Metastatic pattern in squamous cell carcinoma of the hard palate and maxillary alveolar ridge: clinical experience and review of the literature

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1 Oral Cancer (2017) 1: ORIGINAL ARTICLE Metastatic pattern in squamous cell carcinoma of the hard palate and maxillary alveolar ridge: clinical experience and review of the literature Johannes Buller 1,2 Matthias Zirk 1,2 Joachim E. Zöller 1,2 Matthias Kreppel 1,2 Received: 14 February 2017 / Accepted: 16 May 2017 / Published online: 23 May 2017 Ó Springer International Publishing 2017 Abstract Purpose Oral squamous cell carcinoma of the hard palate and upper alveolar ridge is rare with only few published current data regarding regional metastases after elective neck dissection or adjuvant therapy. Our aim was to investigate the incidence of initial and delayed nodal metastasis and to identify predictive factors. Methods In a retrospective cohort study, we enrolled 48 primarily surgical-treated patients from 2004 to Results Pathological initial nodal metastasis rate was 13.3% (6/45). Poor histologic grade (p = 0.048), lymphovascular infiltration (p \ 0.001) and perineural infiltration (p = 0.01) correlated with initial nodal metastasis, while advanced T-stage showed no significance (p = 0.07). Regional recurrences occurred in 14.6% of patients (7/48) and tended to emerge less frequently after therapeutic than elective neck dissection. Tumor involvement of the vestibular alveolar mucosa was a prognostic factor for developing regional recurrence (p = 0.034). Overall nodal disease rate was 27.1% (13/48). Disease-free and overall survival rates were at 73 and 93%, respectively. Conclusions The presence of poor histologic characteristics is a high risk for nodal metastasis. In patients with tumors in contact with the upper vestibular fold, the & Johannes Buller johannes.buller@uk-koeln.de 1 2 Department for Oral and Cranio-Maxillo and Facial Surgery, University of Cologne, Kerpener Str. 62, Cologne, Germany Center for Integrated Oncology (CIO) Cologne-Bonn, Cologne, Germany hypothesis of an impact on metastasis needs further validation. Keywords Hard palate Maxillary Alveolus Squamous cell carcinoma Oral cancer Introduction In all types of malignant neoplasms, oral squamous cell carcinoma (OSCC) accounts for less than 2% in women and 4% in men for the central European population [1]. The incidence of OSCC restricted to the hard palate and maxillary ridge is very low, with an estimated 10% of all OSCC. Surgery is the predominant curative therapy, and adjuvant radiation, with or without concurrent chemotherapy, leads to enhanced loco-regional tumor control and survival outcome in advanced staged cancers [2]. The pathologically detected lymph node status at presentation is a major prognostic factor for survival outcome [3], and an advanced tumor stage is associated with recurrence risk [4]. More than 80% of tumor relapse occurs within the first two years after primary surgery [5]. Because of the specific anatomic setting in the maxilla with close proximity to adjacent bone in tumors of the hard palate and upper alveolar ridge, T-stage fails to predict loco-regional recurrence risk. Instead, clear resection margins are a main predictive factor for tumor control [6]. Metastatic patterns have been investigated in detail for tumors localized in the floor of the mouth and tongue, whereas there are no such data for maxillary OSCC [7]. Consequently, we performed a 10-year retrospective study to investigate the regional metastatic behavior and to evaluate predictive factors for this specific tumor subsite.

2 8 Oral Cancer (2017) 1:7 14 Patients and methods Patients In a retrospective data collection, we enrolled all surgically treated patients who were primarily diagnosed with an OSCC of the hard palate (C05.0) and the gingiva of the maxillary alveolar ridge (C03.0) between 2004 and 2014 at a single university hospital. Cases with tumors localized in the soft palate and the mucosa of the cheek, as well as those with synchronous malignant neoplasm, remote metastasis or post neoadjuvant therapy were excluded. In addition to the clinical data, initial therapy and histopathological results, the history data of the tumor after-care program were reviewed until In our institution, therapeutic surgical neck treatment is performed as a modified radical neck dissection of level I V en bloc and patients with no sign of lymph node metastasis after staging routinely undergo an elective neck dissection (END) of level I III. Clinical and outcome variables The tumor localization was re-evaluated on the basis of the existing clinical documentation and magnetic resonance imaging and/or computer tomography staging results. According to the description by Yang et al. we distinguished between tumors in the anterior maxilla up to the level of the distal proximal surfaces of the first premolars and tumors located posterior to this region [8]. Considering the combined supplementary area of the palatal artery and the course of the lymphatic drainage following the corresponding vessels, we supplemented an own classification. Tumors were labeled as palatal when expanding to the palatal alveolar ridge or the hard palate. Tumors whose expansions were limited to the vestibular gingiva of the alveolar process were labeled as vestibular. The staging process performed during the evaluating phase included the clinical examination of the oral cavity and the neck, a radiological imaging by CT and/or MRI of the head and neck region, an X-ray or CT of the thorax and a sonography of the abdomen. To confirm the diagnosis, an incisional biopsy of the invasion front of the tumor was performed. Lymph node metastasis occurring during the follow-up (FU) period was defined as cervical recurrence. Statistical evaluation The data were evaluated using SPSS Statistics for Windows (version 23, IBM Corp). In the multivariate analysis, the review of the clinical and pathological variables for the association to performance variables describing metastatic and recurrence behavior using the asymptotic two-tailed v 2 test by Pearson and the t test by Fisher were calculated. A p value of p = 0.05 was regarded as statistically significant. Time from surgery until death, local recurrence, cervical recurrence or a delayed cervical metastasis is defined as disease-free survival (DFS). Overall survival (OS) is defined as the period between surgery and death or end of FU. Overall and DFS analysis was performed by applying the Kaplan Meier method. Patients with the last observation date scheduled before the end of the FU period, who were not documented as deceased, were censored in the further evaluation. Review of the literature We implemented a literature review of the US National Library of Medicine and National Institutes of Health database (PubMed) addressing the key words squamous cell carcinoma, hard palate, maxillary alveolus and gingiva. Results Initial treatment Forty-eight out of 64 patients presenting with a maxillary oral squamous cell carcinoma in the evaluation period were primary surgically treated and met inclusion criteria. All 48 patients had microscopic tumor-free resection margins after the first approach. At first presentation, 7 patients with clinical positive N-stage received a therapeutic neck dissection (TND) and 93% of patients with clinical absence of neck metastasis (38/41) received an END. In three cases with cn0-results, no END was performed due to poor general health. Five out of 7 patients with clinical positive nodes had no histologically confirmed metastasis after TND. Four out of 38 patients (11%) had histologically confirmed clinically occult metastasis. Either END was extended to TND in case of positive nodes in frozen section at time of surgery or level IV and V were dissected in a second procedure after final pathology. Initially, 13% of patients (6/45) had pathologically proven positive nodes, with 5 cases ipsilateral and one case bilateral (Table 1). Both lymphovascular infiltration and perineural infiltration were associated with initial positive nodes (Table 2). Follow-up Mean FU time is 53 months ( months). All 6 patients with pn? remained with absence of regional recurrences (Table 3). Seven patients (14.6%) had a regional recurrence during the FU and none emerged after TND, but in patients receiving END (0% [0/11] vs. 20.6%

3 Oral Cancer (2017) 1: Table 1 Patients clinicopathologic data, n = 48 Variable n % Pathological T-stage pt pt pt4a Pathological N-stage pn pn pn2b pn2c Differentiation grade Good Moderate Poor Undifferentiated Lymphovascular permeation Negative Positive Perineural invasion Negative Positive Tumor site Hard palate Alveolar ridge n = 45 [7/34]; p = 0.101, v 2 test). The patients with initially confirmed histological metastasis (n = 6) and the patients with metastatic recurrences (n = 7) result in a total rate of lymph node metastasis of 27.1% (13/48). Application of adjuvant radiation therapy or chemoradiotherapy compared to surgery alone led to similar rates of local (16.7% [2/12] vs. 19.4% [7/36]; p = 0.831, v 2 test) and regional recurrences (Table 4). A local recurrence developed in 9 patients (18.8%). In 5 of these patients, a regional recurrence developed simultaneously or subsequently (mean value 5 months, min. 0, max. 12) rather than solely regional recurrences (72 vs. 29%). In all patients with local or regional recurrences, salvage surgery could be conducted, besides one case with subsequent palliative radiation. In 33 patients, neither a regional nor a local recurrence occurred during the FU period. The 5-year rate of DFS and OS is 73 and 93% for the entire cohort, respectively (Kaplan Meier method). In 62.5% (30/48) of patients, tumor location was in the region defined as posterior of hard palate or alveolar ridge; in 8.3% (4/48), the tumor expansion affected both regions and 29.2% (14/48) were isolated in the anterior area. In 16.7% of anterior and 12.1% of posterior located and comprehensive tumors, cervical initially pathological confirmed metastases existed, with no statistical significance (p = 0.692, v 2 test). During FU, cervical recurrence occurred less frequently, but without statistical significance in anterior maxillary tumors than in tumors located completely or partially posterior (Table 4). Tumors infiltrating the buccal mucosa of the upper alveolar ridge showed in 9.1% of cases initial lymph node involvement and palatal Table 2 Association between clinicopathologic variables and initial nodal metastasis, n = 45 Variable pn0 n % pn? n % p value Pathological T-stage pt1/ pt Differentiation grade G1/ G3/ Lymphovascular invasion Negative \0.001 Positive Perineural invasion Negative Positive Anterior Posterior involvement Palatal Vestibular mucosa involvement

4 10 Oral Cancer (2017) 1:7 14 Table 3 Regional and local recurrence ID Primary neck treatment Pathological N-stage Adjuvant therapy Local recurrence site Regional recurrence site 1 END N0 IL, level Ib 2 END N0 Palatal arch BL, level IIa? III 4 TND N2b CRT 5 TND N1 RT 10 TND N1 RT Oropharynx, CL 11 TND N2c RT 13 END N0 Maxilla IL, level IV? V 15 TND N1 CRT 16 END N0 RT Buccal mucosa CL, level III 20 END N0 Soft palate, CL IL, level IIa 25 END N0 Maxilla 30 TND N1 Palatal arch 36 END N0 Maxilla CL, IIa 37 END N0 CRT CL, IIb 38 END N0 Palatal arch ID identification number of patient with either initial cervical metastasis, local or regional recurrence END elective neck dissection IL ipsilateral BL bilateral TND therapeutic neck dissection CL contralateral CRT chemoradiotherapy RT radiotherapy tumors in 14.7% (Table 2). Regional recurrences occurred significantly more frequently after resection of buccal than palatal-located tumors (33.3% [4/12] vs. 8.3% [3/36], p = 0.034, v 2 test). Discussion In patients with OSCC and node-negative neck, a metaanalysis of four studies has shown a reduced risk of death caused by disease after END as opposed to the watch-andwait strategy with TND in case of delayed metastasis [9], even though it appears to be an advantage in OS in early stage tumors as it is reported in a recently published prospective randomized study [10]. Indeed, in a further current retrospective study, no difference became apparent in OS between END (90%) and watch-and-wait approach (86%, p = 0.54) [11]. In conformity within both studies, there is a preponderance of delayed metastasis for watchand-wait approach compared to END, with 13% (9/70) versus 5% (6/) [11] and 74% (108/146) versus 31% (25/ 81), respectively [10]. Additionally, there is prospectively collected data from the 1980s and 1990s addressing the prevalence of clinical N-stage and survival outcome [12 15]. However, through changes in the demographic build-up of patient cohorts [16], precise radiological imaging for staging [17] as well as the introduction of optional chemotherapy additionally to the conventional adjuvant radiation therapy [18], these data are limited in explanatory value. To date, there are only a few retrospective studies considering a comparable clinical and radiological indication for END (Table 5). In the present study, the rate of END and TND is, besides the examination of Yang et al. to our knowledge, one of the highest of recent studies specific for the maxillary carcinoma [19]. Our content survival rate might be explained by our high rate of END as it was similarly observed by Yang and Poeschl [19, 20]. However, due to the study design by Poeschl et al. with restriction to inclusion of cn0 patients, the general regional recurrence rate of 18% is comparable with the 14.6% of our study [20]. The actual result of the Poeschl study is the missing difference between the END group and watch-andwait group of the OS (86 vs. 82%) and recurrence rates (17 vs. 18%). In a recently published study, the watch- andwait strategy of the authors is viewed as a therapeutic

5 Oral Cancer (2017) 1: Table 4 Association between clinicopathologic variables and regional recurrence, n = 48 Variable No nodal recurrence Nodal recurrence p value n % n % Pathological T-stage pt1/ pt3/ Differentiation grade G1/ G3/ Anterior Posterior involvement Palatal Vestibular mucosa involvement Type of neck dissection END TND Adjuvant therapy None RT/CRT n = 45 END elective neck dissection TND therapeutic neck dissection RT radiotherapy CRT chemoradiotherapy option with a rate of 22% delayed metastases, and 80% of them were operable at the time of discovery [21]. On the contrary, in the study conducted by Zhang et al. 11% out of 91 patients with maxillary carcinoma and clinical N0-status after END developed a regional lymph node recurrence and after sole monitoring, 31% delayed metastases during FU (p = 0.033) [22]. The authors of a British cohort study evaluated the role of END in comparing maxillary carcinomas with the remaining oral cavity. Brown et al. described a significantly higher rate in delayed cervical metastasis and recurrences for maxillary carcinoma with 26% as opposed to 7% (p = 0.001). Their explanatory note supposes a reduced frequency of the performed ENDs in maxillary carcinomas (28 vs. 55%, p = 0.001) [23]. Even though the existence of initial lymph node metastases is a deteriorating factor with a higher 5-year OS rate at pn0 status [24], all 6 patients with pn? results after END have remained without lymph node recurrence in our investigation. This observation fits the results from a retrospective study with tumors located predominantly in the tongue (72%) and only few tumors in the maxillary alveolar ridge (2%), in which there is only a minimal difference between the rate of the lymph node recurrence after END and initial pn? or pn0 results, with 19 and 12%, respectively. When an adjuvant irradiation was conducted (p = 0.056), the recurrence rate in pn? patients was reduced to 11% [25]. In our study, the absence of recurrences in all 6 patients with pn? results could be explained with the postoperative irradiation, though we found no evidence for less recurrence after adjuvant treatment in general. Similar to recent reports about the role of histologic risk factors [26], in our study, perineural or lymphovascular invasion was significantly associated with initial positive nodes. The rate of 13.3% of histopathological confirmed lymph node metastases recorded in the present study is below the listed range of 17 54% specifically mentioned for maxillary OSCC in related cohort studies [11, 19, 22, 23, 27 30]. In 9.4% of patients with one-sided END (3/32), recurrent metastases occurred in the non-dissected side of the neck, that are assigned to initial clinical occult metastases by some authors and occur in 10 30% of the time [22, 27, 28, 31], such as histopathological detected occult metastases after END [8, 19, 20, 22, 30] (Table 5). In the study of Mourouzis et al. 2 out of 13 total patients with cn0-result developed cervical metastases (15%) in the course of 18 months [31].

6 12 Oral Cancer (2017) 1:7 14 Table 5 Retrospective studies regarding oral maxillary squamous cell carcinoma (patient data ) Metastases at presentation Surgery TND END/ cn0 pn?/ END Total pn?/ ND Adjuvant treatment Metastases at follow-up n (%) W&W Total RR Total metastases LR 5-OS Montes et al. [27] Mourouzis et al. [31] Beltramini et al. [28] Poeschl et al. [11] Yang et al. [19] Dalal et al. [29] Eksander et al. [30] Brown et al. [23] Zhang et al. [22] /11 (27) 0/3 (0) 3/6 (50) RT 3 (14) CRT 1 (7) /13 (8) 0/1 (0) 3/4 (75) 4 (24) 2/12 (17) /57 (26) /74 (49) /54 (94) /18 (33) /69 (57) /35 (34) /91 (37) Yang et al. [8] /51 (69) Present study /41 (93) 0/15 (0) 8/23 (35) RT 6 (9) 6/42 (14) 3/36 (8) 3/36 (8) a RT 6 (8) 7/38 (18) 5/51 (10) 11/64 (17) 0/6 (0) 7/13 (54) 11/37 (30) 3/12 (25) 7/34 (21) 14/51 (27) 4/38 (11) 32/65 (49) 9/20 (45) 16/43 (37) 11/46 (24) 6/45 (13) RT 6 (9) CRT 7 (10) 3/8 (38) 5/14 (36) 5/16 (31) 6/14 (43) 2/14 (14) 5/16 (31) 3/16 (19) NA 6/65 (9) 14/65 (22) NA NA 13/74 (18) RT 15 (50) NA 10/30 (33) RT 30 (31) NA 17/97 (18) RT 21 (49) 5/23 (22) RT 9 (9) 18/57 (32) n = 12 (58) 16/74 (22) EX (84) NA 2/67 (3) NA 10/67 (15) 5/20 (25) 24/100 (24) RT 13 (21) NA 10/62 (16) RT 7 (15) CRT 5 (10) TND therapeutic neck dissection in cn? patients END elective neck dissection ND total neck dissections W&W watch and wait RR regional recurrent and delayed metastases LR local recurrence (loco-regional recurrence was added to RR and LR, respectively) 5-OS 5-year overall survival RT radiotherapy CRT chemoradiotherapy NA not analyzed EX patients with cn? excluded 0/3 (0) 7/48 (15) NA 4/30 (13) NA 17/97 (18) 16/43 (37) 8/43 (19) 34/100 (34) 15/100 (15) NA 9/62 (15) 13/48 (27) 9/48 (19) (88) (66) (44) (40) (57) (57) (93) In 8 cn0 cases with only observation in the study of Montes et al. 3 patients developed late cervical metastasis (38%) in the course of 16 months [27]. In the present study, all regional recurrences developed in patients who received END. No regional recurrence was observed in patients who initially presented with pn? and were treated with TND and irradiation. Therefore, we hold undetected micro-metastases in END specimen to account for regional recurrences in patients with no further extended neck treatment. Micro-metastases are invisible in the conventional light microscopic assessment of a lymph node in thin section technique [32]. For this nodal involvement, which needs further immunohistochemical examination, a prevalence of about 20% is reported [33]. However, in 1 patient, it remains unclear whether we observed a case of delayed metastasis after END and level-skipping metastatic seed to the ipsilateral level IV and V or it was caused by recurrent metastatic spread. The latter could be explained by occult persistence of local residual tumor with induction of a secondary cervical metastasis, especially on the ipsilateral side of the neck that underwent dissection [34]. Simental et al. assumed this connection in 2 patients, where after lymph node metastases occurred, a local recurrence was diagnosed within months. Likewise, an influence of

7 Oral Cancer (2017) 1: regional recurrence risk through local tumor relapse seems entirely possible, in that 5 out of 7 cases with recurrence in the neck had also local recurrence. Finally, we cannot distinguish if the observed cervical recurrences were indeed occult disease that was initially missed or re-spread subsequent to local recurrence. Comparing to related studies, the local recurrence risk of 18.8% in our observation is in line with the published range of 13 19% [8, 19, 22, 23, 27, 29 31]. Despite lack of evidence, a presentation of second primary tumors in dysplastic epithelial fields must be considered [35]. Although the T4-stage and poor differentiation grade are both well-known independent factors for a worsened prognosis of recurrence [36], our results showed significance for the differences in histological grading but not for pathological T-stage. Moreover, our results showed an uneven higher rate of developing metastatic disease if tumors involved the buccal alveolar mucosa. Similarly, carcinomas of the maxillary gingival buccal complex are reported to have an aggressive metastatic behavior [37]. One congruent observation was made by Zhang et al. who reported a significantly increased rate of 70% of initially confirmed cervical metastases of tumors expanding in the upper vestibular fold (p \ 0.01) [22]. Furthermore, in sagittal extent, the regional recurrence rate in tumors with sole or comprehensive involvement of the posterior maxilla was higher but showed no clear difference (17.6 vs. 7.1%, p = 0.349) as opposed to isolated involvement in the anterior region. Similarly, Beltramini et al. reported a higher metastatic rate of 37% (2/7) in the dorsal hard palate compared to 10% (2/20) in the anterior region [28]. Because comprehensive tumor infiltration of the soft palate which anatomically forms the anterior wall of the nasopharynx leads to a not negligible increase in risk for initial lymph node metastasis [38], this tumor localization was excluded in our study. Meng et al. observed a significantly lower 5-year OS of 27% in patients with involvement of the soft palate as opposed to 77% (p = 0.001) in patients with isolated tumors of the hard palate. Even though the rate of adjuvant irradiation was 51% higher with involvement of soft palate than involvement of the hard palate (27%), more regional recurrences developed when the soft palate was infiltrated (42 and 15%, respectively, p = 0.001) [38]. In a Chinese study, a significantly higher 5-year OS of 36% was described in tumors limited to the hard palate as opposed to 27% of tumors involving the soft palate (p = 0.017) [39]. In a recent study, 45% of the patients had a tumor invading the soft palate, and a significant association with initial lymph node metastases was reported (22 vs. 11%, p \ 0.05) [40]. We conclude the established risk factors, histological differentiation grade, lymphovascular infiltration and perineural infiltration have reached significance to the risk of initial neck metastasis, but obviously the limited study cohort T-stage has failed to reach a predictive value. In addition, the finding of a potential higher risk of regional recurrence for tumors infiltrating the upper vestibular fold than for palatal localization requires further evaluation in larger cohort series. Our data for overall cervical metastasis in 27% of all patients showed an aggressive characteristic of this tumor subsite, though initially the clinical occult metastasis rate of 11% was low. 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