Non-keratinizing Nasopharyngeal Carcinoma Research Articles

Salvage endoscopic nasopharyngectomy for recurrent nasopharyngeal carcinoma in a non-endemic area.

To analyze oncological outcomes of endoscopic surgical treatment of locally recurrent EBV-related undifferentiated non-keratinizing nasopharyngeal carcinoma (uNK-NPC) in a non-endemic area. Retrospective review of patients affected by recurrent uNK-NPC treated with nasopharyngeal endoscopic resection (NER) in a tertiary-care referral center from 2003 to 2022, by evaluating survival rates, prognostic factors, and follow-up strategies. The oncological outcomes of 41 patients were analyzed, over a mean follow-up period of 57 months. The 5-year overall, disease-specific, and disease-free survival of the cohort were 60.7% ± 8.9%, 69% ± 9%, and 39.7% ± 9.2%, respectively. The local (rT) and regional (rN) extension of recurrent disease, stage of disease, and status of resection margins appeared to significantly influence survivals. After a mean follow-up period of 21 months, a further recurrence after NER was observed in 36.6% of cases. Skull base osteonecrosis induced by previous irradiation and post-surgical bone remodeling represent the major challenges for early detection of further local relapses during postoperative follow-up. NER appeared as a safe and effective treatment for recurrent uNK-NPC. The adequate selection of patients eligible for NER is essential, to maximize the chances to cure and minimize the risk of local complications.

Primary Hepatocellular Carcinoma Revealed on 68 Ga-DOTATATE in a Patient With Nasopharyngeal Carcinoma.

A 56-year-old man underwent a prospective study (ChiCTR2300070081), which is a head-to-head comparison of 18 F-FDG and 68 Ga-DOTATATE PET/MR in EB-positive nonkeratinizing nasopharyngeal carcinoma after chemotherapy. Bilateral cervical abnormal lymph nodes were both detected by 18 F-FDG and 68 Ga-DOTATATE PET/MRI, whereas 2 hepatic lesions only were shown on 68 Ga-DOTATATE, which subsequent pathologically proved to be primary hepatocellular carcinoma.

Comprehensive single-cell transcriptomic and proteomic analysis reveals NK cell exhaustion and unique tumor cell evolutionary trajectory in non-keratinizing nasopharyngeal carcinoma

BackgroundNonkeratinizing nasopharyngeal carcinoma (NK-NPC) has a strong association with Epstein-Barr virus (EBV) infection. The role of NK cells and the tumor cell evolutionary trajectory in NK-NPC remain unclear. In this study, we aim to investigate the function of NK cell and the evolutionary trajectory of tumor cells in NK-NPC by single-cell transcriptomic analysis, proteomics and immunohistochemistry.MethodsNK-NPC (n = 3) and normal nasopharyngeal mucosa cases (n = 3) were collected for proteomic analysis. Single-cell transcriptomic data of NK-NPC (n = 10) and nasopharyngeal lymphatic hyperplasia (NLH, n = 3) were obtained from Gene Expression Omnibus (GSE162025 and GSE150825). Quality control, dimension reduction and clustering were based on Seurat software (v4.0.2) process and batch effects were removed by harmony (v0.1.1) software. Normal cells of nasopharyngeal mucosa and tumor cells of NK-NPC were identified using copykat software (v1.0.8). Cell-cell interactions were explored using CellChat software (v1.4.0). Tumor cell evolutionary trajectory analysis was performed using SCORPIUS software (v1.0.8). Protein and gene function enrichment analyses were performed using clusterProfiler software (v4.2.2).ResultsA total of 161 differentially expressed proteins were obtained between NK-NPC (n = 3) and normal nasopharyngeal mucosa (n = 3) by proteomics (log2 fold change > 0.5 and P value < 0.05). Most of proteins associated with the nature killer cell mediated cytotoxicity pathway were downregulated in the NK-NPC group. In single cell transcriptomics, we identified three NK cell subsets (NK1-3), among which NK cell exhaustion was identified in the NK3 subset with high ZNF683 expression (a signature of tissue-resident NK cell) in NK-NPC. We demonstrated the presence of this ZNF683 + NK cell subset in NK-NPC but not in NLH. We also performed immunohistochemical experiments with TIGIT and LAG3 to confirm NK cell exhaustion in NK-NPC. Moreover, the trajectory analysis revealed that the evolutionary trajectory of NK-NPC tumor cells was associated with the status of EBV infection (active or latent). The analysis of cell-cell interactions uncovered a complex network of cellular interactions in NK-NPC.ConclusionsThis study revealed that the NK cell exhaustion might be induced by upregulation of inhibitory receptors on the surface of NK cells in NK-NPC. Treatments for the reversal of NK cell exhaustion may be a promising strategy for NK-NPC. Meanwhile, we identified a unique evolutionary trajectory of tumor cells with active status of EBV-infection in NK-NPC for the first time. Our study may provide new immunotherapeutic targets and new sight of evolutionary trajectory involving tumor genesis, development and metastasis in NK-NPC.

Abstract CT107: Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors

Abstract BACKGROUND: Intra-tumoral Clostridium novyi-NT (non-toxic) is an attenuated strain of C. novyi lacking alpha toxin replication within hypoxic tumor regions, causing tumor cell lysis and inflammation. Immunotherapy (IO) augments anticancer activity with intratumoral agents in prior preclinical and clinical studies. This phase 1b dose escalation study assessed safety and potential synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors. METHODS: We enrolled patients with percutaneous injectable, solid tumors to receive single intratumoral injection of C. novyi-NT administered on Day 8 across 4 dose cohorts (3 × 10^4 to 100 × 10^4 spores, 3+3 design) with pembrolizumab 200mg IV Q3weekly starting on Day 0 up to 24 months. Primary objectives: Safety, tolerability and maximum tolerated dose (MTD) of combination. Secondary objectives: anti-tumor activity of combination in the injected tumor lesion and overall response by iRECIST 1.1. RESULTS: At data cutoff on October 24, 2022, 16 patients were enrolled and evaluable for toxicity and efficacy. It was well tolerated across all cohorts without dose limiting toxicities with median number of 5 cycles administered (1-34). 10 patients (63%) experienced progression; 1 withdrew consent; 1 completed therapy; 1 came off trial due to toxicity (immune related dermatitis) and 3 patients remain on trial. Median age was 62.5 years (40-71) while all patients (100%) had performance status of 1. 8 (50%) received prior IO and 7 (44%) had &amp;gt; 4 lines of prior therapies. Confirmed overall objective response rate (ORR) was 25% in 4 patients [non-keratinizing undifferentiated nasopharyngeal squamous carcinoma (NPC), human papilloma virus positive squamous cell carcinoma of base of tongue, vulvar melanoma and chordoma] with 3 partial responses (PR) and 1 complete response (CR). Among responders, median duration of response was 8.18 months and 1/4 (25%) had prior IO. NPC patient completed 24 months on trial to completion with best response at PR (-87%) while vulvar melanoma patient remains on trial with best response at CR (-100%). Median injected tumor size was 2.65cm (1-11) with confirmed ORR in injected lesions at 19% with 2 PRs and 1 CR. Most prevalent grade 1 and 2 adverse events were injection site reaction (25%), pyrexia (19%), pruritus (13%), leukopenia (13%) and anemia (13%). No grade 3 or 4 treatment related adverse events noted. Signs and symptoms of C. novyi-NT germination (infection) including fever, injection site pain, erythema, swelling, tenderness, and in some cases, ulceration, spontaneous drainage, tissue sloughing, bleeding, and malodor were observed in 5 patients. CONCLUSIONS: Intratumoral C. novyi-NT with pembrolizumab demonstrates clinical activity with favorable tolerability in patients regardless of tumor histology. This study is ongoing to define the recommended phase 2 dose (NCT03435952). Citation Format: Blessie Elizabeth Nelson, Filip Janku, Siqing Fu, Ecaterina I. Dumbrava, David S. Hong, Daniel Karp, Aung Naing, Jordi Rodon, Apostolia Tsimberidou, Rodabe N. Amaria, Anthony Conley, Senthil Damodaran, Kanwal P. Raghav, Brent L. Kreider, David Tung, Mary Varterasian, Khashayarsha Khazaie, Sarina Piha-Paul. Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT107.

TNF Receptor Associated Factor 2 (TRAF2) Signaling in Cancer.

Simple SummaryTumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) is an intracellular adapter protein with E3 ligase activity, which interacts with a plethora of other signaling proteins, including plasma membrane receptors, kinases, phosphatases, other E3 ligases, and deubiquitinases. TRAF2 is involved in various cancer-relevant cellular processes, such as the activation of transcription factors of the NFκB family, stimulation of mitogen-activated protein (MAP) kinase cascades, endoplasmic reticulum (ER) stress signaling, autophagy, and the control of cell death programs. In a context-dependent manner, TRAF2 promotes tumor development but it can also act as a tumor suppressor. Based on a general description, how TRAF2 in concert with TRAF2-interacting proteins and other TRAF proteins act at the molecular level is discussed for its importance for tumor development and its potential usefulness as a therapeutic target in cancer therapy.Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.

Mutational landscape of nasopharyngeal carcinoma based on targeted next-generation sequencing: implications for predicting clinical outcomes

BackgroundThe aim of this study was to draw a comprehensive mutational landscape of nasopharyngeal carcinoma (NPC) tumors and identify the prognostic factors for distant metastasis-free survival (DMFS).MethodsA total of forty primary nonkeratinizing NPC patients underwent targeted next-generation sequencing of 450 cancer-relevant genes. Analysis of these sequencing and clinical data was performed comprehensively. Univariate Cox regression analysis and multivariate Lasso-Cox regression analyses were performed to identify factors that predict distant metastasis and construct a risk score model, and seventy percent of patients were randomly selected from among the samples as a validation cohort. A receiver operating characteristic (ROC) curve and Harrell’s concordance index (C-index) were used to investigate whether the risk score was superior to the TNM stage in predicting the survival of patients. The survival of patients was determined by Kaplan–Meier curves and log-rank tests.ResultsThe twenty most frequently mutated genes were identified, such as KMT2D, CYLD, and TP53 et al. Their mutation frequencies of them were compared with those of the COSMIC database and cBioPortal database. N stage, tumor mutational burden (TMB), PIK3CA, and SF3B1 were identified as predictors to build the risk score model. The risk score model showed a higher AUC and C-index than the TNM stage model, regardless of the training cohort or validation cohort. Moreover, this study found that patients with tumors harboring PI3K/AKT or RAS pathway mutations have worse DMFS than their wild-type counterparts.ConclusionsIn this study, we drew a mutational landscape of NPC tumors and established a novel four predictor-based prognostic model, which had much better predictive capacity than TNM stage.

Lymphoepithelial carcinoma of the oral mucosa. A rare histopathologic subtype of squamous cell carcinoma

<h3>Objectives</h3> Lymphoepithelial carcinoma (LEC) represents a rare histopathologic subtype of squamous cell carcinoma (SCC), which shares morphologic similarities with non-keratinizing undifferentiated nasopharyngeal carcinoma (NPC). LEC may be etiologically associated with EBV, especially in endemic regions. Although being described in several locations of the head and neck, the oral mucosa seems to be an infrequent site of involvement. Herein, we present a case of an EBV-negative oral LEC and discuss the diagnostic challenges. <h3>Findings</h3> A 51 year-old male Filipino patient suffering from chronic kidney disease presented for the evaluation of a swelling in the right mandible, first noticed by the patient a few days ago. Clinically, the right posterior mandibular gingiva appeared enlarged and hemorrhagic, covered by ulcerated mucosa, while the adjacent teeth displayed high mobility. Extraorally, a painful and slightly movable lymph node in the right submandibular area was palpated. Radiographic evaluation revealed extensive bone loss in the right posterior mandible. With a provisional diagnosis of lymphoma or SCC, an incisional biopsy was performed. Histopathologic examination revealed invasion of the underlying connective tissue by pleomorphic cells of epithelioid morphology, occasionally arranged in syncytial islands, arising from a partially ulcerated, non-keratinized squamous epithelium. A prominent diffuse lymphocytic cell infiltrate surrounding the tumor cells was also detected. The neoplastic cells expressed pancytokeratin, CK5/6, p63, and p40, while p16, LMP-1, and in situ hybridization for EBV RNA were negative. A final diagnosis of moderately to poorly differentiated SCC with features indicative of LEC was rendered and the patient was referred for further management. <h3>Conclusions</h3> LEC should be considered in the differential diagnosis of undifferentiated malignant neoplasms displaying close association with diffuse lymphoid aggregates. The evaluation of nasopharynx is justified to rule out metastatic NPC, as the separation of these two entities microscopically is not feasible.

Epstein-Barr virus-induced ectopic CD137 expression helps nasopharyngeal carcinoma to escape immune surveillance and enables targeting by chimeric antigen receptors.

Non-keratinizing nasopharyngeal carcinoma (NPC) is a malignancy with a poor prognosis for relapsing patients and those with metastatic disease. Here, we identify a novel disease mechanism of NPC which may be its Achilles' heel that makes it susceptible to immunotherapy. CD137 is a potent costimulatory receptor on activated T cells, and CD137 agonists strongly enhance anti-tumor immune responses. A negative feedback mechanism prevents overstimulation by transferring CD137 from T cells to CD137 ligand (CD137L)-expressing antigen presenting cells (APC) during cognate interaction, upon which the CD137-CD137L complex is internalized and degraded. We found ectopic expression of CD137 on 42 of 122 (34.4%) NPC cases, and that CD137 is induced by the Epstein-Barr virus latent membrane protein (LMP) 1. CD137 expression enables NPC to hijack the inbuilt negative feedback mechanism to downregulate the costimulatory CD137L on APC, facilitating its escape from immune surveillance. Further, the ectopically expressed CD137 signals into NPC cells via the p38-MAPK pathway, and induces the expression of IL-6, IL-8 and Laminin γ2. As much as ectopic CD137 expression may support the growth and spread of NPC, it may be a target for its immunotherapeutic elimination. Natural killer cells that express a CD137-specific chimeric antigen receptor induce death in CD137+ NPC cells, in vitro, and in vivo in a murine xenograft model. These data identify a novel immune escape mechanism of NPC, and lay the foundation for an urgently needed immunotherapeutic approach for NPC.

Integration of MRI-Based Radiomics Features, Clinicopathological Characteristics, and Blood Parameters: A Nomogram Model for Predicting Clinical Outcome in Nasopharyngeal Carcinoma

PurposeThis study aimed to develop a nomogram model based on multiparametric magnetic resonance imaging (MRI) radiomics features, clinicopathological characteristics, and blood parameters to predict the progression-free survival (PFS) of patients with nasopharyngeal carcinoma (NPC).MethodsA total of 462 patients with pathologically confirmed nonkeratinizing NPC treated at Sichuan Cancer Hospital were recruited from 2015 to 2019 and divided into training and validation cohorts at a ratio of 7:3. The least absolute shrinkage and selection operator (LASSO) algorithm was used for radiomics feature dimension reduction and screening in the training cohort. Rad-score, age, sex, smoking and drinking habits, Ki-67, monocytes, monocyte ratio, and mean corpuscular volume were incorporated into a multivariate Cox proportional risk regression model to build a multifactorial nomogram. The concordance index (C-index) and decision curve analysis (DCA) were applied to estimate its efficacy.ResultsNine significant features associated with PFS were selected by LASSO and used to calculate the rad-score of each patient. The rad-score was verified as an independent prognostic factor for PFS in NPC. The survival analysis showed that those with lower rad-scores had longer PFS in both cohorts (p < 0.05). Compared with the tumor–node–metastasis staging system, the multifactorial nomogram had higher C-indexes (training cohorts: 0.819 vs. 0.610; validation cohorts: 0.820 vs. 0.602). Moreover, the DCA curve showed that this model could better predict progression within 50% threshold probability.ConclusionA nomogram that combined MRI-based radiomics with clinicopathological characteristics and blood parameters improved the ability to predict progression in patients with NPC.

Combined Association of Tumoral PD-L1 Expression and Pretreatment Presence of Epstein-Barr Virus DNA With Risk Stratification and Prognosis of Patients With Nasopharyngeal Carcinoma.

BackgroundLittle is known about whether the combination of tumor programmed death-ligand 1 (PD-L1) expression and pretreatment EBV DNA status can help stratify nasopharyngeal carcinoma (NPC) patients by risk of metastasis or predict prognosis.MethodsPD-L1 expression was assessed using immunohistochemical staining of 78 non-keratinizing NPC patients with clinical data. Survival outcomes and independent prognostic factors were identified.ResultsSeventy-eight patients were included, high PD-L1 expression was observed in 25 of 43 patients (58%) with metastasis, while it was observed only in 7 of 35 patients (20%) without metastasis. Multivariate analyses showed that progression-free survival (PFS) was independently predicted by tumoral PD-L1 expression and pretreatment EBV DNA status. When combining, 93.75% patients with high PD-L1 and EBV infection developed distant metastasis, and those patients were associated with worse PFS.ConclusionsBoth PD-L1 expression and pretreatment EBV DNA are closely related to metastasis and prognosis of NPC patients. Their combination can facilitate risk stratification and prognosis prediction, which may improve disease treatment and management.

Association between Foxp3 Tumor Infiltrating Lymphocyte Expression and Response After Chemoradiation in Nasopharyngeal Carcinoma

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a carcinoma originating from the surface epithelium of the nasopharynx with the highest incidence in China and South East Asia. Currently, many researchers are developing tumor microenvironment which can be assessed by tumor-infiltrating lymphochyte, and its association with treatment response in several tumors, including NPC. Foxp3, known as a regulatory T cell (Treg) marker, plays a role in the immunoregulatory environment of tumor cells and can be used as a prognostic factor. The relationship between Foxp3 expression and treatment response is considered as one of the factors affecting the prognosis of NPC. AIM: This study aims to determine the relationship between Foxp3 expression and treatment response in NPC. MATERIALS AND METHODS: A cross-sectional study was done to analyze the association between Foxp3 and treatment response in NPC. This study included 60 samples who were diagnosed with non-keratinizing NPC at the Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/Cipto Mangunkusumo Hospital from January 2018 until December 2020. Immunohistochemistry was done to evaluate the expression of Foxp3. Foxp3 expression was evaluated in the intratumoral and peritumoral areas. RESULTS: Among 60 patients, the number of males were more than females (66.7%, 33.3%, respectively) with a ratio of 2:1. There was statistically significant difference between intratumoral and total Foxp3 expression and treatment response (p &lt; 0.05, p = 0.001, respectively); however, no significant differences found between peritumoral Foxp3 expression and treatment response (p = 0.114). CONCLUSION: Foxp3 expression had a statistically significant relationship with response therapy after chemoradiation.

Clinicopathological characteristics of SMARCB1(INI1)-deficient sinonasal carcinoma

Objective: To investigate the clinicopathological characteristics, diagnosis, differential diagnosis and prognostic factors of SMARCB1 (INI1)-deficient sinonasal carcinoma (SDSC). Methods: Sixteen cases of SDSC diagnosed in the Department of Pathology, Beijing Tongren Hospital from January 2016 to September 2020 were enrolled. Ninety-nine cases of small round cell malignant tumors of the head and neck were selected as the control, including poorly-differentiated squamous cell carcinoma (n=10), poorly-differentiated adenocarcinoma (n=5), undifferentiated carcinoma (SNUC, n=4), NUT carcinoma (n=5), neuroendocrine carcinoma (n=10), and other non-epithelial tumors [olfactory neuroblastoma (n=10), rhabdomyosarcoma (n=10), NK/T-cell lymphoma (n=10), malignant melanoma (n=10), Ewing's sarcoma/primitive neuroectodermal tumor (EWS/PNET, n=5)] and non-keratinizing undifferentiated nasopharyngeal carcinoma (n=20). The clinical and pathologic characteristics of SDSC, and immunohistochemical (IHC) expression of broad-spectrum CKpan, CK7, CK8/18, CK5/6, p63, p40, p16, INI1, NUT and neuroendocrine markers (Syn, CgA, CD56) were evaluated. In situ hybridization (ISH) was used to detect EBER and fluorescence in situ hybridization (FISH) to detect INI1 gene deletion. Results: The 16 cases of SDSC accounted for 1.3% (16/1 218) of all malignant sinonasal tumors in the author's unit during this time period, and 2.4% (16/657) of all malignant epithelial tumors. Microscopically, there was no clear squamous and adenomatous differentiation, but "rhabdoid-like" cells, are often seen. All SDSC cases were positive for CKpan and CK8/18, negative for INI1; Epstein-Barr virus was not detected by ISH; and INI1 gene deletion was observed in all 11 SDSC patients with FISH. Twelve cases were followed up for 3-47 months. One died of tumor-related diseases half a year after diagnosis, and the remaining patients were alive with tumor, the longest survival time was 47 months. Conclusion: SDSC should be differentiated from a variety of poorly-differentiated tumors in the sinonasal area. Histologically, SDSC has no clear differentiation, but the tumor cells are characteristically basal-like or rhabdoid-like, with non-specific vacuoles, translucent or vacuolar nuclei, prominent nucleoli and necrotic foci. They are negative for INI1 IHC staining, and FISH demonstrates INI1 gene deletion. The clinical prognosis is still unclear, further studies on its biologic behavior and treatment methods are warranted.

Somatostatin receptor imaging with [68Ga]Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) in patients with nasopharyngeal carcinoma.

To explore the feasibility of [68Ga]Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) in patients with non-keratinizing nasopharyngeal carcinoma (NPC) and to evaluate whether [68Ga]Ga-DOTATATE PET/CT could be used for non-invasive determination of somatostatin receptor 2 (SSTR2) expression in NPC. This prospective study included patients with NPC who underwent [68Ga]Ga-DOTATATE PET/CT between February and May 2021. The [68Ga]Ga-DOTATATE and [18F]FDG uptakes in primary and metastatic NPC lesions were calculated and compared, and the [68Ga]Ga-DOTATATE uptake between SSTR2 score groups was analysed. A total of 36 participants (25 patients, initial staging; 11 patients, recurrence detection) were included; 33 patients also underwent [18F]FDG PET/CT for staging/restaging as a part of their routine diagnostic workup. [68Ga]Ga-DOTATATE PET/CT showed an intense tracer uptake in primary and metastatic NPC lesions. The radiotracer uptake was higher with [68Ga]Ga-DOTATATE than with [18F]FDG PET in primary NPC lesions (SUVmax: 12.03 vs. 10.07, P = 0.048; tumour-to-brain ratio: 36.16 vs. 0.86, P < 0.001) and regional lymph node metastases (median SUVmax: 9.11 vs. 6.12, P < 0.001) and comparable in bone and visceral metastases. Importantly, most NPC lesions showed intense SSTR2 expression (85.7%), which was strongly correlated with the [68Ga]Ga-DOTATATE uptake. The SUVmax of SSTR2-negative lesions was significantly lower than that of SSTR2-positive lesions (SUVmax: 4.95 vs. 12.61, P = 0.013). [68Ga]Ga-DOTATATE PET/CT is a promising imaging modality for detecting primary and metastatic NPC, with favourable image contrast and comparable diagnostic efficacy when compared to [18F]FDG PET/CT. An intense SSTR2 expression was observed in most NPCs, and this expression was significantly correlated with the [68Ga]Ga-DOTATATE uptake.

Epstein-Barr virus microRNA BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7.

Non-keratinizing nasopharyngeal carcinoma, the major subtype of nasopharyngeal carcinoma, is characterized by low differentiation and a close relation to Epstein-Barr virus infection, which indicates a link between Epstein-Barr virus oncogenesis and loss of differentiation, and raises our interest in investigating the involvement of Epstein-Barr virus in nasopharyngeal carcinoma dedifferentiation. Our previous study showed abundant expression of an Epstein-Barr virus-encoded microRNA, BART10-3p, in nasopharyngeal carcinoma tissues, but the association between BART10-3p and nasopharyngeal carcinoma differentiation remains unknown. Here, we examined the expression and prognostic value of BART10-3p, and undertook bioinformatics analysis and functional assays to investigate the influence of BART10-3p on nasopharyngeal carcinoma differentiation and proliferation and the underpinning mechanism. Microarray analysis identified BART10-3p as the most significantly upregulated Epstein-Barr virus-encoded microRNA in nasopharyngeal carcinoma tissues and the upregulation was confirmed in two public datasets. The expression of BART10-3p was an independent unfavorable prognosticator in nasopharyngeal carcinoma and its integration with the clinical stage showed improved prognosis predictive performance. Bioinformatics analysis suggested a potential role of BART10-3p in tumor differentiation and progression. Functional assays demonstrated that BART10-3p could promote nasopharyngeal carcinoma cell dedifferentiation, epithelial-mesenchymal transition, and proliferation in vitro, and tumorigenicity in vivo. Mechanistically, BART10-3p directly targeted the 3'UTR of ALK7 and suppressed its expression. Reconstitution of ALK7 rescued BART10-3p-induced malignant phenotypes. Overall, our study demonstrates that BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7, suggesting a promising therapeutic opportunity to reverse the malignant phenotypes of nasopharyngeal carcinoma.

The prognostic significance of race in nasopharyngeal carcinoma by histological subtype.

Race has been shown to have variable prognostic importance in nasopharyngeal carcinoma (NPC). However, previous studies are limited by a lack of comprehensive treatment, epidemiologic, and comorbidity data. This was a retrospective cohort study utilizing the National Cancer Database from 2004 to 2016. Multivariable Cox proportional hazards regressions were used to calculate adjusted hazard ratios (aHR) for overall survival. A cohort of 9995 patients met inclusion and exclusion criteria. Race, insurance, comorbidity, treatment, stage, age, and histology were independent prognosticators. Among patients with keratinizing NPC, Asians and Hispanics had superior survival (aHR 0.58 [95% confidence interval (CI) 0.48-0.69], aHR 0.76 [95% CI 0.61-0.96]) compared to white patients. Among patients with non-keratinizing differentiated NPC, Asians and black patients had improved survival (aHR 0.71 [95% CI 0.56-0.91], aHR 0.72 [95% CI 0.54-0.95]) compared to white patients. Race was not prognostic in non-keratinizing undifferentiated NPC. The prognostic significance of race varies across histological subtypes of NPC.

Association between SOX2 and OCT4 expression and the chemoradiation therapeutic response in undifferentiated non-keratinizing nasopharyngeal carcinoma

BACKGROUND Self-renewal ability of cancer stem cells (CSS) is one of the possible causes for nasopharyngeal carcinoma (NPC) to relapse and metastasize. SOX2 and OCT4 are markers for expression of the embryonic stem cells and crucial for the progression of various malignancies. This study was aimed to analyze the association between SOX2 and OCT4 expression and chemoradiation therapeutic response in undifferentiated non-keratinizing NPC.&#x0D; METHODS This cross-sectional study used archival data from Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital from January 2014 to December 2016. The outcomes were classified into good-response (complete and partial response) and poor-response groups (progressive and stable disease) based on response evaluation criteria in solid tumors (RECIST). SOX2 and OCT4 immunohistochemistry staining was performed using the initial specimen (before chemoradiation therapy) and positively expressing tumor cells were counted. Staining intensity was graded as: strong, moderate, weak, and negative. Strong and moderate staining was considered positive expression.&#x0D; RESULTS 33 males and 8 females were included; 48% were ≥50 years old. Most of the patients had stage IV (n = 35) and several patients had stage II (n = 3) and III (n = 3). More cells expressed OCT4 in the good-response group than the poor-response group (61.3% versus 37.0%, p = 0.009). Meanwhile, there were less cells expressing SOX2 in the good-response group than the poor-response group (36.3% versus 61.1%, p = 0.097).&#x0D; CONCLUSIONS This study suggests that OCT4 is a potential predictive marker for therapeutic response in patients with NPC.

A Comprehensive Analysis of Treatment Management and Survival Outcomes in Nasopharyngeal Carcinoma.

To comprehensively investigate nasopharyngeal carcinoma (NPC) treatment, overall survival (OS), and the influence of clinical/sociodemographic factors on outcome. Retrospective database study. National Cancer Database. The 2004-2015 National Cancer Database was queried for all patients with NPC receiving definitive treatment. Log-rank tests and Cox proportional hazards models were used for statistical analyses. A total of 8260 patients with NPC were included (71.4% male; 42.5% with keratinizing histology; mean ± SD age, 52.1 ± 15.1 years), with a 5-year OS of 63.4%. Multivariate predictors of mortality included age ≥65 years (hazard ratio [HR], 1.81; P < .001), Charlson/Deyo score ≥1 (HR, 1.27; P = .001), American Joint Committee on Cancer clinical stage III to IV (HR, 1.85; P < .001), and government insurance or no insurance (HR, 1.53; P < .001). Predictors of survival included female sex (HR, 0.82; P = .002), Asian/Pacific Islander race (HR, 0.74; P < .001), nonkeratinizing/undifferentiated histology (HR, 0.79; P = .004), and receiving treatment at academic centers (HR, 0.87; P = .02). Chemoradiotherapy (CRT) demonstrated improved OS as compared with radiotherapy (RT) only for stage II (P = .006) and stage III (P = .005) and with RT or chemotherapy only in stage IVA NPC (P < .001). When compared with CRT alone, surgery plus CRT provided OS benefits in keratinizing (P = .013) or stage IVA (P = .030) NPC. When compared with RT, CRT provided OS benefits in keratinizing (P = .005) but not nonkeratinizing (P = .240) or undifferentiated (P = .390) NPC. Substandard radiation dosing of <60 Gy and <30 fractions were associated with inferior OS (both P < .001). NPC survival is dependent on a variety of clinical/sociodemographic factors. Stage-specific treatments with optimal OS include CRT or RT for stages I to II and CRT for stage III to IV. The large representation of nonendemic histology is valuable, as these cases are not well characterized.

S2595 Solitary Liver Lesions Are Not Always HCC: Metastasis From an Uncommon Site Mimicking a Primary Liver Lesion

INTRODUCTION: Non-hepatocellular lesions may be found incidentally during imaging work-up for metastatic disease secondarily involving the liver, with metastatic tumors being the most common malignant neoplasms of the liver. The most common primary site of these metastasis is colorectal cancer, followed by breast, lung, and pancreas. Clinical history can be vital in the work-up of primary versus metastatic malignancy in tumors with less common sites of origin, especially when only a solitary liver lesion is identified and initially more suggestive of a primary liver lesion. CASE DESCRIPTION/METHODS: Seventy-two-year-old man who presented to the liver clinic for evaluation of a liver lesion seen on whole body scan (PET). Patient did not have prior history of liver disease or cirrhosis. He denied smoking, drinking alcohol or illicit drug use. He had no chronic or active hepatitis with good synthetic liver function (INR 1.1 sec, bilirubin 0.4 mg/ dL, albumin 4.2 g/dL, creatinine of 1.04 mg/ dL and alpha fetoprotein was less than 2 ng/ml). Past history significant for nasopharyngeal squamous carcinoma 3 years ago treated with chemoradiation. His last colonoscopy was unremarkable. PET scan showed interval appearance of the tracer avid low-attenuation lesion in the left lobe of the liver, segment 4A, concerning for primary neoplasm. He underwent a liver biopsy which showed poorly differentiated malignant cells. The malignant cells were positive for squamous markers p63 and CK5/6 on immunohistochemical stain (Image 1-2). In situ hybridization for EBV was also positive, consistent with metastatic non-keratinizing nasopharyngeal carcinoma. Patient was referred to oncology for further management. DISCUSSION: Liver metastases from head and neck cancer are rare (4.4%) and has a median survival of 4 months. When present in the liver, metastatic EBV-associated non-keratinizing nasopharyngeal carcinoma can histologically mimic hepatocellular carcinoma, neuroendocrine tumors, and small cell carcinoma. In the context of a solitary hepatic lesion on imaging, exclusion of hepatocellular carcinoma requires correlation with the patient's prior history and immunohistochemical staining on biopsy tissue. In this case, the known history of nasopharyngeal carcinoma helped to exclude the rare possibility of a primary squamous cell carcinoma of the liver, which has been proposed to arise following chronic irritation in patients with biliary cysts or stones, with resultant squamous metaplasia and malignant transformation.Image 1.: Liver biopsy showing positive immunohistochemical marker: Cytokeratin 5/6.Image 2.: Liver biopsy showing positive immunohistochemical marker: P53.

Circulation EBV Mir-Bart-7 Relating to Clinical Manifestation in Nasopharyngeal Carcinoma.

Objective:Nasopharyngeal Carcinoma (NPC) is an endemic head and neck malignancy in Asia Pacific regions that is associated with chronic infection by Epstein-Barr virus (EBV). EBV miR-BART-7 is a microRNA (miRNA) encoded by EBV that regulates malignant behavior of NPC. However, the role and function of miR-BART7 are not clear, particularly the relation of circulating levels and patient’s clinical presentation. Methods:Circulating miR-BART-7 levels were measured by using qRT-PCR and were correlated with clinical and pathological data. Result: Of 52 NPC patients included in this study, 85% were diagnosed in the late stages (Stage III-IV). 73% of tumors were non-keratinizing undifferentiated NPC, 92% of tumors were WHO class III histology and all cases were EBV-IgA positive. Over-expression of miR-BART7-3p was correlated with positive regional lymph nodes in newly diagnosed (4.61 fold changes, p<0.05). Conclusion: Over-expression of circulating EBV miR-BART7 correlated with positive regional lymph nodes reflecting the diagnostic and prognostic values of circulating miR-BART7 for patients with NPC.

Identifying the distant metastasis genes by next-generation sequencing panel in nasopharyngeal carcinoma.

e18547 Background: Even though local and regional controls have been substantially improved in nasopharyngeal carcinoma (NPC) in the contemporary era of intensity-modulated radiotherapy with extensive use of combined chemotherapy, the distant metastasis becomes the major cause of treatment failure and cancer-related death. To date, the genes contributed to metastasis of NPC is still unclear. The aim of this study was to identify the genes which lead to distant metastasis. Methods: A total of forty primary nonkeratinizing NPC patients were diagnosed at Shandong Cancer Hospital in this study. The formaldehyde-fixed paraffin embedded (FFPE) taken from primary sites or metastatic lymph nodes were performed next-generation sequencing (NGS) panel (Shanghai OrigiMed Co., Ltd.) to determine variated genes, such as single nucleotide variants (SNV), copy number variants (CNV) and rearrangement. These patients were followed up until Febr. 8, 2020. The genes related to distant metastasis were identified by logistic regression. Moreover, this study compared the frequency of mutated gene between our data and Catalog of Somatic Mutations in Cancer (COSMIC) database by the Chi-square test or Fisher’s exact test. Results: The study included 31 men and 9 women. The median age of the patients at diagnosis was 47 years (range 15–71 years). With the median follow-up of 10.6 months (range 16.8–72.3 months), 7 patients had distant metastasis and 1 undergone recurrent. Notably, EMSY and MCL1 variants were contributed to NPC distant metastasis (OR = 31, P = 0.049). The top eight SNV of genes in our study were CYLD, KMT2D, BAP1, EP300, TP53, ATM, NFKBIA and SPEN. When compared to COSMIC database, the mutant frequencies of CYLD, EP300 and BAP1 in our study were significantly higher than that of COSMIC database. However, the mutant frequencies of IDH2 and KMT2C were significantly lower than COSMIC database. Conclusions: This is the first study which suggests that EMSY and MCL1 variants were involved in the metastasis of NPC. The study identified 5 genes, which mutation frequency is significantly different from the COSMIC database. The study provided a molecular basis for a comprehensive understanding of, and exploring targeted therapies for nasopharyngeal carcinoma.