Nasopharyngeal carcinoma and nasal allergy: any correlation? (Original Article).

Abstract

Although it has been observed that nasal allergy is rarely seen in patients who have nasopharyngeal carcinoma, to our knowledge, no actual study of such a lack of association has been previously reported. To fill this void, we conducted a pilot study to investigate any such inverse relationship. We conducted skin-prick allergen tests on 22 patients with newly diagnosed but not-yet-treated nasopharyngeal carcinoma. Combining these test results with findings on the history and clinical examination, we concluded that only one of the 22 cancer patients (4.5%) had allergic rhinitis. Our study also confirmed the validity of using findings on the history, clinical examination, and skin-prick testing as a reliable means of diagnosing allergic rhinitis.

Introduction

It has been observed that nasal allergy is rarely seen in patients who have nasopharyngeal carcinoma.' However, this observation has never been proved, and to the best of our knowledge, no previous study has been conducted to confirm or refute such a relationship. In an attempt to fill this void, we conducted a pilot study to investigate the incidence of nasal allergy among patients with nasopharyngeal carcinoma. We also studied the reliability of findings on the history, clinical examination, and skin-prick allergen testing as diagnostic criteria for allergic rhinitis.

Patients and methods

Our study was conducted at the University Malaya Medical Center in Kuala Lumpur, Malaysia. We performed the study in two stages. First, we attempted to verify the reliability of using the history, the clinical examination, and the skin-prick allergen test as a definitive method of diagnosing allergic rhinitis; two groups of subjects were recruited for this purpose (the positive control group and the negative control group). Once we validated the reliability of this method, we used these diagnostic criteria to determine the prevalence of allergic rhinitis in patients with newly diagnosed but not-yet-treated nasopharyngeal carcinoma (the carcinoma group).

Positive control group. The positive control group was made up of 22 subjects--17 men and five women, aged 25 to 68 years (mean: 45.0)-who were known to have nasal allergy. They had been selected from the case load at our otolaryngology outpatient clinic. These subjects all had the typical history and clinical findings associated with allergic rhinitis, especially during exposure to dust. At the time of their skin-prick test, no patient had taken an antihistamine during the previous 7 days.

Negative control group. The negative control group was made up of 22 healthy subjects--17 men and five women, aged 24 to 65 years (mean: 43.0)--who did not have any nasal allergy. This group was assembled from patients and hospital staff members in an effort to create a group that resembled a normal population. The members of both control groups were carefully selected to ensure that they were age-and sex-matched with the patients in the carcinoma group.

Carcinoma group. The carcinoma group was made up of 22 patients--17 men and five women, aged 25 to 67 years (mean: 43.5)--who had been newly diagnosed with nasopharyngeal carcinoma. The carcinoma group included 19 Chinese (15 men and four women) and three Malays (two men and one woman).

The patients in the carcinoma group had had their diagnosis confirmed by histology, but they had not yet undergone any treatment for their carcinoma. For this study, they were interviewed by questionnaire, and they were asked about any personal history or symptoms of food or environmental allergy and any family history of allergy. They also underwent a clinical examination to identify any evidence of allergy, with special emphasis on the nasal examination.

Skin-prick testing of the two control groups was carried out in the otolaryngology outpatient clinic or in the otolaryngology ward of the hospital, where resuscitation equipment was available. Patients in the carcinoma group underwent skin-prick testing at our center's Department of Immunology.

During all skin-prick tests, 15 allergens and three control solutions were used (table). The allergens included foodstuffs, aeroallergens, and animal and insect components that commonly provoke allergic reactions in Malaysia. Two concentrations of histamine (1 mg/ml and 10 mg/ ml) were used as positive controls, and phosphate-buffered saline (PBS), the carrier substance in diluting the allergens, was used as the negative control. The PBS was prepared so that it resembled the concentration and pH level of serum in the body. In order to avoid any investigator error, a single researcher (N.P.) conducted all skin-prick tests.

Skin-prick tests were conducted by making 18 pricks on the forearm; each site was numbered to correspond to a particular antigen or control. A 6-[micro]l drop of each antigen solution was applied to the forearm with a pipette. A sterile lancet or 25-gauge needle was used to puncture the skin through the solution. Lancets and needles were cleaned with PBS solution after each prick. Excess allergen was removed from the skin with an absorbent paper tissue. Reactions were evaluated after 15 minutes.

The results of the skin-prick tests were interpreted in conjunction with each patient's history and clinical findings. When the history and the skin test were positive, a diagnosis of allergy was confirmed. When they were negative, allergy was excluded. A skin test was considered to be positive if the allergen produced an induration either larger than 3 mm or larger than the reaction produced by the positive control. If the negative control caused a reaction, the results of that particular test were considered to be unreliable.

Results

In the positive control group, all 22 patients had a positive skin test (figure). In the negative control group, positive skin-prick tests were seen in three of the 22 patients (13.6%) (figure). Upon further questioning, one of these patients admitted to having experienced occasional rhinitis and sneezing during spring cleaning, but these symptoms had not caused him any inconvenience and he had not considered them bothersome enough to report. Another negative control who tested positive on skin-prick testing said that he had experienced allergic manifestations (e.g., sneezing) during childhood, but he had been symptom-free ever since. In all, we considered our findings conclusive enough to validate our diagnostic criteria.

In the carcinoma group, only one of the 22 patients (4.5%), a Malay man, had a positive skin test (figure). Although the results of his clinical examination were normal, he did provide a typical history of vasomotor rhinitis-that is, nasal congestion during exposure to cold air. No other patient in the carcinoma group had a personal or family history of nasal symptoms or allergy.

Discussion

The diagnosis of nasal allergy based only on the history and clinical findings can be difficult. The addition of skin-prick testing, however, has helped make the diagnosis more reliable. (2) Our first goal was to test this reliability by using the two control groups, and we succeeded. All 22 patients who had a history and clinical evidence of allergic rhinitis had a positive skin-prick test. Conversely, 19 of the 22 patients in our negative control group (86.4%) had a negative skin-prick test, and two of the three whose tests were positive actually had experienced some degree of allergic symptoms in the past. Therefore, we concluded that the combination of the history, clinical examination, and a skin-prick test is a reliable indicator of the presence or absence of nasal allergy.

Having established the validity of our diagnostic criteria, We set about to confirm or rule out the presence of allergic rhinitis in the 22 patients who had been newly diagnosed with nasopharyngeal carcinoma. Using these criteria, we found that only one of these patients (4.5%) had allergic rhinitis. Although his clinical findings did not correspond to his history and skin test results, we concluded that the latter two criteria represented a positive result. It is possible that this patient had intrinsic rhinitis and that his allergy was not associated with his nasal symptoms. Therefore, we conclude that there appears to be an inverse relationship between nasopharyngeal carcinoma and nasal allergy.

The role of immunology in oncology research is well known. Cytotoxic T cells and natural killer T cells form part of the highly efficient defense mechanism that keeps the occasional ectopic malignant cell in check. T-lymphocyte dysregulation has been found to play a major role in airway allergy. (3) Recent evidence suggests that T-lymphocyte activation, the recruitment of [T.sub.H]2 cells ,and the generation of [T.sub.H]2 cytokines (particularly interleukins 4 and 5) lead to local tissue eosinophilia and IgE mast-cell activation. (4) This allergen-induced T-cell activation is more marked in the nose than in other parts of the airway. (5) It has been established that T cells, their subsets (particularly [T.sub.H]2), and their cytokines play a major role in allergy. (6-8)

Our findings lead us to ask several questions:

* Could there be a correlation between T-cell production in allergy and the low incidence of allergy in nasopharyngeal carcinoma? The possibility that the number of cytotoxic T cells and other T-cell subunits increases in patients with allergy warrants further study. Documentation has already been established that cell-mediated immunity is depressed in patients with nasopharyngeal carcinoma. (9)

* Is it possible that patients with allergy experience cross-reactivity and an increase in cytotoxic T cells during the activation of T lymphocytes that leads to an increase in cell-mediated immunity?

* Is it possible that the humoral immunity involved in allergy affects the cell-mediated immunity that regulates neoplastic proliferations (e.g., natural killer cells or cytotoxic cells)?

* Or is it possible that an increase in nasal discharge and rhinitis results in less contact between carcinogens and Rosenmuller's fossa in patients with allergic rhinitis?

The answers to these questions lie beyond the scope of our study and need to be addressed in further research.

Figure. Bars indicate the number and percentage of positive and negative
skin-prick tests in the three groups.

                                 Positive result  Negative result

Positive control group (n = 22)     22 (100%)            0
Negative control group (n = 22)      3 (13.6%)          19 (86.4%)
Carcinoma group (n = 22)             1 (4.5%)           21 (95.5%)

Note: Table made from bar graph

Table. Allergens used in skin-prick testing

Histamine, 1 mg/ml (positive control)
Histamine, 10 mg/ml(positive control)
Phosphate-buffered saline (negative control)
Acacia
Aspergillus (Aspergillus flavus)
Cat hair
Cockroach
Crab
Epithelial mix
Grass mix
House dust
House dust mites (Blomia tropicalis)
House dust mites (Dermatophagoides farinae)
House dust mites (Dermatophagoides pteronyssinus)
Mold mix
Oyster
Soybean
Shrimp

Acknowledgment

The authors acknowledge the late Dr. K.N. Subramaniam, associate professor of otolaryngology, for his contributions to this article.

References

(1.) Raman R. Nasopharyngeal carcinoma and nasal allergy [letter]. Arch Otolaryngol Head Neck Surg 1987;113:438.

(2.) Bernstein JA. Allergic rhinitis. Helping patients lead an unrestricted life. Postgrad Med 1993;93(6):124-8, 131-2.

(3.) Kline JN, Hunninghake GW. T-lymphocyte dysregulation in asthma. Proc Soc Exp Bid Med 1994;207:243-53.

(4.) Durham SR, Till SJ, Corrigan CJ. T lymphocytes in asthma: Bronchial versus peripheral responses. J Allergy Clin Immunol 2000;106(Suppl):S221-6.

(5.) Rowe-Jones JM. The link between the nose and lung. Perennial rhinitis and asthma-is it the same disease? Allergy 1997;52(Suppl):20-8.

(6.) Ricci M, Matucci A, Rossi O. T cells, cytokines, IgE and allergic airways inflammation. J Investig Allergol Clin Immunol 1994;4:214-20.

(7.) Karlsson MG, Hellquist HB. Phenotype switch and activation of T lymphocytes in patients with allergic rhinitis. ORL J Otorhinolaryngol Relat Spec 1994;56:166-72.

(8.) Howarth PH, Salagean M, Dokic D. Allergic rhinitis: Not purely a histamine-related disease. Allergy 2000;55(Suppl 64):7-16.

(9.) Wara WM, Wara DW, Phillips TL, Ammann AJ. Elevated IgA in carcinoma of the nasopharynx. Cancer 1975;35:1313-15.

From the Department of Otolaryngology, University of Malaya Medical Center, Kuala Lumpur, Malaysia.

Reprint requests: N. Prepageran, Department of Otolaryngology, University of Malaya Medical Center, 50603 Kuala Lumpur, Malaysia. Phone: [phone]; fax: [phone]; e-mail: [e-mail]