Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in Southeast Asia with reported incidence rate ranging from 10 to 53 cases per 100,000 persons per year [
1]. Although it is a relatively uncommon cancer in western countries with an incidence rate of less than 1 case per 100,000, it poses a significant health problem in regions of the US where there is large population of Asians. External beam radiation therapy is considered the primary mode of treatment for previously untreated NPC. This is mainly due to the high degree of sensitivity of this tumor to radiation as well as the anatomic constraints for surgical access in this highly complex region. Despite advances in diagnostic and treatment modalities, loco-regional failure is still significant with reported rates of 15.6% to 58% [
1,
2]. The addition of chemotherapy concurrent with radiation has been shown to improve survival in patients with NPC [
3].
Although the molecular events responsible for the pathogenesis of NPC remain to be elucidated, the final common pathway appears to be a disruption of the mechanisms involved in the regulation of cell cycle progression, leading to uncontrolled cell proliferation. The most critical point in cell cycle regulation is the G
1 checkpoint. It is here that complex interactions take place to determine whether the cell will exit the cell cycle and go into a quiescent state (G
0) or enter into the S phase and proceed with cell division [
4]. These complex interactions involve a large number of regulatory proteins such as cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors. Among the cyclins involved in G1 phase, cyclin D1 appears to be most strongly implicated in human carcinogenesis. Cyclin D1, through its interaction with cyclin-dependent kinase-4 or 6 (CDK-4/6), forms a complex that inactivates the tumor suppressor protein retinoblastoma (pRb) through phosphorylation [
4]. Phosphorylation of pRb releases transcription factors such as E2Fs which then activate a series of events that allow entry into S-phase and cell division [
4]. An increased level of cyclin D1 expression has been reported in a number of malignancies [
5] including esophageal, ovarian, breast, uterine, colon, lung, prostate, lymphoma, as well as head and neck cancers. Between 30% to 83% of head and neck squamous cell carcinoma (HNSCC) were reported to be associated with cyclin D1 over-expression [
6,
7]. The progression of cells from G1 to S phase, on the other hand, is blocked by a potent tumor suppressor protein, p16, which acts to disrupt the cyclin D1/CDK-4/6 complex. Deletions, mutations, or methylation of the p16 gene has been implicated in the development of a variety of human malignancies, including head and neck cancer [
6,
8].
The disruption of the "Retinoblastoma/cyclin D1/p16 pathway" involved in the regulation of the G1 checkpoint also appears to play an important role in the tumorigenesis of NPC. Over-expression of cyclin D1 and/or loss of p16 has been reported in several studies on NPC. These studies found an increased level of cyclin D1 expression in 30% [
7] to 66% [
9] and the lack of expression of p16 in 40% to 70% of previously untreated NPC specimens [
9‐
12].
Although a large body of data exists on cyclin D1 and p16 expressions in HNSCC including NPC, to the best our knowledge, no previous studies have been reported on the expression level of these proteins in recurrent HNSCC. We set out in this study to examine the expression level of cyclin D1 and p16 in recurrent NPC that have failed previous treatment with radiation +/- chemotherapy.