ORIGINAL RESEARCH–HEAD AND NECK SURGERY Histological differentiation of primary oral squamous cell carcinomas in an area of betel quid chewing prevalence Ku-Hao Fang, MD, Huang-Kai Kao, MD, Ming-Hui Cheng, MD, MHA, Yu-Liang Chang, DDS, PhD, Ngan-Ming Tsang, MD, DSc, Yu-Chen Huang, DDS, Li-Yu Lee, MD, Jau-Song Yu, PhD, Sheng-Po Hao, MD, and Kai-Ping Chang, MD, PhD, Taoyuan, Taiwan No sponsorships or competing interests have been disclosed for this article. ABSTRACT OBJECTIVES: This study evaluated associations between the histological differentiation of oral squamous cell carcinoma and additional clinicopathological manifestations, adverse events after treatment, and the outcomes of patients in a region prevalent for betel quid chewing. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: A total of 150 patients with primary oral squamous cell carcinomas who underwent surgery with or without adjuvant therapy were enrolled. RESULTS: Well, moderate, and poorly differentiated oral squamous cell carcinomas were reported in 54 (36%), 84 (56%), and 12 (8%) patients, respectively. There were no significant differences among different histological differentiations in age, sex, tumor, node, metastasis stage, bone invasion, depth of invasion, and history of carcinogen exposure. However, we found significant associations between tumor histological dif- ferentiation and nodal metastasis (P  0.0001), extracapsular spread (P = 0.002), and perineural invasion (P  0.0001). In the analysis of adverse events for survival during patient fol- low-up, oral squamous cell carcinomas with poor differentia- tion had a higher probability of developing neck recurrence (P = 0.001) and distant metastasis (P = 0.019), but not local recur- rence or a second primary cancer. For survival analysis, uni- variate analysis showed that patient age, tumor stage, extracap- sular spread, presence of perineural invasion, and tumor differentiation were significant factors. Multivariate analysis further demonstrated that poor differentiation (P = 0.007) was still a statistically significant factor. CONCLUSION: The current study demonstrates that poorer tumor histological classifications of oral squamous cell carci- noma are significantly associated with positive nodal status, extracapsular spread, perineural invasion of primary tumors, and the probability of developing neck recurrence and distant metastasis after treatment. © 2009 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. O ral squamous cell carcinoma (OSCC) is the most com- mon cancer of the head and neck, accounting for approximately three percent of all newly diagnosed cancer cases worldwide. 1 Despite recent advances in surgical tech- niques, radiotherapy, and chemotherapy, the long-term sur- vival of patients with OSCC has remained at approximately 50 to 60 percent over the past three decades. 2 These unsat- isfactory treatment results may be explained by the fact that OSCCs frequently present with extensive local invasion and a high probability of cervical lymph node metastasis. These unfavorable facts highlight the need for continuous efforts by medical professionals to improve patient treat- ment modalities and protocols. In particular, the high probability of locoregional recurrence constitutes one of the major therapeutic problems in current management. Thus, identification of prognostic markers for risk strat- ification of patients with OSCC might be clinically useful in predicting the biological aggressiveness of OSCC tu- mors and in enabling the design of tailored therapies and strategies for OSCC treatment. Although the tumor, node, metastasis (TNM) staging system set by the American Joint Committee on Cancer (AJCC) typically provides a well-recognized basis for esti- mating patient prognosis and therapeutic planning, it cannot be used to predict OSCC tumor biology. 3 In other words, a small fraction of patients characterized as having early stage OSCC may actually have aggressive disease as evidenced by unfavorable histopathological features, or vice versa. 3 To more accurately predict treatment outcomes, investigators have developed and refined multiple parameters of his- topathological assessments over recent decades, including definition of histological differentiation. 3-7 However, the prognostic value of histological tumor differentiation is a Received June 23, 2009; revised August 18, 2009; accepted September 18, 2009. Otolaryngology–Head and Neck Surgery (2009) 141, 743-749 0194-5998/$36.00 © 2009 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2009.09.012