Primary Adrenal Lymphoma: Two Case Series From China.

Objective: Primary adrenal lymphoma (PAL) is a rare form of adrenal mass. We summarize our experience in its clinical presentation, biochemical indexes, radiological features, pathological information, therapy regimens, and outcomes. Methods: This was an institutional review board-approved retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of PAL at the Chinese People's Liberation Army General Hospital and the First Affiliate Hospital of Xiamen University between July 2007 and July 2017. Results: Twenty-six patients were identified. The mean age at presentation was 60.84 ± 13.14 years with a male-to-female ratio of 2.25:1 (18:8). The most common presenting symptoms were loss of appetite (65%, 17/26), weight loss (62%, 16/26), abdominal pain (58%, 15/26), and fatigue (58%, 15/26). The levels of lactate dehydrogenase (75%, 15/20), ß2-microglobulin (100%, 10/10), C-reactive protein (82%, 14/17), and ferritin (88%, 7/8) and the erythrocyte sedimentation rate (83%, 10/12) were elevated. Bilateral involvement was seen in 21 of 26 patients (81%); 12 of 19 evaluated patients with bilateral lesions (63%) were confirmed to have adrenal insufficiency. On computed tomography (CT), the mean tumor diameter was 7.31 ± 3.35 cm and the median Hounsfield density was 37.0 HU (range: 31.0-45.0 HU); 67% (10/15) and 27% (4/15) of lesions presented with mild and moderate enhancement after injection of contrast medium. 18F-fluorodeoxyglucose positron emission tomography (FDG PET)-CT revealed not only an adrenal tumor but also extra-adrenal lesions. Diffuse large B-cell lymphoma (DLBCL) was the most common phenotype (92%, 24/26). Ninety-two percent (24/26) of patients received chemotherapy while 8% (2/26) received unilateral adrenalectomy plus chemotherapy. The prognosis of PAL was poor, with a general survival time of 7.20 ± 5.18 months. Conclusion: PAL is a rare disease. The clinical characteristics of PAL include loss of appetite and weight loss. Endocrine evaluation should be performed to determine whether patients have adrenal insufficiency, especially patients with bilateral lesions. FDG-PET appears to be more accurate than other imaging modalities in revealing extra-adrenal sites. Better therapy is required to improve the poor prognosis of PAL.

Extranasal extranodal NK/T cell lymphoma: A post-transplantation lymphoproliferative disease.

Extranodal NK/T cell lymphoma (ENKTL) is a rare form of non-Hodgkin lymphoma. It mostly occurs in the upper respiratory tract. Cutaneous involvement can be seen among the extranasal ENKTLs. After solid organ and haematopoietic stem cell transplantation, post-transplantation lymphoproliferative disease because of immunosuppressive therapy is usually B cell-derived; T and NK/T cell-derived disease is rarely seen. A 43-year-old female patient who had renal transplantation 14 years ago presented with cutaneous ulceration and subcutaneous nodules located in the abdomen. The patient was diagnosed with ENKTL, nasal type. Although it is rare, ENKTL nasal type is a lymphoproliferative disease that should be considered in the differential diagnosis of ulcerated cutaneous tumoural lesions.

Primary adrenal extranasal NK/T cell lymphoma with subcutaneous involvement demonstrated on FDG PET/CT: A clinical case report.

RATIONALE: Primary adrenal non-Hodgkin lymphomas are predominant diffuse large B cell lymphoma with frequently bilateral adrenal involvement, but the occurrence of nasal type extranodal NK/T cell lymphoma is relatively rare. PATIENT CONCERNS: A 40-year-old woman complaining of left back pain for 2-month was admitted to our department. DIAGNOSIS: Based on the feature of enhanced computed tomography (CT) images which showed huge bilateral well-defined adrenal masses with heterogeneous enhancement, she was tentatively diagnosed as having primary adrenal malignancy. Postoperative pathology revealed the diagnosis of primary adrenal Epstein-Barr virus-associated nasal type extranodal NK/T-cell lymphoma. INTERVENTIONS: Then, she underwent F-fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography (PET)/CT examination for staging, which showed homogeneously increased FDG uptake in the right adrenal gland and left thigh subcutaneous lesion, as well as heterogeneous increased FDG uptake in the left adrenal gland region with no abnormal uptake in the nasal cavity. Subsequently, the patient has performed 7 cycles of gemcitabine, L-asparaginase, ifosfamide, dexamethasone, etoposide (GLIDE) regimen and autologous stem cell transplantation. OUTCOMES: Fortunately, the subsequent 2 follow-up FDG PET/CT scans within 1 year revealed complete resolution with no abnormal FDG uptake in the initially involved sites after 7 cycles of GLIDE chemotherapy and autologous stem cell transplantation. LESSONS: The enhanced CT and FDG PET/CT features of primary adrenal extranasal NK/T cell lymphoma are huge bilateral well-defined adrenal masses with heterogeneous enhancement, high FDG uptake, especially with subcutaneous involvement. And the awareness of this entity may help clinicians to differentiate it from other primary adrenal tumors and make reasonable therapeutic strategies. Besides, FDG PET/CT scan is very useful for the treatment follow-up of the primary adrenal extranasal NK/T cell lymphoma.

c-Myc mediated upregulation of long noncoding RNA SNHG12 regulates proliferation and drug sensitivity in natural killer/T-cell lymphoma.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor outcomes. The treatment of NKTCL requires intensive chemotherapy. Long noncoding RNAs (lncRNAs) have been implicated in many cancers, including NKTCL. The elucidation of the multidrug resistance (MDR) may greatly contribute to explore novel therapeutic strategies. Herein, we explored the roles and potential regulatory mechanism of lncRNAs small nucleolar RNA host gene 12 (SNHG12) in MDR of NKTCL. We found that SNHG12 was upregulated in NKTCL tissue sections, and its high expression was positively correlated with clinical grade of malignancy of NKTCL. c-Myc and SNHG12 expression was upregulated in NKTCL cell lines. c-Myc- and SNHG12 overexpression promoted proliferation and inhibited sensitivity to cisplatin (CDDP) in NK/T-cell lymphoma cell line YTS cells, and c-Myc and SNHG12-downregulation inhibited proliferation and enhanced sensitivity to CDDP in SNK-6 cells. Moreover, c-Myc- and SNHG12 overexpression increased Ki67 and P-gp expression in YTS cells, whereas c-Myc and SNHG12-downregulation reduced the Ki67 and P-gp expression in SNK-6 cells. Correlational analyses revealed that c-Myc expression was positively correlated with SNHG12 expression in NKTCL tissues. Mechanism research showed that SNHG12 was a direct transcriptional target of c-Myc and c-Myc promoted SNHG12 expression in NKTCL cell lines. Further research showed that SNHG12 overexpression reversed the effects of c-Myc downregulation on proliferation and sensitivity to CDDP in NKTCL cell lines. Taken together, our findings first report that c-Myc mediated upregulation of SNHG12 promotes proliferation and inhibits drug sensitivity in NKTCL, which provides new insights into the therapeutic target for NKTCL.

Gambogic acid induces cell apoptosis through endoplasmic reticulum stress triggered inhibition of Akt signaling pathways in extranodal NK/T-cell lymphoma cells.

As the chemotherapeutic resistance of extranodal NK/T-cell lymphoma (ENKTL) rises year by year, searching for novel chemoprevention compounds has become imminent. Gambogic acid (GA) has recently been shown to have anti-tumor effects, but its role and underling mechanism in ENKTL are rather elusive. In the present study, we showed that GA inhibited the cell growth and potently induced the apoptosis of ENKTL cells in vitro in a time- and concentration-dependent manner. Furthermore, GA induced cell death through endoplasmic reticulum stress (ERS) mediated suppression of Akt signaling pathways and finally the release of the caspase-3 proteases. Overall, our data provided evidences supporting GA as a potential therapeutic agent for ENKTL, which may facilitate further preclinical development of anti-tumor drugs.

Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma.

Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor-normal samples, we have identified a hotspot mutation (c.419T>C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-κB more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-κB, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-κB from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS.

[The clinical observation of NK/T-cell lymphoma of the nasal type]. / Klinicheskoe nabliudenie NK/T-kletochnoi limfomy nazal'nogo tipa.

The objective of the present work was to present the results of the clinical analysis of the patient presenting with natural killer (NK)/T-cell lymphoma of the nasal type. We undertook the analysis of the medical documentation concerning the case of interest. It was shown that the development of progressive perforation of the nasal septum and the pronounced destructive changes in the intranasal and adjacent structures following the endonasal surgical interventions made necessary differential diagnostics between the condition under consideration and certain latent disorders (such as Wegener's granulomatosis, leprosy, syphilis, leishmaniasis, dirofilariasis tuberculosis, etc.). The study has demonstrated that the negative results of the analysis imply the necessity of special attention to the possibility of development of oncological diseases including hematological disorders (e.g. NK/T-cell lymphoma) and the repeat careful follow-up examination of the patients by the experienced experts.

Risk stratification on the basis of Deauville score on PET-CT and the presence of Epstein-Barr virus DNA after completion of primary treatment for extranodal natural killer/T-cell lymphoma, nasal type: a multicentre, retrospective analysis.

BACKGROUND: Assessment of tumour viability after treatment is essential for prediction of treatment failure in patients with extranodal natural killer/T-cell lymphoma (ENKTL). We aimed to assess the use of the post-treatment Deauville score on PET-CT and Epstein-Barr virus DNA as a predictor of residual tumour, to establish the risk of treatment failure in patients with newly diagnosed ENKTL. METHODS: In a retrospective analysis of patient data we assessed the prognostic relevance of the Deauville score (five-point scale) on PET-CT and circulating Epstein-Barr virus DNA after completion of treatment in consecutive patients with ENKTL who met eligibility criteria (newly diagnosed and received non-anthracycline-based chemotherapy, concurrent chemoradiotherapy, or both together) diagnosed at the Samsung Medical Center in Seoul, South Korea. The primary aim was to assess the association between progression-free survival and risk stratification based on post-treatment Deauville score and Epstein-Barr virus DNA. With an independent cohort from two different hospitals (Hong Kong and Singapore), we validated the prognostic value of our risk model. FINDINGS: We included 102 patients diagnosed with ENKTL between Jan 6, 2005, and Nov 18, 2013, in the study cohort, and 38 patients diagnosed with ENKTL between Jan 7, 2009, and June 27, 2013, in the validation cohort. In the study cohort after a median follow-up of 47·2 months (IQR 30·0-65·5), 45 (44%) patients had treatment failure and 33 (32%) had died. Post-treatment Deauville score and Epstein-Barr virus DNA positivity were independently associated with progression-free and overall survival in the multivariable analysis (for post-treatment Deauville score of 3-4, progression-free survival hazard ratio [HR] 3·607, 95% CI 1·772-7·341, univariable p<0·0001; for post-treatment Epstein-Barr virus DNA positivity, progression-free survival HR 3·595, 95% CI 1·598-8·089, univariable p<0·0001). We stratified patients into three groups based on risk of treatment failure: a low-risk group (post-treatment Epstein-Barr virus negativity and post-treatment Deauville score of 1-2), a high-risk group (post-treatment Epstein-Barr virus negativity with a Deauville score 3-4, or post-treatment Epstein-Barr virus positivity with a Deauville score 1-2), and treatment failure (Deauville score of 5 or post-treatment Epstein-Barr positivity with a Deauville of score 3-4). This risk model showed a significant association with progression-free survival (for low risk vs high risk, HR 7·761, 95% CI 2·592-23·233, p<0·0001; for low risk vs failure, HR 18·546, 95% CI 5·997-57·353, p<0·0001). The validation cohort showed the same associations (for low risk vs high risk, HR 22·909, 95% CI 2·850-184·162, p=0·003; for low risk vs failure, HR 50·652, 95% CI 6·114-419·610, p<0·0001). INTERPRETATION: Post-treatment Deauville score on PET-CT scan and the presence of Epstein-Barr virus DNA can predict the risk of treatment failure in patients with ENKTL. Our results might be able to help guide clinical practice. FUNDING: Samsung Biomedical Research Institute.

Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator.

The expansion of myeloid-derived suppressor cells (MDSCs) and its correlation with advanced disease stage have been shown in solid cancers. Here, we investigated the functional features and clinical significance of MDSCs in extranodal NK/T cell lymphoma (ENKL). A higher percentage of circulating HLA-DR(-)CD33(+)CD11b(+) MDSCs was observed in ENKL patients than in healthy controls (P < 0.05, n = 32) by flow cytometry analysis. These MDSCs from ENKL patients (ENKL-MDSCs) consisted of CD14(+) monocytic (Mo-MDSCs, >60 %) and CD15(+) granulocytic (PMN-MDSCs, <20 %) MDSCs. Furthermore, these ENKL-MDSCs expressed higher levels of Arg-1, iNOS and IL-17 compared to the levels of MDSCs from healthy donors, and they expressed moderate levels of TGFß and IL-10 but lower levels of CD66b. The ENKL-MDSCs strongly suppressed the anti-CD3-induced allogeneic and autologous CD4 T cell proliferation (P < 0.05), but they only slightly suppressed CD8 T cell proliferation (P > 0.05). Interestingly, ENKL-MDSCs inhibited the secretion of IFNγ but promoted IL-10, IL-17 and TGFß secretion as well as Foxp3 expression in T cells. The administration of inhibitors of iNOS, Arg-1 and ROS significantly reversed the suppression of anti-CD3-induced T cell proliferation by MDSCs (P < 0.05). Importantly, based on multivariate Cox regression analysis, the HLA-DR(-)CD33(+)CD11b(+) cells and CD14(+) Mo-MDSCs were independent predictors for disease-free survival (DFS, P = 0.013 and 0.016) and overall survival (OS, P = 0.017 and 0.027). Overall, our results identified for the first time that ENKL-MDSCs (mainly Mo-MDSCs) have a prognostic value for patients and a suppressive function on T cell proliferation.

Pulmonary Extranodal Natural Killer/T-Cell Lymphoma (Nasal Type): A Case Report and Radiological Image Review.

An 83-year-old woman presented with intermittent fever for 2 weeks. Chest radiography and computed tomography images showed multiple nodules and masses scattered in both lung fields. Tissue samples obtained by computed tomography-guided needle biopsy revealed extranodal natural killer/T-cell lymphoma (ENKL). The lung is the major site of involvement and the skin may be the primary site. The radiological imaging of this case is different from the cases reported before. Besides, we reviewed the medical records of our hospital and searched the Pubmed database and found 12 cases altogether (include the case presented), which were diagnosed with pulmonary ENKL, and the features of chest images were studied. To our knowledge, this is the first time that the chest imaging features of pulmonary ENKL were reviewed. We conclude that if the radiographic manifestations are multiple patchy consolidations or multiple nodules and masses in both lungs with or without bilateral pleural effusions, the diagnostic considerations should include ENKL.

The prevalence of Epstein-Barr Virus-positive lymphoid cells in nasal mucosa: an extremely rare event.

BACKGROUND: The prevalence of EBV (Epstein-Barr virus)-positive lymphoid cells is unknown. Because EBV is implicated in the etiology of extranodal NK/T-cell lymphoma, nasal type (nasal ENKL), the presence of EBV-positive lymphoid cells (EPLs) in nasal mucosa specimens is expected. This study evaluated the presence of EBV-positive lymphoid cells in the nasal mucosa of 420 patients who had undergone surgical resection of lesions of the nasal cavity due to nasal septal deviation, chronic paranasal rhinosinusitis, chronic hypertrophic rhinosinusitis, nasal polyps, allergic rhinitis, papillomas, and cysts. METHODOLOGY: Three representative 1.0-mm-diameter core biopsies were taken from one paraffin-embedded donor tissue block per case and subsequently arranged in new recipient paraffin blocks with a trephine. EBV in situ hybridization study was performed to detect EPLs. RESULTS: None of the cases demonstrated EPLs. CONCLUSION: The presence of EPLs in the nasal mucosa is an extremely rare event in immunocompetent individuals. Therefore, the detection of EPLs in nasal biopsy specimens should prompt the pathologist to perform further testing to exclude the possibility of nasal ENKL.

[Differential diagnosis of rheumatic diseases and blood cancers involving the nasal cavity and accessory sinuses].

AIM: To provide the clinical, laboratory, radiological, morphological, and immunomorphological signs that permit the differential diagnosis to be made in patients with involvement of the nasal cavity and accessory sinuses (NCAS). SUBJECTS AND METHODS: In the period 2009 to 2013, the Laboratory for Intensive Therapy for Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, associated the disease onset with NCAS involvement in 39 (7.6%) of 512 examinees. NCAS involvement was present at disease onset in 100% of the patients with natural killer (NK) cell lymphoma (NK/T lymphoma), in 84.5% of those with Wegener granulomatosis (WG), in 29.5% of those with IgG4-related disease (IgG4-RD), and in 17.5% of those with sarcoidosis. Such an onset could be extremely rarely observed in histiocytosis. RESULTS: Despite the similar clinical manifestations, NCAS involvements in NK/T lymphoma of nasal type and WG at disease onset show clear differences in the laboratory and systemic manifestations of these diseases. The patients with lymphoma have no characteristic laboratory abnormalities at disease onset, except the 100% presence of Epstein-Barr virus (EBV) DNA in blood and, only as a tumor grows, fever appears and there are elevated C-reactive protein and lactate dehydrogenase levels and pronounced destructive changes in the facial bones with mandatory hard palate destruction; at the same time the signs of systemic involvement are virtually absent. The patients with WG at disease onset have fever, high erythrocyte sedimentation rate, elevated C-reactive level, significant anemia, leukocytosis and 90% are found to have anti-neutrophil cytoplasmic antibodies with the rapid development of systemic manifestations: involvements of the lung, kidney, and peripheral nervous system. Destructive changes in the facial bones are minimal and hard palate destructions are absent. The patients with IgG4-RD, sarcoidosis, and juvenile xanthogranuloma have similar clinical and laboratory manifestations in the absence of hemorrhagic nasal discharge, nasal septal perforation, and facial bone destruction, with the practically involvement of the salivary/lacrimal glands and orbital regions. A third of the patients are observed to have different allergic manifestations, moderate eosinophilia, and signs of autoimmune disorders (the presence of rheumatoid and antinuclear factors, hypergammaglobulinemia). Elevated serum IgG4 levels are characteristic of IgG4-RD. CONCLUSION: Blood anti-neutrophil cytoplasmic antibodies, EBV DNA, and IgG4 levels should be determined in all patients with NCAS involvement. Mini-invasive incision biopsies of the nasal mucosa, orbital regions, and major salivary glands should be done, by morphologically verifying the diagnosis of sarcoidosis, histiocytosis, and WG and by making an immunomorphological examination to diagnose NK/T lymphoma and IgG4-RD.

The Glasgow Prognostic Score (GPS) as a novel and significant predictor of extranodal natural killer/T-cell lymphoma, nasal type.

The Glasgow Prognostic Score (GPS), an inflammation-based prognostic score including C-reactive protein and albumin, shows significant prognostic value in several types of solid tumors. The prognostic value of GPS in lymphoma remains unclear. We performed this study to evaluate the prognostic significance of GPS in extranodal natural killer (NK)/T-cell lymphoma (ENKL). We retrospectively analyzed 164 patients with newly diagnosed ENKL. The prognostic value of GPS was evaluated and compared with that of International Prognostic Index (IPI), Prognostic Index for Peripheral T-cell lymphoma unspecified (PIT), and Korean Prognostic Index (KPI). Patients with higher GPS tended to have more adverse clinical characteristics, lower rates of complete remission (P < 0.001), inferior progression-free survival (PFS, P < 0.001), and inferior overall survival (OS, P < 0.001). Multivariate analysis demonstrated that high GPS, age > 60 years, and elevated LDH were independent adverse predictors of OS. GPS was found superior to IPI, PIT, and KPI in discriminating patients with different outcomes in low-risk groups (all P < 0.05). GPS is an independent predictor of survival outcomes in ENKL. Inflammatory response might play an important role in the progression of ENKL and survival of patients with ENKL.

Lethal T- and NK-cell lymphomas mimicking granulomatous panniculitidies: a clinicopathologic study of three cases.

An infiltrate mimicking subcutaneous panniculitis associated with a granulomatous response represents an uncommon histopathologic presentation of lymphoma. We report three cases, comprising one case each of nasal-type extranodal NK/T-cell lymphoma, cutaneous γ/δ T-cell lymphoma and human T-lymphotropic virus-I associated adult T-cell leukemia/lymphoma, which based on initial histopathologic and/or clinical presentation were thought to represent systemic lupus erythematosus, sarcoidosis and psoriasiform dermatitis, respectively. Excisional biopsies of indurated lesions performed at our institute; however, in each case showed an atypical subcutaneous lymphohistiocytic infiltrate associated with a variable number of granulomas. Extensive immunophenotypic characterization, in conjunction with histomorphologic and molecular analysis, established the diagnosis of lymphoma in all instances. All patients had a rapidly progressive clinical course and death was attributable to complications of lymphoma shortly after diagnosis. These cases highlight the importance of using a multimodality diagnostic approach to distinguish lymphomas masquerading as granulomatous panniculitis from inflammatory or reactive disorders associated with such histopathologic patterns.

Central nervous system involvement in CD4+/CD56+ hematodermic neoplasm: a report of two cases.

CD4+/CD56+ hematodermic neoplasm, formerly known as blastic NK-cell lymphoma, is an uncommon, aggressive non-Hodgkin's lymphoma with cutaneous, lymph node, and bone marrow involvement at presentation. The disease is characterized by early leukemic phase; however, central nervous system involvement is rarely reported. Herein we describe two cases of CD4+/CD56+ hematodermic neoplasm with meningeal manifestation. Microscopic analysis and flow cytometry of cerebrospinal fluid proved to be diagnostic; however, imaging studies were not informative. These observations call attention to the possibility of central nervous system involvement, which could be more common than expected previously. Authors recommend routine cerebrospinal fluid analysis and prophylactic intrathecal chemotherapy in patients with this highly aggressive disease.

Nasal-type NK/T-cell lymphoma with palatal ulcer as the earliest clinical manifestation: a case report with literature review.

Extranodal nasal natural killer (NK)/T-cell lymphoma is a very rare kind of lymphoma, Oral cavity involvement of extranodal natural killer/T-cell lymphoma, nasal type is extremely rare, and its clinicopathologic features are also poorly understood. Recently, we experienced an unusual case of Epstein-Barr virus-associated, extranodal NK/T-cell type with a unhealed palatal ulcer as the earliest clinical feature. It is a challenge for oral medicine specialists to make the early diagnosis for this special type of tumor.