Histological differentiation of primary oral squamous cell carcinomas in an area of betel quid chewing prevalence

Otolaryngology–Head and Neck Surgery (2009) 141, 743-749

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 differentiation 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 follow-up, oral squamous cell carcinomas with poor differentiation had a higher probability of developing neck recurrence (P ⫽ 0.001) and distant metastasis (P ⫽ 0.019), but not local recurrence or a second primary cancer. For survival analysis, univariate analysis showed that patient age, tumor stage, extracapsular 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 carcinoma 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 common cancer of the head and neck, accounting for approximately three percent of all newly diagnosed cancer cases worldwide.1 Despite recent advances in surgical techniques, radiotherapy, and chemotherapy, the long-term survival of patients with OSCC has remained at approximately 50 to 60 percent over the past three decades.2 These unsatisfactory 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 treatment 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 stratification of patients with OSCC might be clinically useful in predicting the biological aggressiveness of OSCC tumors 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 estimating 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 histopathological 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.

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

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topic of current debate.3-7 Some experts have even suggested that most OSCCs are moderately differentiated and that grading based on differentiation is of limited prognostic value.8 Although this idea may be accurate in some regions where moderately differentiated OSCCs are the predominant subtype, in other geographic areas, poorly differentiated OSCCs may predominate.9 Furthermore, it has also been reported recently that the grading of tumor histological differentiation is important for predicting survival of OSCC patients, implying that histological OSCC tumor differentiation might have a pivotal role in directed treatment outcomes under current treatment protocols.5,6 To the best of our knowledge, there are currently no reports addressing the possible association between OSCC histological classifications and other clinicopathological manifestations, such as perineural invasion, extracapsular spread (ECS), and failure patterns after treatment. The aim of this retrospective study was to investigate the outcome of patients with OSCC treated by surgical resection as the primary modality with or without the use of adjuvant treatment and to evaluate whether histological differentiation may provide supplemental prognostic value in addition to the current TNM system. In the current study, the association between OSCC differentiation, patient characteristics, and other clinicopathological manifestations were addressed. In addition, the prognostic value of histological differentiation for predicting locoregional control, distant metastasis, and overall survival was also evaluated.

MATERIALS AND METHODS Patient Characteristics Between December 2003 and June 2007, 150 consecutive patients with OSCC who underwent surgery as the primary modality of therapy at Chang Gung Memorial Hospital (Linko Medical Center, Taoyuan, Taiwan) and subsequent regular follow-up or follow-up until death were included in the study. All patients were followed for at least 18 months or until death. Patients who were lost to follow-up or had at least one of the following conditions were considered ineligible for the study: unresectable or inoperable cancer; other primary cancer (synchronous or metachronous); recurrent cancer; distant metastasis; history of malignancy; treatment with neoadjuvant therapy; medical contraindication for surgery. Lesions diagnosed as carcinoma in situ, verrucous carcinoma, or a histologically basaloid subtype were not included in the study. This study was approved by the hospital institutional review board. Patients in the study underwent standard preoperative workups according to institutional guidelines, including a detailed history, complete physical examination, CT or MRI, chest radiographs, bone scan, and abdominal ultrasonography. The primary tumors were excised with adequate surgical margins and the tumor margin tissues were sent for cryosectioning and examination intraoperatively to ensure that the surgical margins were free of tumor. Various

types of neck dissection were performed according to the primary tumor site and clinical lymph node status.10 After surgical treatment, pathological tumor and nodal staging according to the AJCC Cancer Staging Manual (2002) was used to determine whether adjuvant treatment was indicated.11 Postoperative radiotherapy was performed on patients with pathological T4 tumors and positive lymph nodes within six weeks following surgery. Patients with pathological multiple neck lymph nodes metastasis and/or ECS and/or positive surgical margins received adjuvant concurrent chemoradiotherapy. In this series, two patients had positive surgical margins in the permanent pathological reports of resected primary OSCC tumors. The chemotherapy was a cisplatin-based regimen and the total radiation dose was 66 Gy. The prescribed dose was delivered 1.8 to 2 Gy per day for five days per week. All patients attained regular follow-up visits every two months for the first year after discharge, every three months for the second year, and every six months thereafter.

Histopathology The histological differentiations were determined on the basis of the original pathology reports examined by multiple pathologists at this single institute. For each patient, we recorded the following data: age at presentation, sex, anatomical subsite of the oral cavity, and permanent pathological findings of tumor differentiation (well, moderately, or poorly differentiated OSCC), bone invasion, perineural invasion, tumor depth, tumor status (T), pathological lymph node status (N), overall stage, and ECS status. TNM staging was performed according to the AJCC 2002 guidelines.11 The tumors were graded into well, moderately, and poorly differentiated OSCC according to established criteria.8 Well-differentiated OSCC closely resembles normal squamous epithelium. Moderately differentiated OSCC contains heightened mitotic activity, including abnormal mitoses and distinct nuclear pleomorphism, and there is usually less keratinization. In poorly differentiated OSCC, immature cells predominate, with numerous typical and atypical mitoses and minimal keratinization.8 When mixed histological features were encountered, the predominant features were used for classification. If tumors had balanced histological features between two groups, the highest applicable grade was assigned to the tumor.

Data and Statistical Analysis Patient characteristics and OSCC tumor characteristics were stratified according to various clinicopathological factors and evaluated with the ␹2 test, Fisher exact test, Student t test, Wilcoxon test, or Kruskal-Wallis test, where appropriate. The factors evaluated included sex, age, alcohol consumption, betel quid chewing, tobacco smoking, TNM staging, and other pathological findings. All statistical analyses were performed with SPSS Inc (Chicago, IL) or SAS Insti-

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Histological differentiation of primary oral squamous . . .

tute (Cary, NC) software. The time to death by any cause from the date of surgical removal of the primary tumor was calculated for each patient. All patients received follow-up consultations at our outpatient clinic until March 2009 or until death. Risk factors were defined and adjusted hazards ratios for overall survival (OS) were estimated by means of univariate and multivariate regression analyses and a Cox proportional hazards model. All P values were two-sided with the significance level set at P ⬍ 0.05.

RESULTS Patient age at diagnosis for the entire cohort of 150 patients with OSCC ranged from 21.9 to 85.0 years (median 50.9 yrs). There were 141 males and nine females. The associated subsites and number of involved patients were buccal mucosa (58), gum (21), hard palate (5), lip (5), floor of the mouth (6), and tongue (55). Well, moderately, and poorly differentiated OSCCs were reported for 54 (36%), 84 (56%), and 12 (8%) patients, respectively. The prevalence of tobacco smoking, alcohol consumption, and betel quid chewing was 53.3, 84.7, and 84.7 percent, respectively. There were no significant differences between different histological differentiation groups and sex (P ⫽ 0.263), age (P ⫽ 0.712), alcohol consumption (P ⫽ 0.576), betel quid chewing (P ⫽ 0.623), and smoking (P ⫽ 0.147). Patient

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characteristics for the different histological differentiation groups are listed in Table 1. Table 2 shows clinicopathological characteristics of three different histologically differentiated groups. Significant associations were noted between histological differentiation and nodal metastasis (P ⬍ 0.0001), ECS (P ⫽ 0.002), and perineural invasion (P ⬍ 0.0001). These associations indicated that more poorly differentiated OSCCs tended to result in cervical metastasis, ECS, and perineural invasion. There were no significant differences between the three histological differentiation groups in T stage (P ⫽ 0.918), overall stage (P ⫽ 0.067), bone invasion (P ⫽ 0.438), and depth of invasion (P ⫽ 0.926). In the analysis of adverse events affecting survival during follow-up, including local recurrence, neck recurrence, second primary cancer of the upper aerodigestive tract, and distant metastasis, we found that the more poorly differentiated OSCCs were more likely to result in neck recurrence (P ⫽ 0.001) and distant metastasis (P ⫽ 0.019). Overall, 15 of the 150 patients had neck recurrence, including no patients (0%) in the well-differentiated histology group, 11 patients (13.1%) in the moderately differentiated group, and four patients (33.3%) in the poorly differentiated group. Distant metastasis developed in 15 of the 150 patients, including one (1.9%) patient in the well-differentiated group, 11 (13.1%) patients in the moderately differentiated group, and three (25.0%) patients in the poorly differentiated group. However, there was no difference in the length

Table 1 Patient characteristics correlated with the three different histological classifications of oral squamous cell carcinomas

Sex Female Male Age, yrs Range Mean ⫾ SD Subsites Buccal Gum Hard palate Lip Mouth floor Tongue Alcohol consumption Yes No Betel nut chewing Yes No Smoking Yes No Total

Well differentiated, n (%)

Moderately differentiated, n (%)

Poorly differentiated, n (%)

3 (5.6) 51 (94.4)

4 (4.8) 80 (95.2)

2 (16.7) 10 (83.3)

33.1-82.5 52.54 ⫾ 13.07

21.9-85.0 52.41 ⫾ 12.61

29.5-70.9 49.31 ⫾ 12.00

P value 0.263 0.712

19 9 2 4 3 17

(35.2) (16.6) (3.7) (7.4) (5.6) (31.5)

33 11 2 1 2 35

(39.3) (13.1) (2.4) (1.2) (2.4) (41.6)

6 1 1 0 1 3

(50.0) (8.3) (8.3) (0) (8.3) (25.0)

27 (50.0) 27 (50.0)

45 (53.6) 39 (46.4)

8 (66.7) 4 (33.3)

0.576

46 (85.2) 8 (14.8)

72 (85.7) 12 (14.3)

9 (75.0) 3 (25.0)

0.623

45 (83.3) 9 (16.7) 54

74 (88.1) 10 (11.9) 84

8 (66.7) 4 (33.3) 12

0.147

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Table 2 Tumor pathological factors correlated with the three different histological classifications of oral squamous cell carcinomas

T stage T1, T2 T3, T4 N stage N (⫺) N (⫹) Overall stage I, II III, IV Extracapsular spread Negative Positive Perineural invasion Negative Positive Bone invasion Negative Positive Depth of invasion, mean ⫾ SD (mm) Total

Well differentiated, n (%)

Moderately differentiated, n (%)

Poorly differentiated, n (%)

28 (51.9) 26 (48.1)

45 (53.6) 39 (46.4)

7 (58.3) 5 (41.7)

47 (87.0) 7 (13.0)

44 (52.4) 40 (47.6)

4 (33.3) 8 (66.7)

27 (50.0) 27 (50.0)

27 (32.1) 57 (67.9)

3 (25.0) 9 (75.0)

51 (94.4) 3 (5.6)

64 (76.2) 20 (23.8)

7 (58.3) 5 (41.7)

49 (90.7) 5 (9.3)

58 (69.0) 26 (31.0)

3 (25.0) 9 (75.0)

44 (81.5) 10 (18.5) 9.85 ⫾ 10.26 54

69 (82.1) 15 (17.9) 10.42 ⫾ 6.98 84

8 (66.7) 4 (33.3) 10.33 ⫾ 7.41 12

P value 0.918 ⬍0.0001* 0.067 0.002* ⬍0.0001* 0.438 0.926

N (–), no cervical metastasis; N (⫹), positive cervical metastasis. *Statistically significant.

of period from treatment to neck recurrence and distant metastasis in the same comparison among the three differentiation groups. Local recurrence (P ⫽ 0.753) and second

primary cancer (P ⫽ 0.936) also were not significantly different among the three different differentiation groups (Table 3).

Table 3 Correlation between oral squamous cell carcinoma histological classifications and adverse events impacting survival during follow-up

Local recurrence Yes No Time to local recurrence Neck recurrence Yes No Time to neck recurrence Second primary cancer Yes No Time to second cancer Distant metastasis Yes No Time to distant metastasis Total *Kruskal-Wallis test. †Statistically significant. ‡Wilcoxon test.

Well differentiated, n (%)

Moderately differentiated, n (%)

Poorly differentiated, n (%)

5 (9.3) 49 (90.7) 14.19 ⫾ 10.06

9 (10.7) 75 (89.3) 10.97 ⫾ 8.15

2 (16.7) 10 (83.3) 8.04 ⫾ 2.35

0 (0) 54 (100)

11 (13.1) 73 (86.9) 7.81 ⫾ 3.84

4 (33.3) 8 (66.7) 6.41 ⫾ 3.48

6 (11.1) 48 (88.9) 28.61 ⫾ 15.55

8 (9.5) 76 (90.5) 14.97 ⫾ 14.73

1 (8.3) 11 (91.7) 18.77

1 (1.9) 53 (98.1) 31.13 54

11 (13.1) 73 (86.9) 8.37 ⫾ 6.93 84

3 (25.0) 9 (75.0) 9.26 ⫾ 4.62 12

P value

0.753 0.812* 0.001† 0.571‡ 0.936 0.107‡ 0.019† 0.692‡

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Histological differentiation of primary oral squamous . . .

In the survival analysis for OS, we conducted univariate and multivariate analyses with a Cox proportional regression model incorporating various prognostic factors, including age, sex, T stage, N status, cell differentiation, perineural invasion, and bone invasion. Univariate analysis showed that patient age (⬎51 yrs, median age, P ⫽ 0.040), T stage (T3-T4 vs T1-T2, P ⫽ 0.014), N status (ECS (⫹) vs N0, P ⬍ 0.0001), perineural invasion (P ⬍ 0.0001), and differentiation (moderate vs well, P ⫽ 0.034; poor vs well, P ⬍ 0.0001) were significant factors determining OS, whereas sex and the presence of bone invasion were not significant (P ⫽ 0.356 and P ⫽ 0.282, respectively). In the multivariate analysis adjusted by the various factors mentioned above, age (P ⫽ 0.002), T stage (T3-T4 vs T1-T2, P ⫽ 0.033), N status (ECS [⫹] vs N0, P ⫽ 0.001), and differentiation (poor vs well, P ⫽ 0.008) were still statistically significant factors for OS (Table 4). These results demonstrate that along with advanced age, advanced T stage, and the presence of ECS, the poorly differentiated tumor cell type was also an independent prognostic factor for OS.

DISCUSSION The value of tumor histological differentiation in OSCC prognosis has remained undetermined in the current clinical literature. In the present study, we demonstrate a strong association between histological differentiation and OS by multivariate analysis. Huang et al5 demonstrated that the histological grading of OSCC exclusively from the buccal

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mucosa (well vs moderately ⫹ poorly differentiated OSCCs) was the most important independent prognostic factor affecting survival rate. Likewise, some authors also reported that the grading of cell differentiation was helpful in predicting survival in patients with OSCC. However, Bundgaard et al3 and Brandwein-Gensler et al4 argued that overall histological grading was determined by many factors and the pooling of statistically significant parameters yielded an overall prognostic conclusion that blurred the weight of individually significant parameters in survival analysis. Other investigators7,12,13 have reported a lack of correlation between primary OSCC histological classification and patient prognosis. One possibility of these diverse conclusions may stem from the fact that the composition of the three cell differentiation categories of OSCC tumors differs between individual geographic areas, with the predominant type of differentiation localized to particular regions.8,9 Carcinogen exposure also varies between individual geographic areas. Previous epidemiological studies have shown that OSCC is highly prevalent in areas in which betel quid is chewed, including India and Taiwan, compared with the relatively low incidences in Western countries.14 Also, betel quid chewing may affect the common tumor sites of OSCC tumors. Cancers of tongue and buccal mucosa constitute the majority of OSCCs in India and Taiwan, but the Western registries show cancers of the mouth floor are the most frequent.14 In areas in which there is no betel quid chewing, most OSCCs are categorized as moderately differentiated, resulting in no prognostic difference with respect to histological differentiation. However, in this area of betel quid

Table 4 Cox proportional hazard models for overall survival

Age (yrs)* ⬎51 vs ⱕ51 Sex Male vs female T stage T3, T4 vs T1, T2 N status N (⫹) ECS (–) vs N (–) ECS (⫹) vs N (–) Differentiation Moderate vs well Poor vs well Perineural invasion Yes vs no Bone invasion Yes vs no

Univariate crude HR (95% CI)

P value

Multivariate adjusted HR (95% CI)

P value

1.992 (1.030-3.852)

0.040†

3.224 (1.524-6.821)

0.002†

2.547 (0.349-18.564)

0.356

3.230 (0.424-24.610)

0.257

2.279 (1.178-4.407)

0.014†

2.470 (1.072-5.693)

0.033†

2.354 (0.946-5.853) 5.996 (2.864-12.553)

0.065 ⬍0.0001†

1.988 (0.766-5.160) 4.223 (1.740-10.251)

0.158 0.001†

2.648 (1.072-6.539) 7.934 (2.735-23.018)

0.034† ⬍0.0001†

1.770 (0.668-4.690) 5.592 (1.551-20.163)

0.251 0.008†

3.633 (1.883-7.010)

⬍0.0001†

1.353 (0.612-2.993)

0.455

1.513 (0.711-3.220)

0.282

0.992 (0.411-2.391)

0.985

HR, hazard ratio; CI, confidence interval; N (⫺), no cervical metastasis; N (⫹) ECS (⫺), positive cervical metastasis without extracapsular spread; ECS (⫹), positive cervical metastasis with extracapsular spread. *Median age. †Statistically significant.

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chewing prevalence, well and poorly differentiated SCCs account for nearly half of all OSCC tumors according to the results of the current study and another previous study,15 implying the potential to use histological differentiation as a prognostic factor. A recent study derived from an animal model demonstrated that the betel quid component could induce proliferation and differentiation of oral epithelial cell.16 Betel quid exposure was also shown to alter the differentiation of normal keratinocytes in vitro and to play a critical role when associated with poorly differentiated and more invasive OSCCs in vivo.17 Nonetheless, because no association could be found between betel quid chewing and cell differentiation in the current study, the influence of betel quid chewing on OSCC differentiation in this patient cohort remains to be elucidated. In the current study, no association was found between OSCC differentiation and many clinocopathological manifestations, including age, sex, tumor site, alcohol consumption, betel quid chewing, tobacco consumption, T stage, overall stage, bone invasion, and depth of tumor invasion. However, cervical metastasis, ECS, and perineural invasion were significantly associated with poorer OSCC differentiation. Only two previous reports addressed the possible association of OSCC differentiation with cervical metastasis. Kademani et al6 reported that tumors with higher histological grades (poorer differentiation) were more likely to present with cervical metastasis at diagnosis. Likewise, Huang et al5 demonstrated that, compared with well-differentiated OSCCs, moderate/poor differentiation of buccal mucosa OSCCs tended to present with positive nodal disease. Similarly, we also found in the present patient cohort that more poorly differentiated OSCCs had a higher probability of presenting with cervical metastasis. Furthermore, to the best of our knowledge, the current study also provides the first evidence indicating strong associations between OSCC tumor histological differentiation and the presence of ECS and perineural invasion. Thus, more poorly differentiated OSCCs had higher probabilities of developing cervical metastases, ECS, and perineural invasion of the primary tumors. Cervical metastasis, especially when presenting with ECS and perineural invasion of the primary OSCC, have been frequently shown to be prominent negative indicators for head and neck cancer patient prognosis.18-22 We further analyzed the occurrence of adverse events during follow-up after standardized treatment among the three histological classifications. Local recurrence and a second primary cancer were not significantly different among the three differentiation classifications. However, the probability of developing neck recurrence and the distant metastasis rate were higher with poorer differentiated OSCCs. Interestingly, neck recurrence and distant metastasis after treatment were extremely rare in the well-differentiated OSCCs. Only one (1.9%) patient and no (0%) patients developed neck recurrence and distant metastasis, respectively, after treatment in our series. This finding is consistent with a recent study demonstrating that tumor his-

tological grade emerged as the only prognostic factor of significance for locoregional recurrence of SCC of the buccal mucosa.23 Therefore, in addition to establishing that poorer OSCC differentiation increases the probability of developing cervical metastases, ECS, and perineural invasion of the primary tumor, we also demonstrated that more poorly differentiated OSCCs tended to result in neck recurrence and distant metastasis during follow-up after the standardized treatment protocol. Collectively, these novel findings explain why poorly differentiated OSCCs are associated with a poorer prognosis for OS. Conventionally, age, T stage, N stage, ECS, and perineural invasion have well been shown to be important prognostic factors for the OS of patients with OSCC.19,20 In our series, we also found that patient age, T stage, nodal status, poorer histological classifications, and perineural invasion of the primary tumor were prognostic indicators for OSCC by univariate analysis. Advanced age, higher T stage (T3-T4 vs T1-T2), ECS, and poorer histological classification (poorly vs well-differentiated OSCC) were also shown to be statistically significant by multivariate analysis, revealing the independent prognostic value of these individual factors. Thus, more radical surgery for primary cancers and neck management, followed by more intensive adjuvant treatments and follow-up schemes, might be needed for patients with poorly differentiated OSCC. Tumor histological classifications may be used to facilitate the selection of appropriate management and follow-up schemes for patients with OSCC.

CONCLUSIONS To our knowledge, the current study provides the first evidence showing that poorer tumor histological classifications are significantly associated with positive nodal status, ECS, and perineural invasion of primary tumors in patients with OSCC. Furthermore, the probability of developing neck recurrence and distant metastasis following treatment is significantly higher in the two poorer histological classifications, but extremely rare in association with well-differentiated OSCCs. Finally, in the analysis of OS, we found that, in addition to advanced age, higher T stage, and N status (ECS), tumor histological classification was also an independent prognostic indicator in a multivariate analysis. On the basis of these results, medical professionals should consider tumor histological classifications for selection of the most appropriate patient management strategies, such as extent of surgery, adjuvant therapy, and follow-up schemes, for patients with primary OSCC.

AUTHOR INFORMATION From the Departments of Otolaryngology–Head and Neck Surgery (Drs Fang, Hao, and K. P. Chang), Plastic and Reconstructive Surgery (Drs Kao and Cheng), Oral and Maxillofacial Surgery (Drs Y. L. Chang and Huang),

Fang et al

Histological differentiation of primary oral squamous . . .

Radiation Oncology (Dr Tsang), and Pathology (Dr Lee), Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan; and the Graduate Institute of Biomedical Sciences (Dr Yu), Chang Gung University, Taoyuan, Taiwan. Corresponding author: Kai-Ping Chang, MD, PhD, Department of Otolaryngology–Head and Neck Surgery, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 5 Fu-Shin Street, KweiShan, Taoyuan, Taiwan. E-mail address: [email protected].

AUTHOR CONTRIBUTIONS Ku-Hao Fang, data collection, draft preparation; Huang-Kai Kao, data analysis and interpretation; Ming-Hui Cheng, data analysis and interpretation; Yu-Liang Chang, data analysis and interpretation; Ngan-Ming Tsang, data analysis and interpretation; Yu-Chen Huang, data analysis and interpretation; Li-Yu Lee, data analysis and interpretation; Jau-Song Yu, data analysis and interpretation; Sheng-Po Hao, data analysis and interpretation; Kai-Ping Chang, article modification, manuscript editing.

DISCLOSURES Competing interests: None. Sponsorships: None.

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