Association of LMP1 expression and cancer stage of nasopharyngeal carcinoma patients at Dr. Soetomo Regional General Hospital in January 2023 – December 2023

 Corresponding author: Natasha Khairunnisa Ardanianti Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Association of LMP1 expression and cancer stage of nasopharyngeal carcinoma patients at Dr. Soetomo Regional General Hospital in January 2023 – December 2023 Natasha Khairunnisa Ardanianti 1, *, Achmad Chusnu Romdhoni 2 and Betty Agustina Tambunan 3 1 Medical Study Program, Faculty of Medicine, Universitas Airlangga, Surabaya, East java, Indonesia. 2 Department of Otorhinolaryngology Head and Neck Surgery, Faculty of Medicine, Universitas Airlangga, Surabaya, East Java, Indonesia. 3 Department of Clinical Pathology, Faculty of Medicine, Universitas Airlangga, Surabaya, East Java, Indonesia. World Journal of Advanced Research and Reviews, 2025, 27(03), 846–853 Publication history: Received on 05 August 2025; revised on 11 September 2025; accepted on 13 September 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.27.3.3210 Abstract Nasopharyngeal carcinoma (NPC) is the most common multifactorial malignancy of the nasopharynx. Its prevalence rate is the fourth highest among other malignancies in Indonesia, at 1.2 cases per 100,000. The pathogenesis of NPC cases is closely linked to one of its risk factors, Epstein-Barr Virus, specifically the expression of one of its proteins, LMP1, which is found in almost all NPC patient tissue samples. The role of LMP1 (Latent membrane protein 1) has been proven to influence cancer stage that also linked to poor prognosis, overall survival, and metastasis. However, conflicting studies about significance of the relationship between LMP1 and NPC stage were also found. Therefore, this observational analytical quantitative study with a retrospective approach was conducted to clarify the controversy surrounding the relationship between LMP1 and NPC stage. A total of 40 patients met the inclusion criteria. There were 30 males and 10 were female. The dominant age ranged from 41 to 50 years old (32.5%). Thirty-three patients (82.5%) showed LMP1(+) expression, while seven patients (17.5%) were LMP1(-). Most of these NPC patients were in stage IV (75%). Although number of LMP1(+) patient expression was found in most of the patients and seemed increase in late stage of NPC, the correlation with NPC stage from chi-square test was deemed insignificant (p>0.05). Keywords: Nasopharyngeal Carcinoma; Lmp1; NPC Stage; Epstein-Barr virus; Retrospective study 1. Introduction Nasopharyngeal carcinoma (NPC) is the most common multifactorial malignancy of the nasopharynx [1] This carcinoma is endemically distributed worldwide, particularly in Southeast Asia, including Indonesia. Its prevalence rate is the fourth highest among other malignancies in Indonesia, at 1.2 cases per 100,000 population and 12,000 new cases per year [2]. The pathogenesis of NPC cases is closely related to one of its risk factors, Epstein-Barr virus (EBV), particularly the nonkeratinizing subtype. Furthermore, many NPC patients are also known to have EBV antibodies [3]. EBV infection is not directly associated with tumor induction, but rather with an increased risk of cancer in healthy individuals [4]. More than 95% of adults worldwide have been infected with EBV and are healthy carriers of the virus. Transformation of EBV infection into malignancy can occur due to a combination of viral activation and epigenetics, including the development of genetic lesions in cells caused by carcinogens, dietary components, and genetic immunodeficiencies, making it a multifactorial disease [2]. World Journal of Advanced Research and Reviews, 2025, 27(03), 846–853 847 The LMP1 protein is found in nearly all tissue samples from premalignant and preinvasive NPC patients [5,6]. The role of LMP1 expression in mediating invasion, angiogenesis, and metastasis, as well as inducing most inflammatory cytokines and chemokines through the NF-κB and STAT3 pathways, which support tumor progression, has also been demonstrated [7]. These various mechanisms include the induction of matrix metalloproteinase (MMP)-9, the activation of ets-1, c-Met, ezrin, and Mucin 1 (MUC1) through inhibition of cell adhesion, as well as the cooperative interaction between IL-6 and laminin [6]. Furthermore, evidence of a correlation between LMP1 and NPC stage is found in the discovery of higher levels of LMP1 expression in NPC with metastasis compared to those without metastasis [8]. Similar discoveries also highlighted positive associations and results between LMP1 expression with overall survival, tumor progression, and poor prognosis [9,10,11]. These referred investigations implicated LMP1 as pivotal oncogenic driver, particularly in NPC stage, albeit there remain contradictory studies: absence of LMP1 expression in NPC cells [12], the absence of a significant relationship between LMP1 expression and histopathological type, tumor grade (T), nodal status (N), distant metastases (M), and staging [13,14]. Moreover, Khabir et al. [15] observed no association between LMP1 expression and visceral metastasis or disease recurrence. Given the conflicting evidence regarding LMP1’s role and its purported association with NPC stage, this study aimed to clarify this discrepancy. 2. Material and methods This study is an observational quantitative study with retrospective approach. The data collection was done by consecutive sampling according to inclusion criteria. The data contains secondary data of LMP1 expression from representative tissue biopsy paraffin blocks of NPC patients from January 2023–December 2023 from the anatomical pathology installation that is assessed quantitatively (positive/negative expression) through immunohistochemistry and NPC patient stage that evaluated by UICC/AJCC 8th Edition (2017) with the 2020 updated version. The data is grouped based on predetermined variables (positive/negative expression of LMP1 and NPC Stage) and patient characteristics (sex and age group). Then, the data were analyzed using bivariate analysis using chi-square test through SPSS program to determine the association between LMP1 expression and NPC stage. 3. Results and discussion A total of 40 nasopharyngeal carcinoma (NPC) cases that met the inclusion criteria were identified at Dr. Soetomo Regional General Hospital during the period from January 2023 to December 2023. 3.1. Main Characteristic of NPC Patient Tabel 1 General Characteristics of NPC Patients at Dr. Soetomo Regional General Hospital, January 2023–December 2023 Variable Category Frequency Percentage Sex Male 30 75% Female 10 25% Age (years) 10–20 1 2.5% 21–30 1 2.5% 31–40 7 17.5% 41–50 13 32.5% 51–60 10 25% 61–70 6 15% 71–80 2 5% Previous studies have been conducted to identify biomarkers in NPC patients, particularly those targeting EBV oncogenic proteins, one of which is LMP1, which plays a significant role in tumorigenesis and NPC progression. This study examined LMP1 expression alongside NPC stage between January 2023 and December 2023. The results showed 30 male and 10 female patients, consistent with relevant studies on the male-to-female NPC ratio of 2.9:1 [16]. World Journal of Advanced Research and Reviews, 2025, 27(03), 846–853 848 NPC is more common in men than in women due to differences in risky habits, such as smoking and higher alcohol consumption. Furthermore, the 5-year survival rate is considered better in women, at 84% compared to 78% in men [17] due to intrinsic female biological factors, such as hormones and sex chromosomes [18]. Most NPC patients in this study are in the age of 41–50 years old. This age range aligns with research by Fauzan et al. [19] which found that the disease is most often found between the ages of 35 and 55. This is influenced by genetic factors, environmental factors, or exposure to carcinogenic substances at an early age. Notably, two young male patients, aged 18 and 27, were diagnosed earlier at stage II. These cases of NPC occurring at a young age are likely possible due to a genetic predisposition that is susceptible to NPC development. 3.2. LMP1 Expression of NPC Patient Tabel 2 LMP1 Expression in NPC Patients at Dr. Soetomo Regional General Hospital, January 2023–December 2023 Variable Category Frequency Percentage LMP1 Expression Positive 33 82.5% Negative 7 17.5% The pathophysiology of NPC is also closely associated with the presence of EBV's primary oncogenic proteins, one of which is LMP1, which was detected in NPC patients. This is reinforced by the high number of positive LMP1 expression findings in 82.5% of patients in this study. Negative LMP1 expression was also found in 17.5% of 40 NPC patients. This undetectable expression may be due to low LMP1 levels, which makes IHC (immunohistochemistry) testing incapable of detecting them, as it has sensitivity limit compared to other methods (RT-PCR and Western Blotting). However, even though LMP1 levels are considered low and undetectable, its contribution in mediating NPC development remains remarkable [20]. Furthermore, there are factors other than the oncogenic EBV virus, such as HPV, smoking, alcohol, consumption of salted fish with preservatives (nitrosamines), and exposure to other carcinogens [21]. Additionally, genetic alterations have been found in NPC patients independent of EBV, such as missing alleles on chromosomes 3p21.3 and 9p21, which inactivate tumor suppressor genes (RASSF1A and p16), thus facilitating NPC expansion and progression [22]. 3.3. NPC Stage Nasopharyngeal carcinoma is also a disease that is difficult to detect early due to its deep location and nonspecific symptoms [23]. This leads to other factors contributing to delayed diagnosis: doctors not considering the diagnosis of NPC, doctors suspecting NPC but misdiagnosing it during screening, and some patients refusing screening or not seeking follow-up [24]. Upon initial diagnosis of NPC, patients often complain of unilateral ear problems with tinnitus, such as Eustachian tube obstruction, otitis media effusion, conductive hearing loss, and otalgia [2] due to the NPC mass compressing the torus tubarius. Furthermore, neck masses, nasal obstruction, and headaches may also occur [25]. These symptoms often lead to suspicion of ear problems or upper respiratory tract infections, which are then misinterpreted as dental problems. This led to repeated visits to the ENT doctor over the course of a year due to lack of improvement in the same symptoms, ultimately leading to nasal endoscopy and CT scans to detect the NPC mass [24,26] Furthermore, nasal endoscopy screening for NPC masses often results in false-negative results due to the inability to visualize the entire fossa of Rosenmüller, so a contralateral examination is recommended [25]. Other false-negative imaging findings include insufficient contrast, capturing fewer than two sections of the nasopharynx, insufficient axial orientation, and the presence of dental artifacts. Furthermore, misinterpretation of sinusitis symptoms can lead the radiologist to focus more on the sinuses and miss the NPC [25]. These false-negative results, which lead to a missed NPC diagnosis, require further examination with MRI, which has been found to have a sensitivity of >90% [27,28]. World Journal of Advanced Research and Reviews, 2025, 27(03), 846–853 849 Tabel 3 Cancer Stage in NPC Patients at Dr. Soetomo Regional General Hospital, January 2023–December 2023 Variable Category Frequency Percentage Stage Stage I 0 0% Stage II 3 7.5% Stage III 7 17.5% Stage IV 30 75% In this study, the largest number of patients, 30 (75%), were diagnosed with stage IV indicating a tendency for late diagnosis, 7 (17.5%) with stage III, and 3 (7.5%) with stage II. Stage is assessed based on the local extent of the cancer from the site of origin (T), the extent of regional lymph node metastases (N), and the presence or absence of distant metastases (M) by UICC/AJCC 8th Edition (2017) with the 2020 updated version. The most common stage in this study was stage IV, indicating distant metastases, consistent with previous studies [29,30,31]. 3.4. Association of LMP1 Expression and NPC Stage It appears that there is an increase in the number of patients with positive LMP1 expression at higher stages. However, a bivariate chi-square analysis showed no significant results (p>0.05). The statistically insignificant results in LMP1 expression according to the stage of NPC patients are likely due to the undetectable LMP1 expression on IHC due to low levels of expression. A study by Baizig et al. [32] in Tunisia, a NPC-endemic area, found that LMP1 is associated with NPC, but not all NPC cases showed LMP1 expression. Even with higher NPC stages, LMP1 expression was not always positive. However, in clinical and biological contexts, LMP1 is an important factor associated with poor prognosis and the proliferation pathway of nasopharyngeal cancer via IGF-1R. Furthermore, LMP1 has been shown to downregulate cell adhesion to other cells and increase cell motility through the activation of ets-1 and c-Met. Ezrin expression, a link between the plasma membrane and the actin cytoskeleton, can also induce the expression of Mucin 1 (MUC1), which plays a crucial role in tumor invasion and metastasis. LMP1 contributes to the worsening of NPC and acts as a tumor driver [33]. Another study by Liu et al. [34] found that antiapoptotic components involved in NPC progression, such as Bcl-2 via the NF-κB pathway, were also upregulated to prevent cytotoxic signals dependent on LMP1 expression. However, other findings suggest that increased Bcl-2 expression is independent of LMP1, as evidence exists that LMP1 silencing does not affect Bcl-2 expression [35]. However, the two work synergistically to increase the severity of NPC [36]. Furthermore, studies by Yang et al. [37] and Murono et al. [38] found that the angiogenesis factor VEGF (vascular endothelial growth factor) is induced by LMP1 expression through upregulation of COX-2 and the JNKs/HIF-1 pathway. However, a study by Challouf et al. [39] found that LMP1 expression did not correlate with blood vessel density or the degree of vascularization in NPC tissue. This suggests that LMP1 does not play a significant role in angiogenesis in NPC. Similar results were found in studies that found increased LMP1 expression with advanced NPC clinical stage, but this remained uncorrelated [40]. Conversely, despite the finding that NPC stage and LMP1 expression were not directly related and did not appear significant, research by Ye et al. [41] still showed a relationship between LMP1 and clinical stage, meaning LMP1 contributes to tumor progression. This was demonstrated by studies of LMP1 expression, which can play a role in the early stages of cancer formation and tumor development [6], especially NPC that is correlated with EBV infection. It can be concluded that LMP1 is not the sole determinant of NPC progression, but remains relevant as a future biomolecular target. World Journal of Advanced Research and Reviews, 2025, 27(03), 846–853 850 Tabel 4 Cancer Stage and LMP1 Expression in NPC Patients at Dr. Soetomo Regional General Hospital, January 2023– December 2023 NPC Stage LMP1 Expression Positive Negative n % n % Stage II 3 100 0 0 Stage III 6 85.7 1 14.3 Stage IV 24 80 6 20 Total 33 82.5 7 17.5 Table 4 shows LMP1 expression that was found to be higher in patients with stage IV compared to those with stages II and III. Chi-square statistical test using SPSS showed a non-significant association between LMP1 expression and NPC stage (p>0.05). Tabel 5 Chi-square of Cancer Stage and LMP1 Expression in NPC Patients at Dr. Soetomo Regional General Hospital, January 2023–December 2023 Chi-square Value df Asymp. Sig. (2-sided) Pearson Chi-Square . 816a 2 0.665 Likelihood Ratio 1.332 2 0.514 N of Valid Case 40 4. Conclusion Nasopharyngeal carcinoma (NPC) in patients at Dr. Soetomo Regional General Hospital between January 2023 and December 2023 was more common in men, with 30 patients between 41–50 years whereas most patients were already in stage IV (75%), indicating a late diagnosis of NPC. Although positive LMP1 expression was found in 82.5% of patients that mostly in the late stage, no significant correlation was found between LMP1 expression and NPC stage. Future research is expected to conduct with a larger and more representative sample size to identify patients with stage I NPC. Furthermore, more sensitive methods for LMP1 expression testing that include interval data are needed to enhance the detection limit for LMP1 and thereby substantially reduce the risk of false-negative findings. Compliance with ethical standards Acknowledgments We gratefully acknowledge the institutional support provided by Universitas Airlangga. 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