Preservation of Ipsilateral Submandibular Gland Is Ill Advised in Cancer of the Floor of the Mouth or Tongue

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1 The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Preservation of Ipsilateral Submandibular Gland Is Ill Advised in Cancer of the Floor of the Mouth or Tongue Martin Lanzer, MD, DMD; Thomas Gander, MD, DMD; Heinz-Theo L ubbers, MD, DMD; Philipp Metzler, MD, DMD; Marius Bredell, BChD, MBChb, MChD; Sabine Reinisch, MD Objectives/Hypothesis: Preservation of the submandibular gland (SMG) during a neck dissection is gaining popularity and is showing an increasing tendency. The potential benefit, if the SMG is preserved, can be manifold. The aim of this study was to assess the benefit of the preservation of the SMG and the associated risk of recurrent disease in patients with oropharyngeal or oral cavity squamous cell carcinoma. Study Design: Retrospective data analysis of 168 patients, with a follow-up of at least 3 years. Methods: Log-rank test, univariate, and multivariate data analyses and P values for prediction of the excision of SMG on overall-, recurrence free-, and lymph node recurrence free survival. Results: In patients with cancer of the floor of the mouth or tongue, lymph node recurrence-free survival was highly influenced by excision of the SMG (P < 0.001) and occurred in 28.5% of patients in whom the SMG was preserved. In all other tumor sites of the oral cavity and oropharyngeal region, excision of the SMG did not influence lymph node recurrencefree survival (P ). Conclusions: Patients with squamous cell carcinoma (SCC) of the oral cavity or oropharyngeal region will benefit from preservation of the ipsilateral SMG. This is not true for patients with SCC of the surrounding tissue nearest the SMG (i.e., floor of the mouth or the tongue). In such patients, the SMG must be excised. Key Words: preservation, submandibular gland, oral carcinoma, survival. Level of Evidence: 4. Laryngoscope, 124: , 2014 From the Department of General Otorhinolaryngology, Head and Neck Surgery (M.L., S.R.), University Hospital of Graz, Graz, Austria; and the Clinic for Cranio-Maxillofacial Surgery, University Hospital of Zurich (M.L., T.G., H.T.L., P.M., M.B.), Z urich, Switzerland. Editor s Note: This Manuscript was accepted for publication March 6, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Martin Lanzer, MD, DMD, University Hospital of Z urich, Clinic for Cranio-Maxillofacial Surgery, Frauenklinikstrasse 24, CH-8091 Z urich, Switzerland. martin.lanzer@usz.ch DOI: /lary INTRODUCTION The lymph node dissection technique introduced by Crile in the early 20th century included radical excision of muscular, venous, and glandular structures. 1 With the search for more selective tissue-sparing and functionsparing procedures, preservation of the submandibular gland (SMG) during neck dissection has gained popularity and is now performed more frequently. The potential benefits of SMG preservation are numerous. First, resection of the SMG leads to a reduction in the basal salivary outflow; thus, the SMG accounts for 70% to 75% of the unstimulated salivary flow. 2 Primarily a mucinous gland, it is responsible for the sensation of mucosal lubrication, which is important in the prevention of xerostomia. 3 Second, basal salivary flow is important for oral hygiene and the prevention of dental disease. 2 Third, although the SMG is often present within the radiation field in patients with head and neck squamous cell carcinoma (HNSCC), preservation of the gland may provide more targets for agents that either protect salivary function or maximize its stimulatory effects. 4, 5 Fourth, during SMG resection, damage to the marginal branch of the facial nerve (7.7%), hypoglossal nerve (2.9%), and lingual nerve (1.4%) have been described. 6 Fifth, excision of the SMG results in an external contour defect in the upper neck. 3 Finally, the importance of the SMG has also been emphasized in various studies that evaluated preradiation SMG transfer to prevent radiation-induced xerostomia. 7, 8 All of these benefits of SMG preservation must be evaluated thoroughly; one of the most significant prognostic factors for recurrence and survival in patients with HNSCC is the presence of cervical lymph node metastasis. Although relatively rare, involvement of the SMG has been described in 2% to 4% of patients 3, 9 11 with HNSCC involving sublevel 1b. We herewith elucidate the risk of recurrent disease after preservation of the SMG during neck dissection in patients with oral cavity and oropharyngeal squamous cell carcinoma (SCC). The aim of this study was to assess the benefit of preservation of the SMG and the associated risk of recurrent disease. MATERIALS AND METHODS We retrospectively evaluated patients who presented to the Department of Otorhinolaryngology and Head and Neck (ENT) at the Medical University Hospital Graz for treatment of HNSCC between January 1, 1999, and December 31, This 2070

2 study was approved by the institutional ethics committee (EK- Nr ex 09/10). The inclusion criteria were the diagnosis of oropharyngeal or oral cavity SCC and operative treatment at the primary tumor site with/without adjacent adjuvant radiotherapy or radiochemotherapy. Patients were excluded if they had histological findings other than SCC, distant metastasis before neck dissection, or underwent primary treatment outside the ENT department. The study variables examined were age; sex; tumor location, stage, size, and grade; neck lymph node status; histological factors (blood vessel invasion [hemangiosis], lymph vessel invasion [lymphangiosis], extracapsular spread, and perineural invasion); resection margin (positive resection margin defined as < 5 mm 12,13 ); and adjuvant therapy (postoperative chemotherapy and/or adjuvant radiotherapy). Perineural invasion was defined as that present within the body of the tumor and ahead of the invasive front. In patients with a SCC of the oral cavity or oropharyngeal region, ipsilateral SMG was usually excised during treatment. If SMG was preserved, it was the determination of the surgeon that: 1) the surgeon could exclude the intraparenchymal lymph node by palpation, 2) the surgeon could thoroughly dissect level Ib without removing the gland, and 3) the surgeon had found no evidence of the tumor infiltrating the SMG. One experienced pathologist from the ENT department was responsible for the histological evaluation of all pathologic specimens. Therefore, interobserver variability could be excluded. Immunohistochemical methods were only used if hematoxylineosin staining was not sufficient or if the pathologist was in doubt (e.g., differentiation between lymphatic invasion and blood vessel invasion). Evaluation of human papilloma virus was only conducted in patients with a relevant history (e.g., presence of condyloma accuminata). The points of interest in this study were as follows: 1) univariate analysis to evaluate the impact of preservation of the SMD in unilateral neck dissection on lymph node recurrencefree survival, recurrence-free survival, and overall survival; 2) multivariate analysis to evaluate the independent prognostic factors associated with recurrence-free survival and overall survival. Data were collected and processed by building a database of information regarding patient characteristics (sex, age), tumor characteristics (location, size, lymph node status), operative parameters (date, type of resection, resection margin, type of neck dissection, number of levels excised, number of lymph nodes excised, number of positive lymph nodes, excision of nonlymphatic structures), histopathological diagnostic findings (hemangiosis, lymphangiosis, extracapsular spread, perineural invasion), postoperative therapy, second primary tumors, location and time of recurrence, and overall survival. Patient data were analyzed using SPSS software (SPSS Inc., Chicago, IL). Descriptive statistics were computed for each variable. Univariate Cox regression analysis was used for each variable, and odds ratios and P values were calculated. Multivariate Cox regression analysis was used for each predictor variable (P < 0.05) identified as statistically significant in the univariate analysis. We used a forward step-wise (likelihood ratio) procedure. Kaplan-Meier curves were calculated using the log-rank test for statistical evaluation of significance. RESULTS In total, 168 patients were included in the present study (Table 1). Their mean age was 63 years (range, 27 87). Most patients (79.2%) were male. The mean follow-up duration was 44 months (maximum, 128). The majority of patients (n 5 94; 56%) had oropharyngeal cancer. Most patients (n 5 86; 51.2%) presented with tumors of stage IV, followed by tumors of stage II (20.2%), tumors of stage I (15.5%), and tumors of stage III (13.1%). With regard to T-status, most patients presented with a T2 tumor (38.1%). Lymph node status was pn0 in 41.1% of patients, followed by pn2b in nearly 31% of patients. Because patients with distant metastasis at the time of diagnosis were excluded, all patients were stage M0. Most patients had moderately differentiated tumors (37.5%) or poorly differentiated tumors (56.0%). Only a few patients presented with welldifferentiated or undifferentiated tumors. Operative success, defined as a negative resection margin (R0 resection), was achieved in 129 patients (76.8%). The results of neck dissection demonstrated a pn0 status in 41.1% of patients. The SMG was excised during neck dissection in 64 patients (68.1%) with oropharyngeal carcinoma, and was excised in 49 patients (66.2%) with SCC of the oral cavity. Overall survival (P ) and recurrence-free survival (P ) did not differ significantly between patients who did and who did not undergo SMG preservation (Fig. 1). In multivariate Cox regression, a positive resection margin (P ) and extracapsular spread (P ) were the only independent prognostic factors for recurrence-free survival. The lymph node ratio was a highly significant independent prognostic factor for overall survival (P < 0.001). Of all 168 patients, 66 had an SCC of the tongue or floor of the mouth. The SMG was preserved in 21 (31.8%) of these 66 patients. Lymph node recurrencefree survival was highly influenced by excision of the SMG (P < 0.001) and occurred in 28.5% of patients if the SMG was preserved (Fig. 2). Lymph node recurrence affected level Ib, level IIa, and level III. All lymph node recurrences were within the level of neck dissection. Lymph node recurrence occurred in one patient (2.2%) of the excised SMG subgroup. In this patient, lymph node recurrence developed in level IV, outside the level of the former neck dissection. In multivariate Cox regression analysis, excision of the SMG was the only remaining independent prognostic factor for lymph node recurrence (P ). Preservation of the SMG was possible in 34 of 102 patients with an SCC in a site other than the tongue or floor of the mouth (Fig. 3). Excision of the SMG did not influence lymph node recurrence-free survival (P ). Three patients (8.8%) in whom the SMG was preserved developed lymph node recurrence. DISCUSSION In our patients, preservation of the ipsilateral SMG was not beneficial if the tumor was located on either the floor of the mouth or the tongue. There was no drawback with respect to recurrence-free survival or overall survival if the SMG was preserved in patients with an SCC in a site other than the floor of the mouth or tongue. 2071

3 TABLE 1. Demographic Data. Mean Minimum Maximum Count Column N % Age Gender male % female % Follow-up (in month) Localization oral cavity % oropharynx % Staging Stage I % Stage II % Stage III % Stage IV % Classification pt % pt % pt % pt % pn Status pn % pn % pn2a % pn2b % pn2c % pn % Grading well-differentiated % moderately differentiated % poorly differentiated % undifferentiated % Resection Margin negative % positive % Dhiwakar et al. 14 recently stated that SMG preservation in neck dissection is feasible. More important, they confirmed that the SMG, which was excised after neck dissection for further investigation in their study, did not contain any subcapsular or intraparenchymal lymph node tissue or focus of metastatic carcinoma, and the deep Fig. 1. Recurrence-free survival considering preservation of the submandibular gland. Fig. 2. Lymph node recurrence-free survival of patients with carcinoma of the floor of the mouth or tongue. 2072

4 Fig. 3. Lymph node recurrence-free survival of patients other than with carcinoma of the floor of the mouth or tongue. surgical bed had no visible fibroadipose tissue. It has been postulated that, unlike the parotid gland, the SMG is unlikely to be the host tissue for metastases because of its lack of lymph nodes or lymph vessels. 15 Several retrospective series support the absence of involvement of metastatic lymph nodes in the gland. If the SMG is involved, it is due to direct infiltration of the gland from either a large primary tumor of the oral cavity or metastatic lymph nodes outside the gland, 3, 9 11 or through hematogenous spread of cancer originating outside the head and neck. 15 Indocyanine green was recently used to perform lymph node mapping and aid in intraoperative identification of the sentinel lymph node in patients with oropharyngeal and oral cavity cancer. Notably, with respect to the search for lymph nodes, we did not identify any intraglandular lymph nodes or vessels but encountered lymph vessels in close proximity to the SMG. In some cases, it seemed that the lymph vessels had adhered to the capsule of the SMG (Fig. 4). These findings support the embryologic concept that the lymphatic system develops after the SMG has been encapsulated; therefore, lymph nodes and lymphatic channels do not become entrapped within the parenchyma of the gland and remain separate. 16 This concept would also explain the close proximity of the lymph node vessels to the SMG, as shown in Figure 4, because the components of the lymphatic system become displaced and adhere to the capsule with growth of the SMG. DiNardo 17 stated that the principal para-arterial pathways descend from the prevascular and retrovascular nodes during development of the efferent submandibular lymphatic system. Drainage occurs 17 along one or two of the vessels that follow the facial artery to the posterior belly of the digastric and stylohyoid muscles. The accessory paths travel deep into the superficial fascia or into the submental region before arriving at the internal jugular nodes. Figure 4 demonstrates the demarcation of the prevascular lymph nodes and an accessory pathway leading to the internal jugular group. However, in the absence of intraglandular lymph nodes or lymphatic tissue, why would preservation of the SMG have an impact on lymph node recurrence-free survival in patients with cancers of the floor of the mouth or tongue, as demonstrated in this study? In the cohort in whom the SMG was preserved, all lymph node recurrences occurred within neck dissection level Ib, level IIa, or level III. Thus, the lymph node recurrences occurred in the area closely surrounding the SMG. Because the recurrent lymph nodes were not located outside the field of neck dissection, it cannot be argued that the neck dissection did not include the necessary lymph node levels. Considering the above-mentioned previous studies, the existence of intraglandular lymph nodes is unlikely, despite the fact that they have been described in the literature. 17 A plausible explanation for such recurrent disease cases may involve the presence of lymphatic vessels adherent to the capsule of the SMG. If the gland is spared, lymphatic vessels may remain adherent to the capsule; thus, a possible reservoir of cancer cells remains. This is even possible in clinically N0 necks because occult metastasis to the submandibular region is frequent. Submandibular lymph node pads are part of level Ib, which is located near the facial vein, and may be a major metastatic reservoir in patients with oral and oropharyngeal SCC. Therefore, they are routinely removed during neck dissection in such patients, even when clinically N0. Lim et al. 18 reported a 27% rate of occult lymph node metastasis in these nodes also known as perifacial lymph nodes when the primary tumor was an oral cavity tumor; however, the rate of occult lymph node metastasis was only 6% in oropharyngeal tumors. Lim et al. thus concluded that excision of the perifacial lymph nodes is mandatory in patients with lymph node-positive oral cavity carcinomas. Junquera et al. concluded that periglandular metastases frequently occur in patients with carcinoma of the floor of the mouth, but SMG involvement is unusual. 19 Therefore, they came to the same conclusion as Lim et al. We postulate that some of these perifacial lymph nodes may be at risk of incomplete removal when the SMG is preserved. This possibility may be an additional explanation for the increased lymph Fig. 4. Demarcation of accessory lymphatic vessels attached to the submandibular gland using indo-cyanin green. [Color figure can be viewed in the online issue, which is available at com.] 2073

5 node recurrence rate in patients with oral carcinomas and SMG preservation in this study. Direct infiltration is another possible mechanism of involvement of the SMG in patients with oral cancers, especially infiltrative T2 and larger lesions of the floor of the mouth and tongue. In tumors of larger volumes, the pathologist often has difficulty distinguishing between extracapsular spread with SMG infiltration of an involved lymph node and true direct infiltration of a tumor through the mylohyoid muscle to the SMG. It is very important to emphasize that the SMG must not be spared due to the reasoning that postoperative radiation therapy can eliminate possible residual disease. First, this is not oncologically sound reasoning if the possibility to remove all pathological tissue is present. Second, it is known that radiation treatment with as little as 35 Gy causes permanent salivary dysfunction, and no substantial recovery of salivary gland function after radiation exposure has been reported to date. Therefore, patients would not experience the benefit of a spared SMG, because its function is diminished dramatically after the completion of radiotherapy. The ultimate goal of surgery as a first-line treatment will always be to prevent postoperative radiotherapy by removing all tumor tissue and potentially involved tissues. Because this was a retrospective study, the indications for preservation of the SMG cannot be documented in detail. However, the study included patients with small tumors (T1 T2) with a clinically negative neck. Thus, it is not surprising that the Kaplan-Meier curve of the overall recurrence-free survival showed a lower survival rate in patients who underwent SMG resection; those patients also had a higher stage of disease. It is evident that excision of the SMG in patients with carcinomas of the floor of the mouth or tongue leads to a significant reduction in locoregional lymph node recurrence. The occurrence of locoregional lymph node recurrence in these patients is most likely explained by the adherence of the lymphatic vessel system to the SMG and not by missed nodes, missed direct infiltration, or the presence of intraglandular lymph nodes. CONCLUSION Patients with an SCC of the oral cavity or oropharyngeal region will benefit from preservation of the ipsilateral SMG. This is not valid for patients with an SCC of the surrounding tissue nearest the SMG (i.e., floor of the mouth or the tongue). In these patients, the SMG must be excised. In our opinion, due to the adherent lymphatic vessels, the possibility of remaining lymph nodes and/or direct infiltration of the SMG, the submandibular gland must be excised in these patients. BIBLIOGRAPHY 1. Crile G. 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