Subtype Specific Nasopharyngeal Carcinoma Incidence and Survival Trends: Differences between Endemic and Non-Endemic Populations.

BACKGROUND: While nasopharyngeal carcinoma (NPC) is rare in non-endemic regions such as the North America, endemic countries, such as Thailand, continue to struggle with high incidence and mortality rates. NPC has a complex etiology that varies by histological subtype. METHODS: NPC cases (1990-2014) were identified using the International Classification of Diseases for Oncology (ICD-O) code C11 from the Chiang Mai, Khon Kaen, Lampang, and Songkhla cancer registries and compared to Asian/Pacific Islanders (A/PI) from the US SEER program. Age-standardized incidence rates and changes in annual percent change (APC) for overall and subtype specific NPC were assessed using R and Joinpoint. Kaplan Meier curves were generated in SAS to evaluate differences in survival by sex, year of diagnosis and histological subtype. Five-year relative survival estimates were calculated between 2000-2014. RESULTS: Non-keratinizing NPC predominated across all registries except Songkhla, where the keretinizing subtype made up ~60% of all reported cases. Incidence of keratinizing NPC significantly decreased among Chiang Mai males between 1996 and 2014 (APC:-13.0 [95%CI:-16.2, -9.6]), Songkhla females (APC:-4.0 [95%CI: -7.4, -0.5]) and males between 2006 and 2014 (APC:-15.5 [95%CI:-25.0, -4.7]), as well as A/PI females (APC:-5.1 [95%CI:-6,7, -3.4]) and males (APC: -4.8 [95%CI:-5.9, -3.7]). Non-keratinizing NPC increased among Songkhla males (APC:4.3 [95%CI:1.8, 6.9]). The keratinizing subtype exhibited the worst survival, while the non-keratinizing undifferentiated subtype had the best survival. Although US A/PI had the highest 5-year relative survival estimates, among the Thai registries Chiang Mai had the best and Lampang the worst survival. CONCLUSION: Although US A/PIs exhibited similar rates of NPC as seen in the endemic Thai population, improved tobacco control has led to a decrease in keratinizing NPC incidence irrespective of geography. Additionally, while challenges associate with access to care may still exist among rural Thais, chemoradiation was shown to confer a survival benefit in non-keratinizing NPC treatment.

Whole exome sequencing and transcriptome-wide profiling identify potentially subtype-relevant genes of nasopharyngeal carcinoma.

BACKGROUND: To date, no targeted therapy has been approved for nasopharyngeal carcinoma (NPC), suggesting that comprehensive understanding of genomic changes turns out to be an urgent need to break through the calm of currently known therapies of NPC. METHODS: Whole exome sequencing (WES) was performed for 14 NPC patients, including 6 NPC-IIA cases, 8 NPC-IIB cases. The cancer chip expression data named GSE12452 was downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) of each subtype were obtained using the Lima R package. Then gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Protein-protein interaction (PPI) network and Gene Set Enrichment Analysis (GSEA) were performed. Finally 7 potentially subtype relevant genes (PSRGs)1 were obtained. RESULTS: In total, 37 clinically relevant mutations (CRMs)2 were obtained from WES. The 2 NPC subtypes exhibited different mutational landscapes, indicating that different NPC subtypes harbor different CRMs. Notably, we discovered that mutations of CCND1 and FGF family appeared simultaneously in 3 NPC-IIB cases, but 0 in NPC-IIA. In addition, 1395 DEGs were identified from GSE12452. PI3K-Akt signaling pathway showed significant enrichment in both the pathway distribution of CRMs and KEGG analysis of DEGs, suggesting that it is a key pathway in the development of NPC. Through PPI analysis of genes involved in the PI3K-Akt pathways and expression significance analysis of DEGs co-expressed by the 2 subtypes, 54 genes finally were screened for expression significance analysis. The GSEA analysis between patients with high and low expression of 11 candidate genes were performed. As a result, 7 PSRGs were selected, including COL4A1, ASB9, RDH10, TNFRSF21, BACE2, EVA1C and LHX2. CONCLUSIONS: These results indicate that different NPC subtypes have different genetic changes, suggesting that they may be potential targets for the diagnosis and treatment of NPC, and ultimately point to new strategies for intelligence.

Survival impacts of different nodal characteristics and T-classification in N3 nasopharyngeal carcinoma patients.

OBJECTIVES: We investigated the survival impacts of various nodal characteristics and T-classification on nasopharyngeal carcinoma (NPC) patients with the 8th AJCC/UICC staging criteria N3. MATERIALS AND METHODS: Pretreatment MRIs from 110 staged N3 NPC patients were reviewed. There were 23 T1, 25 T2, 32 T3, and 30 T4, respectively. All except one patient belonged to WHO type II pathology. All patients received curative radiotherapy 68.0-76.8 Gy plus different chemotherapy, including induction, concurrent, adjuvant or any combination. Various endpoints, including OS (overall survival), DFS (disease-free survival), LRFFS (locoregional failure-free survival), DMFFS (distant metastasis failure-free survival) were compared between different nodal characteristics and T-classification. RESULTS: There were no statistically significant differences in all analyzed survival curves between various nodal characteristics, including unilateral N3 vs. bilateral N3, "large" nodes (>6 cm) alone vs. "low" nodes (below the caudal border of cricoid cartilage) alone vs. combined "large" and "low" nodes, risk score 1 vs. 2 vs. 3 vs. 4 (by counting the sum of "large" and "low" nodes in the same case), and radiologic extra-nodal extension. Patients with T4, compared with those of T1-3 have worse OS (5-year rates, 42.2% vs. 82.8%, P < 0.0001), DFS (5-year rates, 43.9% vs. 68.9%, P = 0.0037), LRFFS (5-year rates, 69.3% vs. 82.7%, P = 0.0432), and DMFFS (5-year rates, 57.2% vs. 77.7%, P = 0.0163). CONCLUSIONS: Our results support merging previous N3a and N3b as a N3 category in the 8th edition new staging system. Patients with T4N3 diseases have extremely poor outcome and deserve to strengthen the treatment intensity in future trials.

Nodal grouping in nasopharyngeal carcinoma: prognostic significance, N classification, and a marker for the identification of candidates for induction chemotherapy.

OBJECTIVES: This study aimed to evaluate the value of nodal grouping (NG), defined as the presence of at least three contiguous lymph nodes (LNs) within one LN region, in staging and management of patients with non-metastatic nasopharyngeal carcinoma (NPC). METHODS: MR images were reviewed to evaluate LN variables, including NG. The Kaplan-Meier method and multivariate Cox regression models evaluated the association between the variables and survival. Harrell's concordance index (C-index) was used to measure the performance of prognostic models. The outcome of induction chemotherapy (IC) in patients with and without NG was compared using matched-pair analysis. RESULTS: In 1224 patients enrolled, NG was found to be an independent prognostic factor for overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and regional recurrence-free survival. The hazard ratio and 95% confidence interval (CI) of NG for OS (3.86, 2.09-7.12) were higher than those of stage N2 (3.54, 1.89-6.70). On upgrading patients with NG from stages N1 to N2, the revised N staging yielded a higher C-index compared to the American Joint Committee on Cancer system in predicting PFS (0.664 vs. 0.658, p = 0.022) and DMFS (0.699 vs. 0.690, p = 0.005). Results of the matched-pair analysis revealed that for patients with NG in stages N1 and N2, IC was correlated with improved OS (p = 0.022), PFS (p = 0.007), and DMFS (p = 0.021). CONCLUSIONS: NG is a significant prognostic factor for patients with NPC. Patients with NG may be upgraded from stages N1 to N2. NG was also a marker for identifying patients who would benefit from IC. KEY POINTS: • Nodal grouping, defined as the presence of at least three contiguous LNs within one LN region on MRI, was identified as a significant prognostic factor. • In patients with nasopharyngeal carcinoma, nodal grouping may influence lymph node staging. • Nodal grouping was a marker for identifying patients who may benefit from induction chemotherapy.

Prognostic value of radiologic extranodal extension and its potential role in future N classification for nasopharyngeal carcinoma.

PURPOSE: We evaluated the prognostic value of various grades of radiologic extranodal extension (rENE) and their potential roles in N-classification refinement for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: All NPC patients treated with IMRT in our institution between 2005 and 2011 were included. Pre-treatment MR of cN+ cases were reviewed and rENE was recorded asG0: lymph nodes (LNs) without rENE; G1: tumor infiltrating beyond individual nodal capsule(s) into the surrounding fat plane; G2: coalescent nodal mass with unequivocal evidence of rENE; G3: tumor infiltrating beyond nodal capsule into adjacent structures. Multivariable analysis (MVA) assessed prognostic value of rENE for distant metastasis (DM) and death adjusted for age, gender, LDH, T-classification, N-classification, and chemotherapy cycles. RESULTS: A total of 1390 of 1616 (86%) NPC were cN+, and rENE was detected in 826/1390 (59%) patients: 256 (18.4%) G1-rENE, 487 (35%) G2-rENE, and 83 (6%) G3-rENE. MVA confirmed that G2-/G3-rENE had increased risk of DM (HR: 2.05/3.18, both p < 0.001) and death (HR: 1.62/2.39, p = 0.002/p < 0.001), while G1-rENE was non-prognostic (DM: p = 0.172; death: p = 0.320). We propose a refined N: New-N1: N1/N2 without G2-/G3-rENE; New-N2: N1_G2-rENE; New-N3: N2_G2-rENE, N1/N2_G3-rENE, or N3. The New-N classification had a lower AIC and higher c-index for DM (AIC: 3809.6 vs 3830.9; c-index: 0.700 vs. 0.677) and death (AIC: 3693.8 vs. 3705.9; c-index: 0.735 vs. 0.725) versus TNM-8 N. CONCLUSIONS: G2- and G3-rENE are independently prognostic for DM and death in NPC. Compared to the TNM8 N-classification, a refined N-classification incorporating G2- and G3-rENE improves prognostication of DM and mortality risk.

Patterns of EBV-positive cervical lymph node involvement in head and neck cancer and implications for the management of nasopharyngeal carcinoma T0 classification.

OBJECTIVES: Epstein-Barr virus (EBV)-positive cervical lymph node (CLN) metastasis of unknown primary origin is classified as nasopharyngeal carcinoma (NPC) T0 by the American Joint Committee on Cancer staging manual (8th edition). We aimed to investigate the possible primary sites and patterns of EBV-positive CLN metastases and to provide implications for the management of NPC T0 classification. MATERIALS AND METHODS: We retrospectively reviewed 269 patients with newly diagnosed EBV-positive CLN metastatic disease who underwent EBV detection via EBV-encoded RNA in situ hybridization. Fifteen patients with unknown primary tumors underwent follow-up after initial treatment. RESULTS: In patients with EBV-positive CLNs, the most common primary sites after the nasopharynx (51.7%) were the salivary gland (24.5%), lung (7.8%), oropharynx (3.3%), nasal cavity/maxillary (3.3%), oral cavity (2.2%), orbit (1.1%), and liver (0.4%). No primary site was found in 15 patients (5.6%). For salivary gland malignancies, level II and I were the most frequently involved regions. Tumors arising from the lung or liver metastasized to the lower neck (level IV, V, and VI) rather than the upper neck. After initial treatment, 2/15 patients with EBV-positive CLNs of unknown primary exhibited primary NPC and oropharyngeal tumor, respectively. Further, even without prophylactic irradiation to the nasopharynx, only one of 13 unknown primary patients developed NPC. CONCLUSIONS: The origins of EBV-positive CLNs may not be restricted to the nasopharynx alone, and are likely to involve the head and neck or non-head and neck regions. NPC T0 classification should be cautiously assigned to such tumors.

External validity of a prognostic nomogram for locoregionally advanced nasopharyngeal carcinoma based on the 8th edition of the AJCC/UICC staging system: a retrospective cohort study.

BACKGROUND: The tumor-node-metastasis (TNM) staging system does not perform well for guiding individualized induction or adjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We attempted to externally validate the Pan's nomogram, developed based on the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system, for patients with locoregionally advanced disease. In addition, we investigated the reliability of Pan's nomogram for selection of participants in future clinical trials. METHODS: This study included 535 patients with locoregionally advanced NPC who were treated between March 2007 and January 2012. The 5-year overall survival (OS) rates were calculated using the Kaplan-Meier method and compared with predicted outcomes. The calibration was tested using calibration plots and the Hosmer-Lemeshow test. Discrimination ability, which was assessed using the concordance index, as compared with other predictors. RESULTS: Pan's nomogram was observed to underestimate the 5-year OS of the entire cohort by 8.65% [95% confidence interval (CI) - 9.70 to - 7.60%, P < 0.001] and underestimated the 5-year OS of each risk group. The differences between the predicted and observed 5-year OS rates were smallest among low-risk patients (< 135 points calculated using Pan's nomogram; which predicted minus observed OS, - 6.41%, 95% CI - 6.75 to - 6.07%, P < 0.001) and were largest among high-risk patients (≥ 160 points) (- 13.56%, 95% CI - 15.48 to - 11.63%, P < 0.001). The Hosmer-Lemeshow test suggested that the predicted and observed 5-year OS rates had no ideal relationship (P < 0.001). Pan's nomogram had better discriminatory ability compared with the levels of Epstein-Barr virus DNA acid (EBV DNA) and the 7th or 8th AJCC/UICC staging system, although not better compared with the combination of EBV DNA and the 8th staging system. Additionally, Pan's nomogram was marginally inferior to our predictive model, which included the 8th AJCC/UICC N-classification, age, gross primary tumor volume, lactate dehydrogenase, and body mass index. CONCLUSIONS: Pan's nomogram underestimated the 5-year OS of patients with locoregionally advanced NPC at our cancer center, and may not be a precise tool for selecting participants for clinical trials.