2025 Volume 266 Issue 4 Pages 335-342
Allergic rhinitis, especially Japanese cedar pollinosis, is considered a national affliction in Japan. The present exploratory study focused on the AllergoOncologic aspect of head and neck cancer (HNC) from the perspective of serum allergen-specific IgE against Japanese cedar pollen (JCP) for the first time. Serum JCP-specific IgE was measured in seventy-five HNC patients, including the oropharynx, hypopharynx, and larynx, and seventeen nasopharyngeal cancer (NPC) patients as well as forty-two patients with non-allergic benign disease (nABD). The JCP-specific IgE-positive rate was significantly lower in HNC than nABD (p = 0.037). Similarly, there was a clear trend toward a lower JCP-specific IgE score in HNC than nABD (p = 0.069). Further analyses excluding subjects in their 70s or older also showed that the JCP-specific IgE-positive rate was significantly lower in HNC than nABD (p = 0.022). In addition, The JCP-specific IgE score was significantly lower in HNC than nABD (p = 0.045). A lower serum JCP-specific IgE-positive rate in patients with HNC compared with nABD was demonstrated for the first time. An inverse correlation between HNC and Japanese cedar pollinosis was suggested from the perspective of allergen-specific IgE.
Allergic rhinitis (AR) is recognized as a major health problem worldwide. A survey of 1,540 subjects between 20 and 49 years of age demonstrated that the prevalence of AR was 44.2 % in Japan (Sakashita et al. 2010). Seasonal AR caused by Japanese cedar pollen (JCP), also called sugi-pollinosis, is one of the most common diseases in Japan, and it has been considered a national affliction (Yamada et al. 2014).
Allergic immune reactions have been extensively studied regarding their relationship with the cancer risk (Turner et al. 2006; Jensen-Jarolim et al. 2017a). This interdisciplinary field has been attracting marked interest from not only researchers but also clinicians. Accordingly, a Task Force on AllergoOncology within the Immunology Section of the European Academy of Allergy and Clinical Immunology was established in 2014, and it published a position paper providing an update on developments in this field (Jensen-Jarolim et al. 2017b).
Although it is difficult to draw conclusions, a history of allergy has been inversely associated with the risk of cancer at a number of sites, with the exception of a positive association of lung cancer with asthma (Turner et al. 2006). Accordingly, there have been epidemiologic studies demonstrating an inverse relationship between AR and head and neck cancer (HNC) (Michaud et al. 2012; Hsiao et al. 2013). However, with respect to HNC, there have been no reports focusing on AR from the perspective of allergen-specific immunoglobulin E (IgE). In this exploratory study, we demonstrated a decreased serum JCP-specific IgE level in patients with HNC for the first time.
Seventy-five consecutive patients of previously untreated HNC including oropharyngeal, hypopharyngeal, and laryngeal cancer, and 17 consecutive patients of previously untreated nasopharyngeal cancer (NPC) from 2010 to 2012 were retrospectively analyzed. Forty-two consecutive patients with non-allergic benign disease (nABD), but with a male-to female ratio of 15 to 1, consistent with the male predominance of HNC, during the same period were also retrospectively analyzed. This study was approved by the Ethics Committee of Kanazawa University School of Medicine (Approval number: 2015-060).
Measurement of serum total and allergen-specific IgESerum JCP-specific IgE was measured using a clinically applied fluorescence-enzyme immunoassay. The concentration was expressed as grade 0 to 6 according to the concentration calculated from a standard curve (UA/mL). Generally, grade 0 (< 0.35 UA/mL) was considered negative, grade 1 (< 0.7 UA/mL) was considered pseudo-positive, and grade 2 (< 3.5 UA/mL), grade 3 (< 17.5 UA/mL), grade 4 (< 50 UA/mL), grade 5 (< 100 UA/mL), and grade 6 (100 ≤ UA/mL) were considered positive. In the present analyses, grades 0 and 1 were regarded as negative, and grades 2 and above were regarded as positive, as previously reported (Sakashita et al. 2010).
Statistical analysisScores of JCP-specific IgE were compared using the Mann-Whitney U test between two groups and Kruskal-Wallis test among three or more groups. Positive rates were compared using the chi-square test. All analyses were carried out using SPSS 24.0 (IBM Corp., Armonk, NY). In all tests, p < 0.05 was considered significant.
General characteristics of the patients analyzed in this study are shown in Table 1. Forty-two randomly chosen patients with nABD included 14 patients with middle ear cholesteatoma, 12 patients with chronic otitis media, 10 patients with other middle ear disorder, and 6 patients with a cochlear implant. Mean scores of JCP-specific IgE in 75 patients with HNC and 42 patients with nABD were 0.47 and 0.88 (p = 0.069) (Fig. 1). Similarly, positive rates of JCP-specific IgE were 15 and 31% (p = 0.037), respectively (Fig. 2). Among patients with HNC, mean scores of JCP-specific IgE were 0.73, 0.43, and 0.38 in oropharyngeal, hypopharyngeal, and laryngeal cancer, respectively, which did not show a significant difference (p = 0.19) (Fig. 1).
There were no patients of keratinizing NPC (WHO type I). The mean score of JCP-specific IgE was 1.41 in patients with NPC (Fig. 1). Although there was a trend toward a higher level in patients with NPC than those with nABD, it did not reach significance (p = 0.278). On the other hand, a significant difference was observed between patients with HNC and those with NPC (p = 0.010). Similarly, the positive rate of JCP-specific IgE in patients with NPC was 41%, which showed a significant difference compared with patients with HNC (p = 0.013) (Fig. 2). On the other hand, there was no significant difference between subjects with NPC and those with nABD (p = 0.456) (Fig. 2).
Patients’ characteristics.
HNC, head and neck cancer; nABD, non-allergic benign disease; NPC, nasopharyngeal cancer; SD, standard deviation.
Score of serum Japanese cedar pollen-specific IgE.
Scores of serum allergen-specific IgE against Japanese cedar pollen in the total subjects (left panel) and patients with head and neck cancer (HNC) by site (right panel). X indicates the mean. nABD, non-allergic benign disease; NPC, nasopharyngeal cancer; Oro, oropharynx; Hypo, hypopharynx.
Positive rate of serum Japanese cedar pollen-specific IgE.
Positive rates of serum allergen-specific IgE against Japanese cedar pollen in the total subjects (left panel) and patients with head and neck cancer (HNC) by site (right panel). nABD, non-allergic benign disease; NPC, nasopharyngeal cancer; Oro, oropharynx; Hypo, hypopharynx.
Among 42 patients with nABD, who were considered as a control in the present study, 7, 6, 21, and 8 patients were in their 40s, 50s, 60s, and 70s respectively. Positive rates for JCP-specific IgE, the most common allergen in AR patients in Japan, were 29, 50, 38, and 0% in patients in their 40s, 50s, 60s, and 70s respectively. A marked decrease in the positive rate for JCP-specific IgE was clear in those in their 70s compared with those in their 60s or younger. This suggested that a difference in the rate of patients in their 70s would affect analyses of positivity for JCP-specific IgE. Actually, there were 25, 8, and 1 subject in their 70s with HNC, nABD, and NPC, respectively in the present study. Therefore, we also performed subgroup analysis after excluding subjects in their 70s or older (Table 2).
In this setting, mean scores of JCP-specific IgE in 50 patients with HNC and 34 patients with nABD were 0.50 and 1.09, respectively (p = 0.045) (Fig. 3). Similarly, positive rates of JCP-specific IgE were 16 and 38% (p = 0.022), respectively (Fig. 4). Among patients of HNC, mean scores of JCP-specific IgE were 0.55, 0.53, and 0.45 in oropharyngeal, hypopharyngeal, and laryngeal cancer, respectively, with no significant difference (p = 0.87) (Fig. 3).
The mean score of JCP-specific IgE was 1.50 in patients with NPC (Fig. 3). Although a significant difference between subjects with NPC and those with nABD was not observed (p = 0.475), it was significant between patients with HNC and those with NPC (p = 0.022). Similarly, the positive rate of JCP-specific IgE in patients with NPC was 44%, showing a significant difference compared with patients with HNC (p = 0.013) (Fig. 4). On the other hand, there was no significant difference between subjects with NPC and those with nABD (p = 0.713) (Fig. 4).
Patients’ characteristics (< 70 years old).
Score of serum Japanese cedar pollen-specific IgE.
Scores of serum allergen-specific IgE against Japanese cedar pollen in subjects excluding those in their 70s or older (left panel) and patients with head and neck cancer (HNC) by site (right panel). X indicates the mean. nABD, non-allergic benign disease; NPC, nasopharyngeal cancer; Oro, oropharynx; Hypo, hypopharynx.
Positive rate of serum Japanese cedar pollen-specific IgE.
Positive rates of serum allergen-specific IgE against Japanese cedar pollen in subjects excluding those in their 70s or older (left panel) and patients with head and neck cancer (HNC) by site (right panel). nABD, non-allergic benign disease; NPC, nasopharyngeal cancer; Oro, oropharynx; Hypo, hypopharynx.
According to the Practical Guideline for the Management of Allergic Rhinitis in Japan (2024 version), the prevalence of Japanese cedar pollinosis in people in their 10s, 20s, 30s, 40s, and 50s is 45.7-49.5%, while that in people in their 60s is 36.9% (Japan Society of Immunology, Allergology and Infection in Otorhinolaryngology 2024). We also performed a subgroup analysis between subjects in their 50s or younger and those in their 60s. The numbers of patients with nABD, HNC, and NPC in their 50s or younger and those in their 60s were 14, 14, and 8, and 20, 36, and 8 respectively.
In patients in their 50s or younger, the mean sores of JCP-specific IgE in patients with HNC and those with nABD were 0.93 and 1.14, respectively (p = 0.98) (Fig. 5). Similarly, the positive rates of JCP-specific IgE were 29% and 36%, respectively (p = 1.00) (Fig. 6). The mean score of JCP-specific IgE was 2.00 in patients with NPC in their 50s or younger, which was not significantly different from either patients with nABD (p = 0.44) or patients with HNC (p = 0.40). Similarly, the positive rate of JCP-specific IgE was 50% in patients with NPC in their 50s or younger, which was not significantly different from either patients with nABD (p = 0.66) or patients with HNC (p = 0.39).
In patients in their 60s, the mean sores of JCP-specific IgE in patients with HNC and those with nABD were 0.33 and 1.05, respectively (p = 0.013) (Fig. 5). Similarly, the positive rates of JCP-specific IgE were 11% and 40%, respectively (p = 0.018) (Fig. 6). The mean score of JCP-specific IgE was 1.00 in patients with NPC in their 60s, which was not significantly different from either patients with nABD (p = 0.98) or patients with HNC (p = 0.14). The positive rate of JCP-specific IgE was 38% in patients with NPC in their 50s or younger, which was not significantly different from either patients with nABD (p = 1.00) or patients with HNC (p = 0.10).
Score of serum Japanese cedar pollen-specific IgE.
Scores of serum allergen-specific IgE against Japanese cedar pollen in subjects in their 50s or younger (left panel) and subjects in their 60s (right panel). X indicates the mean. nABD, non-allergic benign disease; HNC, head and neck cancer; NPC, nasopharyngeal cancer.
Positive rate of serum Japanese cedar pollen-specific IgE.
Positive rates of serum allergen-specific IgE against Japanese cedar pollen in subjects in their 50s or younger (left panel) and subjects in their 60s (right panel). nABD, non-allergic benign disease; HNC, head and neck cancer; NPC,nasopharyngeal cancer.
Numerous epidemiologic studies have investigated potential associations between allergy and cancer risk (Turner et al. 2006; Turner 2012; Josephs et al. 2013). Recent reviews identified the types of tumors less common in patients with allergy, including pancreatic cancer, glioma, and childhood leukemia, or types of tumors more common in patients with allergy, including lung, skin, and prostate cancer (Turner 2012; Josephs et al. 2013).
On the other hand, the role of allergy in HNC has remained unclear. However, recent meta-analysis and studies demonstrated a significant inverse correlation between HNC and allergy (Michaud et al. 2012; Hsiao et al. 2013). Hsiao et al. (2013) showed an odds ratio of 0.41 in their original study and relative risk 0.76 in a meta-analysis. Similarly, Michaud et al. (2012) showed that individuals with allergies had a 19% lower risk of HNC.
As summarized by Turner (2012), although most previous studies used a self-reported diagnosis for allergy assessment, some studies evaluated total or specific IgE. With respect to HNC, because there had been no reports evaluating specific IgE, the present study focused on AR from the perspective of JCP-specific IgE for the first time, and this is a major strength of the present study.
Although Jensen-Jarolim et al. (2008) defined the field of AllegroOncology and suggested a role for IgE antibodies in natural tumor surveillance as well as in active and passive immunotherapy, there has been limited studies evaluating the association of specific IgE with cancer risk (Wiemels et al. 2009, 2011; Calboli et al. 2011; Schwartzbaum et al. 2012). Among them, Schwartzbaum et al. (2012) demonstrated an inverse association between serum allergen-specific IgE and glioblastoma. Our current results similarly indicate that allergy-associated IgE may be indicative of an immune phenotype that decreases the risk of HNC.
As Josephs et al. (2013) stated in a review, there are several proposed hypotheses for different mechanisms by which allergic immunity protects against or promotes carcinogenesis. Two hypotheses for protection from cancer development involve immunosurveillance and prophylaxis (Josephs et al. 2013). The mechanism of immunosurveillance is that responses to allergens lead to enhanced immune responsiveness and the production of IgE, and that of prophylaxis is that physical effects of allergic reactions expel mutagenic triggers (Josephs et al. 2013). Sherman et al. (2008) observed that an inverse association between allergies and cancer was more commonly found among tissues or organ systems that interface with the external environment. This is in accordance with negative associations of allergy with HNC.
Both mean scores and positive rates of JCP-specific IgE in subjects in their 60s showed a similar trend to those in all subjects except those in their 70s. Both the mean score and the positive rate of JCP-specific IgE in those in their 50s or younger with HNC were higher than those in their 60s with HNC. Thus, there were no significant differences in either the mean scores or the positive rates between patients with HNC and those with nABD or with NPC in their 50s or younger. One reason may be a small number of patients with HNC in their 50s or younger (n = 14), which affects the positive rate of JCP-specific IgE. Another reason may be a relatively low positive rate of JCP-specific IgE in patients with nABD in their 50s or younger in the present study compared with the prevalence of Japanese cedar pollinosis, which is nearly 50% in people in their 50s or younger (Japan Society of Immunology, Allergology and Infection in Otorhinolaryngology 2024). This may be due to a small number of subjects with nABD in their 50s or younger (n = 14).
The present exploratory study demonstrated increased JCP-specific IgE in NPC compared with HNC. Infection with EBV is a unique feature of NPC. Therefore, it may weaken the prophylactic effect of allergy or the immunosurveillance ability of allergy as a part of EBV immune evasion mechanisms (Shen et al. 2015). Although brief initial reports demonstrated the lack of an association of NPC with nasal allergy, recent population-based studies suggested a positive association between AR and NPC (Raman 1987; Prepageran et al. 2003; Chung et al. 2014; Lin et al. 2015). On the other hand, we observed a trend toward higher JCP-specific IgE in NPC than nABD, although the difference was not significant. The small sample size of NPC may have led to this discrepancy between our data and previous reports. An association of oropharyngeal cancer (OPC) with human papillomavirus (HPV) is recently well known. Therefore, whether HPV-associated OPC is related to Japanese cedar pollinosis is of a great interest. The present study included only 11 patients with OPC in their 60s or younger; one of 5 patients with HPV-positive OPC and 2 of 6 patients with HPV-negative OPC showed positive JCP-specific IgE. Due to a small number of patients, we did not reach any conclusion, and a larger research is desired to clarify the relationship.
Limitations of this study include its retrospective design, small number of patients, and lack of information about the presence or absence of clinical symptoms and disease duration of AR, as well as smoking status, alcohol consumption, and genetic factors in patients with HNC. First, in order to minimize selection bias, this study evaluated consecutive patients over an established period of time. However, there is still a possibility of selection bias. Second, among patients with HNC excluding those in their 70s or older, the smoking index, which is calculated by multiplying the number of cigarettes per day by the number of years smoked, was 0 in 2 patients, 1-399 in 4 patients, 400-1,199 in 27 patients, and ≥ 1,200 in 17 patients. The positive rates of JCP-specific IgE were not significantly different among the 4 smoking index groups mentioned above according to the chi-square test (p = 0.81). However, we did not have sufficient data on the smoking status in patients with NPC and nABD. Data on alcohol consumption and genetic factors were not available for all subjects. Although symptomatic as well as sensitized asymptomatic patients were included together in this study because blood data at the diagnosis of HNC were analyzed, allergen-specific IgE is generally evaluable as a biological indicator of the allergy history and immune function (Turner 2012). Further investigation is required to clarify the relationship between AR and HNC or NPC. Because the present study and the previously reported studies are observational, it is not possible to establish a causal relationship between JCP-specific IgE levels and the risk of HPC. Further experimental or longitudinal studies are needed to clarify the mechanism of this inverse correlation.
ConclusionThe present exploratory study demonstrated a lower serum JCP-specific IgE level in patients with HNC compared with non-allergic benign disease for the first time. An inverse correlation between HNC and Japanese cedar pollinosis was suggested from the perspective of allergen-specific IgE.
The authors declare no conflict of interest.
