESULTS: Our results indicated that the median DFS and OS in Arm 1 were significantly better than those in Arm 2. The data also demonstrated that DFS rate and OS rates in Arm 1 were significantly better than those in Arm 2 at all measured time points. CONCLUSION: Patients who undergo surgical excision of stage III MM appear to enjoy prolonged DFS and OS when treated with TIL + IFN-α compared to IFN-α alone.

Extranodal NK/T-cell Lymphoma, Nasal Type Accompanied by PR3-ANCA-associated Glomerulonephritis.

A 62-year-old man exhibiting nasal obstruction and glomerulonephritis with proteinase 3-antineutrophil cytoplasmic antibodies (PR3-ANCAs) was diagnosed with extranodal NK/T-cell lymphoma, nasal type (ENKL) with infiltration of neutrophils with apoptosis. Chemoradiotherapy reduced the tumor, improved the renal function, and decreased the PR3-ANCA levels. ANCA-positivity is observed in immunoinsufficient diseases, in which neutrophils lead to apoptosis and translocate intracellular granules, such as PR3, to the cell surface, triggering the production of ANCAs. In our case, the PR3-ANCA production was derived from the expression of PR3 on the cell surface of apoptotic neutrophils. This is the first report on ENKL describing the mechanism of ANCA development.

[The significance of peripheral blood natural killer cell surface CD107a, NKG2D and serum sMICA in patients with extranodal NK/T cell lymphoma, nasal type].

The expression of CD107a, NKG2D on the surface of natural killer (NK) cells and serum soluble major histocompatibility complex class Ⅰ chain-related A (sMICA) level in patients with extranodal NK/T cell lymphoma, nasal type (ENKL) were detected.We found that CD107a expression was reduced on the surface of NK cells, suggesting impaired NK cell activity in ENKL patients, which may result from decreased NKG2D expression.

[Impact of virus infection and related immunity factorson nasal inverted papilloma].

Objective:To explore the relationship between human papilloma virus infection,TGF-ß,IL-10,IFN-γand nasal inverted papilloma.To explore the relat-ionship between human papilloma virus infection,TGF-ß,IL-10,IFN-γand nasal squamous cell carcinoma.Method:Thirty cases of NIP(including 7 cases of recurrent NIP),23 cases of NSCC,19 cases of NP were collected.In situ hybridization(ISH) was used to detect the infection of HPV6/11,HPV16/18.Immunohistochemical technique(EnVision) was used to detect the expression of TGF-ß,IL-10,IFN-γ.Result:The HPV infection rates of 30 cases of NIP,23 cases of NSCC were 43.33%,52.17%.None of the NP cases was infected with HPV.Nine out of 23 cases of primary NIP were positive in HPV infection (39.13%).Three out of 7 cases of recurrent NIP were positive in HPV infection (42.86%).There were significant differences in the HPV infection rate between NIP and NP as well as between NSCC and NP(P<0.05).No significant difference of HPV infection rate was observed between NIP and NSCC or between recurrent NIP and primary NIP(P>0.05).TGF-ß,IL-10,IFN-γwere expressed in NSCC,NIP and NP.The expression of TGF-ßwas significantly different among NIP,NSCC and NP(P<0.01).The expression of TGF-ßin NIP group was higher than that in NP and NSCC group.There was no significant difference of TGF-ßexpression between NSCC and NP group .The expression of IL-10 was significantly different among NIP,NSCC and NP(P<0.01).The expression of IL-10 in NIP group was lower than that in NP group.There was no significant difference in IL-10 expression between NIP and NSCC or between NSCC and NP.No significant differences of IFN-γexpression was observed among NIP,NSCC and NP(P>0.05).There was no correlation between the expression of TGF-ß,IL-10,IFN-γand HPV infection in NIP and NSCC(P>0.05).Conclusion:HPV infection is related to the pathogenesis of some NIP and NSCC cases.The relationship of between HPV infection and malignance of NIP is not clear.HPV infection is not related to the recurrence of NIP.Abnormal expression TGF-ßand IL-10 may be involved in the pathogenesis of NIP.There is no relationship between IFN-γand the pathogenesis and development of NIP.HPV infection is not related with the expression of TGF-ß,IL-10,IFN-γin NIP and NSCC.

Anti-Hu Antibody Associated Paraneoplastic Cerebellar Degeneration in Head and Neck Cancer.

BACKGROUND: Paraneoplastic syndromes are most frequently associated with small cell lung carcinoma, hematologic and gynecologic malignancies while reports in head and neck cancer are rare. CASE PRESENTATION: We present the case of a 60-year old female patient who developed paraneoplastic cerebellar degeneration upon locoregional recurrence of a poorly differentiated spindle cell carcinoma of the nasal cavity and paranasal sinus. The neurological symptoms, especially ataxia, stabilized after resection of tumor recurrence and concomitant chemoradiotherapy whereas anti-Hu-antibodies remained positive. Despite the unfavorable prognosis of paraneoplastic neurological disorders associated with onconeural antibodies, the patient achieved long-standing stabilization of neurological symptoms. CONCLUSION: We report the first patient with anti-Hu antibodies and paraneoplastic cerebellar degeneration associated with a spindle cell carcinoma of the head and neck. We recommend that evaluation of neurological symptoms in patients with this tumor entity should also include paraneoplastic syndromes as differential diagnoses and suggest early extensive screening for onconeural antibodies.

Establishment and Characterization of a CD20-Positive NK/T-Cell Lymphoma Cell Line.

BACKGROUND: CD20 positive NK/T-cell lymphoma is extremely rare and difficult for clinical treatment. Due to the lack of an established cell model for this disease, less is known about its biological characterization and potential therapeutic options. METHODS: A cell line of NK/T-cell lymphoma, which was enriched by magnetic sorting with proper cell surface markers (CD56) from peripheral blood mononuclear cells (PBMCs) drawn from a 21-year-old male patient with nasal angiocentric NK/T-cell lymphoma, was designated as ZQNK-29. Immunophenotypic analysis of ZQNK-29 was performed by flow cytometric and immunohistochemical analysis. Comparative genomic hybridization (CGH) analysis was used for cytogenetic analysis of ZQNK-29. Potential rearrangements of the immunoglobulin gene and Epstein-Barr virus (EBV) infection were examined by PCR and RT-PCR, respectively. RESULTS: ZQNK-29 cells express the phenotypic T-cell marker (CD3), T cell activation markers (HLA-DR), markers for both NK and cytotoxic T lymphocytes (TIA-1), and B-lineage marker CD20; however, expression of CD56 was not detected in expanded ZQNK-29 cells although this NK cell surface marker was used as one of selective cell surface markers for the initial isolation of NK/T cells. RT-PCR analysis showed that the pattern of gene expressions for infected EBV was latency type III, with the expressions of LMP1, EBNA-1, and EBNA-2; no rearrangements were found in the heavy-chain of the immunoglobulin gene or in the y chain of the T cell receptors (TCRs) gene. CGH analysis demonstrated that ZQNK-29 possessed an abnormal karyotype, 46XY, 1p (dist)+, 4p (dist)+, 4q (mid)-, 5q (mid)-, 9q (dist)+, 16p (dist)+, 16q (dist)+, 17p+, 17q (dist)+, 19q (dist)+, 20p+, 20q+, 21q+, and 22q+. Of these, 1p (dist)+, which has been confirmed to be mitochondrial DNA amplification, is believed to be mainly caused by EBV infection. CONCLUSIONS: ZQNK-29 is a well characterized premature human NK/T-cell lymphoma cell line with expression of the B-cell marker CD20 and will provide a useful pre-clinic model for characterization and potential therapeutic studies of the aggressive NK/T-cell lymphoma.

Epstein-Barr virus-positive plasmacytoma in immunocompetent patients.

AIMS: Extramedullary plasmacytomas are often localized, clinically indolent neoplasms, and affected patients usually respond to radiation therapy or limited cycles of chemotherapy. In contrast, plasmablastic lymphomas are clinically aggressive neoplasms composed of immunoblastic or plasmablastic cells and associated with more mature plasma cells in some cases. Patients with plasmablastic lymphoma usually have a poor prognosis despite aggressive chemotherapy. Evidence of Epstein-Barr virus (EBV) infection is uncommon in plasmacytoma, but common in plasmablastic lymphoma, and is therefore helpful in differential diagnosis. The aim of this study is to describe four cases of plasmacytoma arising in immunocompetent individuals that were diffusely positive for Epstein-Barr virus-encoded small RNA as shown by in-situ hybridization. METHODS AND RESULTS: We describe the clinicopathological and immunophenotypic findings of four EBV-positive plasmacytomas arising in immunocompetent patients. These tumours were characterized by diffuse proliferation of mature-appearing plasma cells intermixed with a briskly reactive, CD8-positive, TIA-1-positive cytotoxic T-cell infiltrate. Long-term follow-up was available for all patients, and all were alive and free of disease at last follow-up (median 43.4 months). CONCLUSIONS: We suggest the term EBV-positive plasmacytoma in immunocompetent patients for these lesions. It is essential to distinguish these tumours from plasmablastic lymphoma, as the latter diagnosis is associated with a much poorer prognosis, and patients require much more aggressive therapy.

[Different methods of antigen retrieval impact on Pan of sinonasal inverted papilloma].

OBJECTIVE: To explore different conditions and buffers of antigen retrieval which affect the CK of SNIP on immunohistochemical staining results. METHOD: Dividing paraffin tissue sections of 11 patients into four groups. Using the Image-Pro Plus Image analyzer and taking five horizons for each section to calculate an average of 200 areas, measured standard optical density of the positive reaction areas. RESULT: It is divided into four groups: high temperature and high pressure citrate buffer retrieval, microwave EDTA buffer retrieval, microwave citrate retrieval, high temperature and high pressure EDTA buffer retrieval. The standard optical density of positive reaction areas respectively express: 0.324 ± 0.051, 0.325 ± 0.056, 0.303 ± 0.061, 0.365 ± 0.023. The rates of CK positive expression with high temperature and high pressure EDTA buffer retrieval is batter than other repairing groups in the same paraffin tissue sections (P < 0.05). CONCLUSION: For the Pan of Sinonasal inverted papilloma, the method of high temperature and high pressure EDTA buffer antigen retrieval can achieve the ideal staining results? which is worth while to promote and maybe as a bet? ter guide of clinic work.