Cervical metastases from squamous cell carcinoma of hard palate and maxillary alveolus: A retrospective study of 10 years

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1 ORIGINAL ARTICLE Cervical metastases from squamous cell carcinoma of hard palate and maxillary alveolus: A retrospective study of 10 years Zinan Yang, MDS, MM, 1,2 Runzhi Deng, MDS, MM, 1 Guowen Sun, DDS, MD, PhD, 1 Xiaofeng Huang, MDS, PhD, 1 Enyi Tang, MDS, MM 1 * 1 Department of Oral and Maxillofacial Surgery, Stomatological Hospital Affiliated Medical School, Nanjing University, Nanjing, Jiangsu province, People s Republic of China, 2 Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangzhou Medical University, Guangzhou, Guangdong province, People s Republic of China. Accepted 23 May 2013 Published online 18 September 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to investigate the incidence of cervical metastasis in squamous cell carcinoma (SCC) of hard palate and maxillary alveolus and to define its impact factors. Methods. We conducted a retrospective study of patients surgically treated for SCC of hard palate and maxillary alveolus from 2002 to In situ hybridization was performed to detect high-risk human papillomavirus (HPV) infection. Results. The incidences of cervical metastasis and occult metastasis were 17.2% (11/64) and 9.8% (5/51), respectively. The pt classification and vascular invasion were correlated with cervical metastasis. Occult metastatic risk was significantly higher among patients with pt4. Presence of positive nodes impaired prognosis significantly. Conclusion. SCC of hard palate and maxillary alveolus has nonnegligible incidences of both overall and occult metastasis, which were highly associated with pt classification. We recommend routine, synchronous elective neck dissection for T4 lesions, whereas observation is an alternative for T1 to T3 lesions. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: squamous cell carcinoma, hard palate, maxillary alveolus, cervical metastasis, neck dissection INTRODUCTION The relative rarity of squamous cell carcinoma (SCC) of hard palate and maxillary alveolus compared with other primary sites in oral cavity has resulted in a paucity of published data concerning its regional metastasis. It had long been believed that SCC of hard palate and maxillary alveolus had a low nodal metastatic risk. However, recent studies showed higher-than-expected results, 1 6 which was comparable to the rest of the oral cavity. 7 Some of them also emphasized the high risk of regional recurrence, which may attribute to the presence of occult cervical metastasis. 3,4,6 As elective neck dissection has been proven beneficial for patients with oral SCC in other sites, 8 10 it may also be essential to apply this procedure to those with hard palate and maxillary alveolus SCC. However, the effect of elective neck dissection for SCC of hard palate and maxillary alveolus has not been systematically evaluated, because it was not a widely accepted routine procedure. *Corresponding author: E. Tang, Department of Oral and Maxillofacial Surgery, Stomatological Hospital Affiliated Medical School, Nanjing University, Nanjing, Jiangsu Province, People s Republic of China. yzn1988@yeah.net Contract grant sponsor: This study was supported in part by the National Key Disciplines Constructional Project Funding, China, in part by the Natural Science Foundation of Jiangsu Province, China (BK ), and in part by the Jiangsu Provincial Clinical Medicine of Science and Technology project, China, (BL ) Our retrospective study of hard palate and maxillary alveolus SCC has been taken to define the risk of both overall and occult cervical metastasis, to identify clinicopathological features, which are correlated with cervical metastasis, and to evaluate the efficacy of routine dissection of cn0 necks. This article will present our results and discuss them with a review of previous literatures. We hope to provide our experience to direct the neck management of SCC in these 2 sites. MATERIALS AND METHODS Patients with SCC of hard palate and maxillary alveolus were identified from the database at Stomatological Hospital Affiliated Medical School, Nanjing University, from January 2002 to December Approval was obtained from the local ethic committee in advance of the study. The TNM stage, type of treatment, and other clinicopathological features were retrieved from medical records. The TNM cancer staging of the primary tumor was according to the International Union Against Cancer on cancer criteria. Patients who met the following criteria were included : (1) primary SCC of the hard palate or maxillary alveolus, confirmed by pathologic examination and; (2) surgical treatment. Exclusion criteria were: (1) prior surgery or radiotherapy; (2) SCC originating from nasal cavity or paranasal sinuses; and (3) tumor invading oropharynx, retromolar area, or buccal mucosa. All patients underwent a complete clinical head and neck examination as well as a CT scan of the primary tumor site and neck before invasive diagnostic HEAD & NECK DOI /HED JULY

2 YANG ET AL. interventions or surgical treatment. Besides palpation, lymph nodes with any of these following characteristics on CT scan would be considered clinically positive: a minimum diameter larger than 10 mm, central necrosis, and 3 or more contiguous and confluent lymph nodes. Anemia was defined as a hemoglobin level <130 g/l for men and <120 g/l for women. Preoperative hemoglobin levels were obtained on the day before surgery. For the primary tumor, a radical resection aimed at 1.5 cm margins was taken. Modified radical neck dissection or radical neck dissection was applied for patients with clinically node-positive necks. Elective neck dissection, mostly as supraomohyoid neck dissection, was a routine procedure for patients with T1 to T4cN0 oral SCC in our hospital. If round-like nodes with a minimum diameter larger than 10 mm were found intraoperative, a frozen section examination would be taken. The neck dissection would be extended to level IV and level V if any nodes were confirmed positive. Postoperative radiotherapy was recommended for patients with positive margins or nodal metastases. Simultaneous chemotherapy would be recommended for these patients if there were other adverse prognostic factors, such as pathologic T4 classification, extracapsular spread, and positive nodes involving level IV or level V. Patients were followed up every 3 months in the first 2 years, every 6 months until the fifth year, and then every year after the fifth year. Recurrence was confirmed through histologic study and sometimes only a CT scan was considered adequate for recurrence. Formalin fixed, paraffin-embedded tissue blocks of these patients were collected and retrieved from the archives of the Department of Pathology in our hospital. In situ hybridization was performed using detection kit (Triplex International Biosciences, China) for high-risk human papillomavirus (HPV), in accord with the manufacturer s recommendations. This detection kit includes labeled probes for HPV type 16/18. Evaluation of the nuclear hybridization signal was assessed by a pathologist that specialized in head and neck pathology (X. H.). All samples were classified as positive or negative. We conducted a literature review using the U.S. National Institute of Health database (PubMed). Statistical analysis used chi-square test or the Fischer exact test for comparative groups. Analysis of difference in mean value was conducted with 2-tailed t test for independent samples. To define the association between the clinicopathological features and overall survival, the Kaplan Meier method was used for univariate analysis, and Cox proportional hazards regression was used for multivariable analysis. In all cases, the level of alpha was set at 0.05 a priori. All analyses were performed in PASW 18.0 (SPSS, Chicago, IL). RESULTS The study population consisted of 27 men and 40 women, ages ranging from 37 to 82 years (61.0 years on average). There were 33 cases of hard palate and 34 cases of maxillary alveolus SCC. Twenty-three tumors (34.3%) were clinically classified as T4, and 13 patients (19.4%) were clinically node-positive. Patient and tumor characteristics at presentation are summarized in Table 1. All patients with clinically node-positive cancer underwent modified radical neck dissection or radical neck TABLE 1. Patient and tumor characteristics at presentation. Characteristic No. of patients % Total patients Age <60 y y Sex Male Female Tobacco Never Yes Alcohol Never Yes Tumor subsite Maxillary alveolus Hard palate Clinical T classification Tis T T T T Clinical N classification N N N N dissection. Fifty-four patients had cn0 necks and 51 of them received elective neck dissection. The surgery type of elective neck dissection can be either supraomohyoid neck dissection or modified radical neck dissection, which was decided by the surgeons. Of the 3 patients who received only primary resections, 1 had Tis tumor and the other 2 had poor systemic conditions. In total, 64 patients received primary neck dissections. Six of them went through bilateral neck dissections because of suspicious contralateral neck metastases or tumors involving opposite sides. Eleven of 64 patients (17.2%) who received neck dissections were proven pathologic node-positive. Details of treatment and pathology are summarized in Table 2. Among patients with cervical metastases, 4 primaries were in hard palate and 7 were in maxillary alveolus. Bilateral metastases were detected in 2 patients. Four of 11 patients (36.4%) had extracapsular extension of lymph nodes. Six of 13 patients with cn1 were confirmed to be pathologic positive. Five patients with cn0 were proven pn1 after elective neck dissections. All subclinical, pathologic positive nodes were found in levels I/II/III. The N classification and distribution of positive cervical lymph nodes are concluded in Table 3. Clinicopathological features, including age, sex, subsite, pt status, pathologic grade, vascular invasion (VI), perineural invasion (PNI), HPV infection, and preoperative hemoglobin level were collected to define their relationship with cervical metastasis. To allow correlation of pt classification with cervical metastatic risk, pt1 to T3 and pt4 cases were placed in 2 groups, respectively. Pathologic grades were also divided into 2 groups. 970 HEAD & NECK DOI /HED JULY 2014

3 CERVICAL METASTASES FROM ORAL MAXILLARY SCC TABLE 2. Details of treatment and pathology. Variables No. of patients % Treatment Surgery alone Surgery and RT Surgery and CRT Treatment for neck END TND None Type of neck dissection SOHND MRND or RND MRND 1 SOHND None Pathologic T classification Tis T T T T Pathologic N classification No neck dissection N N N N Pathologic grade In situ Well differentiated Moderately differentiated Poorly differentiated Abbreviations: RT, radiation therapy; CRT, chemoradiation therapy; END, elective neck dissection; TND, therapeutic neck dissection; SOHND, supraomohyoid neck dissection; MRND, modified radical neck dissection; RND, radical neck dissection. Consequently, none of these factors, including age, sex, pathologic grade, PNI, HPV infection, and preoperative hemoglobin level had significant correlation with cervical metastases. The prevalence of cervical metastases of maxillary alveolar SCC (22.6%) was not significantly different from that of hard palate SCC (12.1%; p 5.331). The incidence of neck disease was 34.6% in pt4 group, which was significantly higher than that in the pt1 to T3 group (5.3%; p <.05). VI was also significantly associated with cervical metastasis (p <.05). Correlations between cervical metastasis and clinicopathological features are shown in Table 4. Correlations between occult cervical metastasis and age, sex, subsite, pt status, pathologic grade, VI, PNI, HPV infection, and preoperative hemoglobin level are calculated in Table 5. Of the 51 patients who had clinically negative necks at presentation and underwent elective neck dissection, the occult cervical metastatic rate was 9.8% (5 of 51 patients). Age, sex, pathologic grade, PNI, VI, and HPV infection were not associated with occult metastasis. SCC of maxillary alveolus seemed to have a higher risk of occult metastasis, although the difference was not significant (16.0% compared with 3.8%; p 5.191). There was a significant correlation between pt status and occult cervical metastasis (28.6% compared with 3.0%; p <.05). Furthermore, we found that patients with cn0 cancer in the anemia group had a higher risk of occult metastasis than those in the normal group (30.0% compared with 4.9%), which achieved statistical significance (p <.05). Median follow-up time was 45 months (range, months). Nine patients were lost to follow-up. Local recurrences were confirmed in 8 patients and 2 patients had locoregional recurrence. No isolated regional recurrence was observed. None of the 3 patients who did not receive neck dissections developed local or regional recurrences during follow-up periods. The overall survival rate for all evaluated patients was 88.0% (59 of 67 patients). Among 8 patients who died, 6 of them died of the progression of oral SCC, the other 2 died shortly after surgery because of other diseases. To investigate predictors of overall survival, multivariate Cox regression was conducted with age, sex, subsite, pt status, N status, margins, pathologic grade, PNI, VI, HPV infection, and preoperative hemoglobin level as variables. N status was an independent predictor of overall survival on multivariable analysis. The presence of neck disease impaired the prognosis significantly. The Kaplan Meier plot of overall TABLE 3. The N classification and distribution of positive cervical lymph nodes. Case no. Age Subsite Type of neck dissection cn classification pn classification Levels of positive nodes (positive/total) Extracapsular spread Right palate MRND 0 2b Level 1 (2/3); level 2 (1/3) No Left maxillary alveolus MRND 0 1 Level 1 (1/2) Yes Left palate MRND 1 2b Level 2 (2/3) No Right maxillary alveolus MRND 1 1 Level 2 (1/1) No Left maxillary alveolus SOHND 0 1 Level 3 (1/3) No Anterior palate MRND in both 2 2c Left level 2 (1/5); right level 1 (2/5); Yes sides right level 2 (1/3) Right maxillary alveolus SOHND 0 1 Level 2 (1/3) No Left maxillary alveolus MRND 0 1 Level 1 (1/3) No Left maxillary alveolus SOHND 1 1 Level 1 (1/4) No Anterior maxillary alveolus MRND in both sides 2 2c Left level 1 (4/4); left level 2 (2/5); right level 1 (2/2); right level 2 (3/3); right level 4 (1/3) Right palate RND 2 2b Level 1 (2/2); level 3 (1/2) Yes Yes Abbreviations: MRND, modified radical neck dissection; SOHND, supraomohyoid neck dissection; RND, radical neck dissection. HEAD & NECK DOI /HED JULY

4 YANG ET AL. TABLE 4. Correlations between cervical metastasis and clinicopathological characteristics. Variables pn0 pn1 p value Age.682 Average Sex.748 Male 23 4 Female 30 7 Subsite.331 Hard palate 29 4 Maxillary alveolus 24 7 pt status.005 Tl T T Pathologic grade.575 Well differentiated 29 5 Moderately or poor differentiated 24 6 PNI.122 No 37 5 Yes 16 6 VI.046 No 37 4 Yes 16 7 HPV.431 Negative Positive 13 1 Hemoglobin level.418 Normal 44 8 Anemia 9 3 Abbreviations: pn1, pathologically node-positive; pn0, pathologically node-negative; PNI, perineural invasion; VI, vascular invasion; HPV, human papillomavirus. survival, stratified by N status, is shown in Figure 1. For patients with cn0 or pn0 disease, the expected 5-year survival rate was 91.1%; meanwhile, for patients with pn1 disease, the rate fell to only 52.5%. DISCUSSION The cervical metastatic risk of SCC of hard palate and maxillary alveolus had been traditionally believed to be low, but recent studies had given challenge to this viewpoint. These studies 2,4 6 showed regional metastatic rates ranged from 13.7% to 40%, which were higher than expected and comparable to other primary sites in oral cavity. 7,11 In our study, the cervical metastatic rate was 17.2%, which agreed with previous studies. Montes et al 3 reported that larger size of tumor at presentation may suggest a higher regional metastatic risk. At the same time, Lin et al 2 suggested that advanced N classification significantly correlated with more advanced T classification. In our study, the pt4 group had a significant higher risk of nodal metastasis than the pt1 to T3 group. This result confirmed previously published works demonstrating pt classification as an important predictor of lymph node metastasis. In addition, the presence of vascular invasion in primary tumors was also associated with higher risk of nodal metastasis. The cervical metastatic rate was 30.4% for patients who were VI-positive compared with 9.8% for patients who were VI-negative (p <.05). This is consistent with previous studies on correlations between VI and cervical metastases. 12,13 No significant correlation between primary tumor subsites and cervical metastasis were detected in our study, although the metastatic rate of maxillary alveolus SCC was higher (22.6% compared with 12.1%; p 5.331). Similar to the study of Lin et al, 2 we conclude that hard palate and maxillary alveolar SCC can be considered as behaving clinically similar. So the management of the neck can follow the same principles for primaries from these 2 adjacent oral sites. For patients with oral SCC, staging of lymph nodes is essential for optimal neck management. However, after current preoperative clinical examinations, including newer radiographic techniques, 20% to 30% of patients with cn0 still have occult metastases. 14,15 Either the watchful waiting policy or elective neck dissection can be applied for this group of patients. Sentinel node biopsy is now emerging as an effective tool for the evaluation of occult metastasis, which has been proven in a multiinstitutional prospective trial on T1/T2cN0 oral SCC. 16 However, frozen section is ineffective to detect micrometastasis, therefore, step serial section and immunohistochemistry are required to achieve satisfying detection rates. 17 In other words, definite pathologic N classification is not available intraoperatively. If positive nodes were detected after primary resection, a second neck dissection was needed. Without a rapid, accurate method of staging sentinel lymph nodes, sentinel node biopsy is unlikely to be widely accepted as an alternative strategy for elective neck dissection, which is now the standard procedure for patients with cn0 oral SCC for both staging and therapeutic purposes. TABLE 5. Correlations between occult cervical metastasis and clinicopathological characteristics. Variables pn0 pn1 p value Age Average Sex Male 19 2 Female 27 3 Subsite.191 Hard palate 25 1 Maxillary alveolus 21 4 pt status.047 T1 T T Pathologic grade.656 Well differentiated 25 2 Moderately or poor differentiated 21 3 PNI.309 No 32 3 Yes 14 2 VI.643 No 33 2 Yes 13 3 HPV.323 Negative 34 5 Positive 12 0 Hemoglobin level.046 Normal 39 2 Anemia 7 3 Abbreviations: pn1, pathologically node-positive; pn0, pathologically node-negative; PNI, perineural invasion; VI, vascular invasion; HPV, human papillomavirus. 972 HEAD & NECK DOI /HED JULY 2014

5 CERVICAL METASTASES FROM ORAL MAXILLARY SCC TABLE 6. Variables predictive of survival. Variables No. of patients 5-y survival, % Univariate analysis p value Multivariable analysis HR p value Age 60 y <60 y Sex Male Female Tumor subsite Hard palate Maxillary alveolus pt status T Tis T N status pn cn0 or pn Margins Positive or close Negative Pathologic grade Moderately or poorly differentiated In situ or well differentiated PNI Yes No VI Yes No HPV Positive Negative Hemoglobin level Anemia Normal Abbreviations: HR, hazard ratio; PNI, perineural invasion; VI, vascular invasion; HPV, human papillomavirus. Univariate comparisons were carried out via log-rank test. Multivariable Cox proportional hazards regression incorporated all variables. Considering elective treatment of the neck, a commonly cited study is the decision tree analysis that proposed that a 20% risk of occult metastasis is the threshold. 18 Recently, several studies reported that rate of regional recurrence ranged from 14.4% to 25.6% for SCC of the hard palate and maxillary alveolus, 1,3,5 which may attribute to the presence of occult cervical metastases. In addition, the incidence of occult metastasis in patients with initially negative necks varied from 8.3% to 20.8%. 1,3 Therefore, elective neck dissections were recommended as a standard procedure for patients with advancing T status. Limitation of these previous studies is that elective neck dissection was not a routine procedure in any of them, which made evaluating the efficacy of elective neck dissection impossible. As benefits of elective neck dissection for patients with oral SCC have been shown 8,12,19 and application of microvascular surgery in reconstruction have been widely accepted, we routinely performed synchronous elective neck dissection for patients with T1 to T4cN0 oral SCC. In the present study, 94.4% patients with clinical negative necks received elective neck dissection, whereas less than 49% of patients were in the elective neck dissection cohort in other studies. 1,3 As far as we know, our series had the largest scale of elective neck dissection cases of SCC in these subsites. In our study, the occult metastatic rate was 9.8% (5 of 51), which was highly correlated with pt classification. The occult metastatic rate was 28.6% in pt4 tumors and 3.0% in pt1 to T3 tumors. Therefore, we suggested that elective neck dissection is essential for patients with T4 tumors, and the nodal metastatic risk of patients with pt1 to T3 tumors is low enough to justify observation. On the other hand, delay of detection of metastatic cervical disease until it is clinically evident is fraught with danger of neck disease progression. 20 The importance of strict follow-up and planned image surveillance for observed patients with cn0 oral SCC was stressed in several studies. 21,22 In our opinion, the watchful waiting strategy can be applied for patients with T1 to T3cN0 disease on conditions of good compliance and close follow-up. Among patients with occult metastases, positive nodes were all detected in levels I/II/III and no skip metastasis were found, which coincided with previous studies. 7,15 In addition, no isolated regional recurrence was detected in patients who received elective neck dissection HEAD & NECK DOI /HED JULY

6 YANG ET AL. FIGURE 1. Kaplan Meier curve, overall survival for squamous cell carcinoma (SCC) of the hard palate or maxillary alveolar based on the presence or absence of cervical nodal disease (n 5 67). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] during follow-up time. These data reveal that levels I/II/ III have the highest risk of harboring occult metastasis from hard palate and maxillary alveolus SCC. Based on these findings, we suggest that supraomohyoid neck dissection is a suitable surgery type as elective neck dissection for patients with cn0 disease of hard palate and maxillary alveolus SCC. We also investigated the prognostic value of several clinicopathological features to overall survival. N status was an independent predictor of overall survival on multivariable analysis. The presence of cervical metastases was an adverse prognostic factor of patients with hard palate and maxillary alveolus SCC, decreasing the 5-year overall survival by nearly one-half when compared with patients with neck negative disease. This is consistent with a previous study. 2 The 5-year survival rate of patients with pt4 disease is lower, which agreed with previous studies, 2,4 but statistical significance was not achieved. HPV infection has been recently implicated as an etiological factor in head and neck SCC, especially in oropharyngeal SCC. However, the role of HPV in oral SCC remains ambiguous. In our study, in site hybridization of high-risk HPV were performed on hard palate and maxillary alveolus SCC tissue specimens. Consistent with other reports on oral SCC, 23,24 15 of 67 patients (22.4%) were positive with HPV type 16/18. No correlation between HPV infection and cervical metastasis were found in our study, which was also suggested in other studies on oral SCC. 24,25 HPV positivity had been associated with better prognosis in head and neck SCC, 26,27 and recently this was also confirmed in oral SCC. 28 In our study, patients who were HPV-positive seemed to have higher estimated survival time, although statistical significance was not achieved. A low concentration of pretreatment hemoglobin had been related to poor prognosis in patients treated surgically in certain cancers Furthermore, 1 of these studies suggested that pretreatment anemia was correlated with higher regional metastatic risk in esophagogastric cancer. 30 In this study, we found that anemia was associated with a higher risk of occult metastases. One proposed mechanism is that anemia contributes to a detrimental tumor oxygenation status, 33 which may lead to malignant progression. 34,35 However, there was a higher percentage of patients with T4 in the anemia group than those in the normal group (60.0% compared with 29.3%; p 5.137), so it is debatable that the impact of anemia on regional metastasis results from anemia in relation to tumor volume. At the same time, we did not find a correlation between cervical metastasis and anemia, although patients with cervical metastasis had lower mean preoperative hemoglobin levels (data not shown). There are several caveats to our findings. For patients with cn0 with SCC of the hard palate and maxillary alveolus, our study has the largest proportion of elective neck dissection cases (51 of 54; 94.4%). But in contrast, we do not have enough patients who underwent the observation strategy. A recent study on stage I/II oral tongue SCC found no differences in prognosis between patients who received elective neck dissection and those who underwent observation, although the nodal recurrence rate was as high as 37% in the observation group. 22 This research revealed the possibility of taking the watchful waiting strategy instead of elective neck dissection for oral SCC, even if the risk of regional recurrence was relatively high. Therefore, we cannot make the conclusion that elective neck dissection can improve the outcome for these patients. In conclusion, the metastatic potential is highly correlated with T classification of hard palate and maxillary alveolus SCC. T4 lesions have higher cervical metastatic rate, which is comparable to other oral cavity sites. Based on these findings, we recommend routine, synchronous elective neck dissection (surgery-type as supraomohyoid neck dissection) for patients with T4 primaries. The watchful waiting strategy can be an alternative for patients with T1 to T3 lesions, on condition of good compliance during follow-up. Acknowledgments The authors thank Enago for the English language review. REFERENCES 1. Poeschl PW, Seemann R, Czembirek C, et al. Impact of elective neck dissection on regional recurrence and survival in cn0 staged oral maxillary squamous cell carcinoma. Oral Oncol 2012;48: Lin HW, Bhattacharyya N. Survival impact of nodal disease in hard palate and maxillary alveolus cancer. Laryngoscope 2009;119: Montes DM, Carlson ER, Fernandes R, et al. Oral maxillary squamous carcinoma: an indication for neck dissection in the clinically negative neck. Head Neck 2011;33: Morris LG, Patel SG, Shah JP, Ganly I. High rates of regional failure in squamous cell carcinoma of the hard palate and maxillary alveolus. Head Neck 2011;33: Brown JS, Bekiroglu F, Shaw RJ, Woolgar JA, Rogers SN. 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