Modulatory role of neuropeptide FF system in macrophages.

Neuropeptide FF (NPFF) is an octapeptide that regulates various cellular processes, especially pain perception. Recently, there has been a growing interest in understanding the modulation of NPFF in neuroendocrine inflammation. This review aims to provide a thorough overview of the regulation of NPFF in macrophage-mediated biological processes. We delve into the impact of NPFF on macrophage polarization, self-renewal modulation, and the promotion of mitophagy, facilitating the transition from thermogenic fat to fat-storing adipose tissue. Additionally, we explore the NPFF-dependent regulation of the inflammatory response mediated by macrophages, its impact on the differentiation of macrophages, and its capacity to induce alterations in the transcriptome of macrophages. We also address the potential of NPFF as a therapeutic molecule in the field of neuroendocrine inflammation. Overall, our work offers an understanding of the influence of NPFF on macrophage, facilitating the exploration of its pharmacological significance in future studies.

The transcriptomic landscape of canonical activation of NLRP3 inflammasome from bone marrow-derived macrophages.

The NLRP3 inflammasome has gained significant attention due to its participation in diverse cellular processes. Nevertheless, the detailed framework of the canonical NLRP3 inflammasome assembly still remains unrevealed. This study aims to elucidate the transcriptomic landscape of the various stages involved in the canonical activation of the NLRP3 inflammasome in BMDMs by integrating RNA-seq, bioinformatics, and molecular dynamics analyses. The model for the canonical activation of the NLRP3 inflammasome was confirmed through morphological observations, functional assessments (ELISA and LDH), and protein detection (western blot). Subsequently, cells were subjected to RNA sequencing following three groups: control, priming (LPS 500 ng/ml, 4 h), and activation (LPS 500 ng/ml, 4 h; ATP 5 mM, 1 h). A total of 9116 differentially expressed genes (DEGs) were identified, which exerted regulatory effects on various pathways, including cell metabolism, ion fluxes, post-translational modifications, and organelles. Subsequently, six hub genes (Sirt3, Stat3, Syk, Trpm2, Tspo, and Txnip) were identified via integrating literature review and database screening. Finally, the three-dimensional structures of these six hub proteins were obtained using the MD-optimized RoseTTAFold and Gromacs simulations (at least 200 ns). In summary, our research offers novel insights into the transcriptomic-level understanding of the assembly of the canonical NLRP3 inflammasome.

Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key factor determining the thermogenesis and cellular heterogeneity and dynamics of brown adipose tissues in mice.

Brown adipose tissue (BAT) is a major site of non-shivering thermogenesis in mammals and plays an important role in energy homeostasis. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a master regulator of cellular metabolic homeostasis and numerous stress responses, has been found to function as a critical driver in BAT thermogenic adaption to cold or obesity by providing proteometabolic quality control. Our recent studies using adipocyte-specific Nfe2l1 knockout [Nfe2l1(f)-KO] mice demonstrated that NFE2L1-dependent transcription of lipolytic genes is crucial for white adipose tissue (WAT) homeostasis and plasticity. In the present study, we found that Nfe2l1(f)-KO mice develop an age-dependent whitening and shrinking of BAT, with signatures of down-regulation of proteasome, impaired mitochondrial function, reduced thermogenesis, pro-inflammation, and elevated regulatory cell death (RCD). Mechanistic studies revealed that deficiency of Nfe2l1 in brown adipocytes (BAC) primarily results in down-regulation of lipolytic genes, which decelerates lipolysis, making BAC unable to fuel thermogenesis. These changes lead to BAC hypertrophy, inflammation-associated RCD, and consequently cold intolerance. Single-nucleus RNA-sequencing of BAT reveals that deficiency of Nfe2l1 induces significant transcriptomic changes leading to aberrant expression of a variety of genes involved in lipid metabolism, proteasome, mitochondrial stress, inflammatory responses, and inflammation-related RCD in distinct subpopulations of BAC. Taken together, our study demonstrated that NFE2L1 serves as a vital transcriptional regulator that controls the lipid metabolic homeostasis in BAC, which in turn determines the metabolic dynamics, cellular heterogeneity and subsequently cell fates in BAT.

The most promising microneedle device: present and future of hyaluronic acid microneedle patch.

Microneedle patch (MNP) is an alternative to the oral route and subcutaneous injection with unique advantages such as painless administration, good compliance, and fewer side effects. Herein, we report MNP as a prominent strategy for drug delivery to treat local or systemic disease. Hyaluronic acid (HA) has advantageous properties, such as human autologous source, strong water absorption, biocompatibility, and viscoelasticity. Therefore, the Hyaluronic acid microneedle patch (HA MNP) occupies a large part of the MNP market. HA MNP is beneficial for wound healing, targeted therapy of certain specific diseases, extraction of interstitial skin fluid (ISF), and preservation of drugs. In this review, we summarize the benefits of HA and cross-linked HA (x-HA) as an MNP matrix. Then, we introduce the types of HA MNP, delivered substances, and drug distribution. Finally, we focus on the biomedical application of HA MNP as an excellent drug carrier in some specific diseases and the extraction and analysis of biomarkers. We also discuss the future development prospect of HA MNP in transdermal drug delivery systems (TDDS).

CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners.

Fine-tuning of osteoclast differentiation (OD) and bone remodeling is crucial for bone homeostasis. Dissecting the mechanisms regulating osteoclastogenesis is fundamental to understanding the pathogenesis of various bone disorders including osteoporosis and arthritis. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), which belongs to the CNC-bZIP family of transcription factors, orchestrates a variety of physiological processes and stress responses. While Nfe2l1 gene may be transcribed into multiple alternatively spliced isoforms, the biological function of the different isoforms of NFE2L1 in bone metabolism, osteoclastogenesis in particular, has not been reported. Here we demonstrate that knockout of all isoforms of Nfe2l1 transcripts specifically in the myeloid lineage in mice [Nfe2l1(M)-KO] results in increased activity of osteoclasts, decreased bone mass and worsening of osteoporosis induced by ovariectomy and aging. In comparison, LysM-Cre-mediated Nfe2l1 deletion has no significant effect on the osteoblast and osteocytes. Mechanistic investigations using bone marrow cells and RAW 264.7 cells revealed that deficiency of Nfe2l1 leads to accelerated and elevated OD, which is attributed, at least in part, to enhanced accumulation of ROS in the early stage of OD and expression of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1α (Nfatc1/α). In addition, NFE2L1 regulates the transcription of multiple antioxidant genes and Nfatc1/α and OD in an isoform-specific manner. While long isoforms of NFE2L1 function as accelerators of induction of Nfatc1/α and antioxidant genes and OD, the short isoform NFE2L1-453 serves as a brake that keeps the long isoforms' accelerator effects in check. These findings provide a novel insight into the regulatory roles of NFE2L1 in osteoclastogenesis and highlight that NFE2L1 is essential in regulating bone remodeling and thus may be a valuable therapeutic target for bone disorders.

Transcriptomic Changes in Mouse Bone Marrow-Derived Macrophages Exposed to Neuropeptide FF.

Neuropeptide FF (NPFF) is a neuropeptide that regulates various biological activities. Currently, the regulation of NPFF on the immune system is an emerging field. However, the influence of NPFF on the transcriptome of primary macrophages has not been fully elucidated. In this study, the effect of NPFF on the transcriptome of mouse bone marrow-derived macrophages (BMDMs) was explored by RNA sequencing, bioinformatics, and molecular simulation. BMDMs were treated with 1 nM NPFF for 18 h, followed by RNA sequencing. Differentially expressed genes (DEGs) were obtained, followed by GO, KEGG, and PPI analysis. A total of eight qPCR-validated DEGs were selected as hub genes. Subsequently, the three-dimensional (3-D) structures of the eight hub proteins were constructed by Modeller and Rosetta. Next, the molecular dynamics (MD)-optimized 3-D structure of hub protein was acquired with Gromacs. Finally, the binding modes between NPFF and hub proteins were studied by Rosetta. A total of 2655 DEGs were obtained (up-regulated 1442 vs. down-regulated 1213), and enrichment analysis showed that NPFF extensively regulates multiple functional pathways mediated by BMDMs. Moreover, the 3-D structure of the hub protein was obtained after MD-optimization. Finally, the docking modes of NPFF-hub proteins were predicted. Besides, NPFFR2 was expressed on the cell membrane of BMDMs, and NPFF 1 nM significantly activated NPFFR2 protein expression. In summary, instead of significantly inhibiting the expression of the immune-related gene transcriptome of RAW 264.7 cells, NPFF simultaneously up-regulated and down-regulated the gene expression profile of a large number of BMDMs, hinting that NPFF may profoundly affect a variety of cellular processes dominated by BMDMs. Our work provides transcriptomics clues for exploring the influence of NPFF on the physiological functions of BMDMs.

The roles of NFE2L1 in adipocytes: Structural and mechanistic insight from cell and mouse models.

Adipocytes play pivotal roles in maintaining energy homeostasis by storing lipids in adipose tissue (AT), regulating the flux of lipids between AT and the circulation in response to the body's energy requirements and secreting a variety of hormones, cytokines and other factors. Proper AT development and function ensure overall metabolic health. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1) belongs to the CNC-bZIP family and plays critical roles in regulating a wide range of essential cellular functions and varies stress responses in many cells and tissues. Human and rodent Nfe2l1 genes can be transcribed into multiple splice variants resulting in various protein isoforms, which may be further modified by a variety of post-translational mechanisms. While the long isoforms of NFE2L1 have been established as master regulators of cellular adaptive antioxidant response and proteasome homeostasis, the exact tissue distribution and physiological function of NFE2L1 isoforms, the short isoforms in particular, are still under intense investigation. With regard to key roles of NFE2L1 in adipocytes, emerging data indicates that deficiency of Nfe2l1 results in aberrant adipogenesis and impaired AT functioning. Intriguingly, a single nucleotide polymorphism (SNP) of the human NFE2L1 gene is associated with obesity. In this review, we summarize the most significant findings regarding the specific roles of the multiple isoforms of NFE2L1 in AT formation and function. We highlight that NFE2L1 plays a fundamental regulatory role in the expression of multiple genes that are crucial to AT metabolism and function and thus could be an important target to improve disease states involving aberrant adipose plasticity and lipid homeostasis.

Prolactin-Releasing Peptide Differentially Regulates Gene Transcriptomic Profiles in Mouse Bone Marrow-Derived Macrophages.

Prolactin-releasing Peptide (PrRP) is a neuropeptide whose receptor is GPR10. Recently, the regulatory role of PrRP in the neuroendocrine field has attracted increasing attention. However, the influence of PrRP on macrophages, the critical housekeeper in the neuroendocrine field, has not yet been fully elucidated. Here, we investigated the effect of PrRP on the transcriptome of mouse bone marrow-derived macrophages (BMDMs) with RNA sequencing, bioinformatics, and molecular simulation. BMDMs were exposed to PrRP (18 h) and were subjected to RNA sequencing. Differentially expressed genes (DEGs) were acquired, followed by GO, KEGG, and PPI analysis. Eight qPCR-validated DEGs were chosen as hub genes. Next, the three-dimensional structures of the proteins encoded by these hub genes were modeled by Rosetta and Modeller, followed by molecular dynamics simulation by the Gromacs program. Finally, the binding modes between PrRP and hub proteins were investigated with the Rosetta program. PrRP showed no noticeable effect on the morphology of macrophages. A total of 410 DEGs were acquired, and PrRP regulated multiple BMDM-mediated functional pathways. Besides, the possible docking modes between PrRP and hub proteins were investigated. Moreover, GPR10 was expressed on the cell membrane of BMDMs, which increased after PrRP exposure. Collectively, PrRP significantly changed the transcriptome profile of BMDMs, implying that PrRP may be involved in various physiological activities mastered by macrophages.

The Emerging Role of Macrophages in Immune System Dysfunction under Real and Simulated Microgravity Conditions.

In the process of exploring space, the astronaut's body undergoes a series of physiological changes. At the level of cellular behavior, microgravity causes significant alterations, including bone loss, muscle atrophy, and cardiovascular deconditioning. At the level of gene expression, microgravity changes the expression of cytokines in many physiological processes, such as cell immunity, proliferation, and differentiation. At the level of signaling pathways, the mitogen-activated protein kinase (MAPK) signaling pathway participates in microgravity-induced immune malfunction. However, the mechanisms of these changes have not been fully elucidated. Recent studies suggest that the malfunction of macrophages is an important breakthrough for immune disorders in microgravity. As the first line of immune defense, macrophages play an essential role in maintaining homeostasis. They activate specific immune responses and participate in large numbers of physiological activities by presenting antigen and secreting cytokines. The purpose of this review is to summarize recent advances on the dysfunction of macrophages arisen from microgravity and to discuss the mechanisms of these abnormal responses. Hopefully, our work will contribute not only to the future exploration on the immune system in space, but also to the development of preventive and therapeutic drugs against the physiological consequences of spaceflight.

CL316243 treatment mitigates the inflammation in white adipose tissues of juvenile adipocyte-specific Nfe2l1 knockout mice.

Nuclear factor-erythroid 2-related factor 1 (NFE2L1) is a key transcription factor that regulates cellular adaptive responses to various stresses. Our previous studies revealed that adult adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice show adipocyte hypertrophy and severe adipose inflammation, which can be worsened by rosiglitazone, a peroxisome proliferator-activated receptor γ agonist. To further assess the crucial roles of NFE2L1 in adipocytes, we investigated the effect of CL316243, a ß3 adrenergic agonist that promotes lipolysis via a post-translational mechanism, on adipose inflammation in juvenile Nfe2l1(f)-KO mice. In contrast to adult mice, 4-week-old juvenile Nfe2l1(f)-KO mice displayed a normal fat distribution but reduced fasting plasma glycerol levels and elevated adipocyte hypertrophy and macrophage infiltration in inguinal and gonadal WAT. In addition, Nfe2l1(f)-KO mice had decreased expression of multiple lipolytic genes and reduced lipolytic activity in WAT. While 7 days of CL316243 treatment showed no significant effect on adipose inflammation in Nfe2l1-Floxed control mice, the same treatment dramatically alleviated macrophage infiltration and mRNA expression of inflammation and pyroptosis-related genes in WAT of Nfe2l1(f)-KO mice. Together with previous findings in adult mice, the current study highlights that NFE2L1 plays a fundamental regulatory role in lipolytic gene expression and thus might be an important target to improve adipose plasticity and lipid homeostasis.

Rifampicin impairs adipogenesis by suppressing NRF2-ARE activity in mice fed a high-fat diet.

Prolonged treatment with rifampicin (RFP), a first-line antibacterial agent used in the treatment of drug-sensitive tuberculosis, may cause various side effects, including metabolic disorders. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, also known as NRF2) plays an essential regulatory role in cellular adaptive responses to stresses via the antioxidant response element (ARE). Our previous studies discovered that NRF2 regulates the expression of CCAAT-enhancer-binding protein ß (Cebpb) and peroxisome proliferator-activated receptor gamma (Pparg) in the process of adipogenesis. Here, we found that prolonged RFP treatment in adult male mice fed a high-fat diet developed insulin resistance, but reduced fat accumulation and decreased expression of multiple adipogenic genes in white adipose tissues. In 3 T3-L1 preadipocytes, RFP reduced the induction of Cebpb, Pparg and Cebpa at mRNA and protein levels in the early and/or later stage of hormonal cocktail-induced adipogenesis. Mechanistic investigations demonstrated that RFP inhibits NRF2-ARE luciferase reporter activity and expression of NRF2 downstream genes under normal culture condition and in the early stage of adipogenesis in 3 T3-L1 preadipocytes, suggesting that RFP can disturb adipogenic differentiation via NRF2-ARE interference. Taken together, we demonstrate a potential mechanism that RFP impairs adipose function by which RFP likely inhibits NRF2-ARE pathway and thereby interrupts its downstream adipogenic transcription network.

Cellular processes involved in RAW 264.7 macrophages exposed to NPFF: A transcriptional study.

Neuropeptide FF (NPFF) is a neuropeptide that modulates various physiological processes. The regulatory role of NPFF in the immune and inflammatory response is currently being revealed. However, the effect of NPFF at the transcriptome level in macrophages has not been fully elucidated. Here, the impact of NPFF on gene expression at the transcriptome level of RAW 264.7 cells was investigated by RNA-seq. RAW 264.7 macrophages were treated with NPFF (1 nM) for 18 h, followed by RNA-seq examination. Differentially expressed genes (DEGs) were acquired, followed by GO, KEGG, and PPI analysis. A total of eight qPCR-verified DEGs were obtained. Next, three-dimensional models of the eight hub proteins were constructed by using homology modeling with Modeller (9v23). Finally, molecular dynamics simulation (300 ns) was performed with GROMACS 2018.2 to investigate the structural characteristics of these hub proteins. NPFF had no detectable effect on the morphology of RAW264.7 cells. A total of 211 DEGs were acquired, and an enrichment study demonstrated that the immune response-related pathway was significantly inhibited by NPFF. Moreover, the molecular dynamics optimized-protein models of the hub proteins were obtained. Collectively, NPFF inhibited the expression of immune-related genes in RAW 264.7 cells at the transcriptome level, which suggested a negative relationship between NPFF and this set of immune-related genes in RAW 264.7 macrophages. Therefore, our data may provide direct evidence of the role of NPFF in peripheral or central inflammatory diseases.

Protracted rosiglitazone treatment exacerbates inflammation in white adipose tissues of adipocyte-specific Nfe2l1 knockout mice.

Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as NRF1) belongs to the CNC-bZIP family and is a master regulator of cellular adaptive responses to various stresses in many cells and tissues. Rosiglitazone (RGZ), a thiazolidinedione agonist of PPARγ, is widely used in the treatment of type 2 diabetes mellitus by stimulating genes which favor storage of triglycerides. Our previous studies demonstrated that loss of Nfe2l1 in adipocytes [Nfe2l1(f)-KO] resulted in diminished subcutaneous white adipose tissue (WAT) mass with adipocyte hypertrophy and severe adipose inflammation, which might be attributed, at least in part, to impaired lipolysis. However, the exact mechanism underlying this phenotype remains unclear. To further clarify the regulatory role of NFE2L1 in adipocyte lipid metabolism, we used protracted RGZ treatment to facilitate lipid accumulation in mice. In Nfe2l1flox/flox control mice, three weeks of RGZ treatment significantly downregulated mRNA levels of a group of inflammation-related genes in WAT. In contrast, the phenotype of Nfe2l1(f)-KO mice was aggravated showing increased transcript expression related to inflammation and pyroptosis in their shrunk WAT. These findings provide deeper insight into the mechanisms by which NFE2L1 regulates the expression of a set of lipolysis-related genes and controls WAT plasticity and global energy homeostasis.

An Emerging Target in the Battle against Osteoarthritis: Macrophage Polarization.

Osteoarthritis (OA) is one of the most prevalent chronic joint diseases worldwide, which causes a series of problems, such as joint pain, muscle atrophy, and joint deformities. Benefiting from some advances in the clinical treatment of OA, the quality of life of OA patients has been improved. However, the clinical need for more effective treatments for OA is still very urgent. Increasing findings show that macrophages are a critical breakthrough in OA therapy. Stimulated by different factors, macrophages are differentiated into two phenotypes: the pro-inflammatory M1 type and anti-inflammatory M2 type. In this study, various therapeutic reagents for macrophage-dependent OA treatment are summarized, including physical stimuli, chemical compounds, and biological molecules. Subsequently, the mechanisms of action of various approaches to modulating macrophages are discussed, and the signaling pathways underlying these treatments are interpreted. The NF-κB signaling pathway plays a vital role in the occurrence and development of macrophage-mediated OA, as NF-κB signaling pathway agonists promote the occurrence of OA, whereas NF-κB inhibitors ameliorate OA. Besides, several signaling pathways are also involved in the process of OA, including the JNK, Akt, MAPK, STAT6, Wnt/ß-catenin, and mTOR pathways. In summary, macrophage polarization is a critical node in regulating the inflammatory response of OA. Reagents targeting the polarization of macrophages can effectively inhibit inflammation in the joints, which finally relieves OA symptoms. Our work lays the foundation for the development of macrophage-targeted therapeutic molecules and helps to elucidate the role of macrophages in OA.

Nrf2 in adipocytes.

White adipocytes play a key role in maintaining whole body energy homeostasis by forming white adipose tissue (WAT). The impairment of WAT formation or WAT dysfunction is clearly associated with severe metabolic disorders. Mature adipocytes are derived from differentiated preadipocytes and are pivotal in energy storage and metabolism. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a member of a family of CNC-bZIP proteins which exert their transcriptional control on genes harboring antioxidant response elements (ARE) in partnership with small musculoaponeurotic fibrosarcoma proteins. The activation of Nrf2-ARE coordinated by specific repressor Kelch-like ECH-associated protein 1 (Keap1) regulates networks of genes controlling diverse homeostatic processes involving adaptive antioxidant response and detoxification among many other adaptive responses. Interestingly, accumulating evidence indicates that Nrf2 may act as a transcription factor in regulating the formation and function of adipose tissues, including adipogenesis, lipid metabolism and insulin sensitivity. In this mini-review, an overview on the distinct roles of Nrf2 in adipocytes is provided. While highlighting the regulatory role of Nrf2 in adipogenesis, recent key findings on Nrf2 in insulin signal transduction and energy metabolism of adipocytes are also summarized.

A Rare Presentation of Melanoma as a Retroperitoneal Mass Seen on FDG PET.

A 55-year-old woman presented with intermittent fatigue and abdominal pain. Ultrasound and CT scan showed a large heterogeneous mass in the retroperitoneum, suggestive of malignancy. F-FDG PET/CT was performed for staging. PET/CT images showed a hypermetabolic retroperitoneal mass. Endoscopy revealed a mass infiltrating the duodenum. Eventually, the mass was pathologically proved to be malignant melanoma. Further extensive clinical, radiological, and endoscopic investigations proved the retroperitoneum to be the primary site.

Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression.

Nuclear factor erythroid 2-related factor 1 (NRF1), a ubiquitously expressed CNC-bZIP transcription factor, plays a critical role in white adipocyte (WAC) biology, whereas the underlying mechanisms remain unknown. The mouse Nrf1 gene is transcribed in a number of alternatively spliced forms, resulting in two long protein isoforms (L-NRF1) containing 741 and 742 amino acids (aa) and multiple short isoforms (S-NRF1). Our previous study found that adipocyte-specific knockout of Nrf1 [Nrf1(f)-KO] in mice disturbs the expression of lipolytic genes in adipocytes, leading to adipocyte hypertrophy followed by inflammation, pyroptosis and insulin resistance. In the present study, we found that the stromal vascular fraction (SVF) cells isolated from white adipose tissues (WAT) of Nrf1(f)-KO mice display augmented adipogenesis showing elevated mRNA and protein expression of adipogenic markers and lipid accumulation. In 3T3-L1 cells, stable knockdown (KD) of all or long isoforms of Nrf1 (termed as A-Nrf1-KD and L-Nrf1-KD, respectively) using lentiviral shRNAs resulted in enhanced and accelerated adipogenic differentiation. Conversely, overexpression of L-NRF1-741, but not any of the S-NRF1, substantially attenuated adipogenesis in 3T3-L1 cells. These findings indicate that L-NRF1 might serve as a critical negative regulator of adipogenesis. Mechanistic investigation revealed that L-NRF1 may negatively regulates the transcription of peroxisome proliferator-activated receptor γ (PPARγ), in particular the master regulator of adipogenesis PPARγ2. Taken all together, the findings in the present study provide further evidence for a novel role of NRF1 beyond its participation in cellular antioxidant response and suggest that L-NRF1 is a negative regulator of PPARγ2 expression and thereby can suppress adipogenesis.

Isolated Nasal Metastasis From Renal Cell Carcinoma 9 Years After Nephrectomy Seen on FDG PET.

A 56-year-old man presented with intermittent epistaxis. Nasopharyngoscope revealed a hemorrhagic mass occupying the left nasal cavity. The patient had a history of renal clear cell carcinoma. F-FDG PET/CT was performed to evaluate the potential lesions systematically. PET/CT images showed low to moderate activity in the region of nasal cavity and paranasal sinuses. No abnormal uptake of F-FDG was observed in the rest of the body. Eventually, the mass was pathologically proved to be metastatic renal clear cell carcinoma.

Laryngeal Extranodal Nasal-type Natural Killer/T-cell Lymphoma: A Clinicopathologic Study of 31 Cases in China.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL-N) initially presented in larynx is a rare condition without distinctive clinicopathologic features, with a challenging pathologic diagnosis. This study aimed to evaluate the clinicopathologic features and diagnosis of laryngeal ENKTL-N and spread awareness regarding ENKTL-N. A series of 31 cases of laryngeal ENKTL in one Chinese institution over a 9-year interval was retrospectively analyzed. Median age was 50 years (range, 13 to 77 y) with a male/female ratio of 5.2:1 (26/5). All patients initially presented with hoarseness and/or laryngalgia, and 10 patients (32.3%) experienced B symptoms. The supraglottic region was the most common site of occurrence (58.1%), the glottic area being the rarest site (6.5%). The mucosal squamous epithelium was detected in 26 specimens and pseudoepitheliomatous hyperplasia was observed in 8 cases (8/26, 30.8%). "Keratin-pearls" and a "pseudoinvasive" pattern were observed in 2 cases. Follow-up data were available for 26 patients (83.9%), the median survival duration was 9 months, and the overall survival rate at 5 years was 29.6%. Univariate analysis revealed that patients experiencing B symptoms (P=0.019) and age above 60 years had a significantly low survival (P=0.049) and that combined radiotherapy and chemotherapy prolongs overall survival (P<0.001). Laryngeal ENKTL-N is a rare entity with high aggressiveness and a poor prognosis. Multiple biopsies are usually required owing to secondary infection and massive necrosis. Laryngeal EKTL-N may mimic inflammatory lesions or well-differentiated squamous cell carcinoma. Therefore, clinical vigilance is essential to prevent misdiagnosis or a delayed diagnosis.