FEASIBILITY OF SUBMANDIBULAR GLAND PRESERVATION IN NECK DISSECTION: A PROSPECTIVE ANATOMIC- PATHOLOGIC STUDY

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1 ORIGINAL ARTICLE FEASIBILITY OF SUBMANDIBULAR GLAND PRESERVATION IN NECK DISSECTION: A PROSPECTIVE ANATOMIC- PATHOLOGIC STUDY Muthuswamy Dhiwakar, MD, MS, 1 Ohad Ronen, MD, 1 James Malone, MD, 1 Krishna Rao, MD, PhD, 2 Stephen Bell, MD, 3 Roy Phillips, MD, 4 Bruce Shevlin, MD, 5 K. Thomas Robbins, MD 1 1 Division of Otolaryngology Head & Neck Surgery, Simmons Cancer Institute at Southern Illinois University, Springfield, Illinois. trobbins@siumed.edu 2 Department of Internal Medicine/Division of Hematology and Medical Oncology, Simmons Cancer Institute at Southern Illinois University, Springfield, Illinois 3 Associated Pathologists, Ltd, St. John s Hospital, Springfield, Illinois 4 Pathology Associates of Central Illinois, Ltd, Department of Laboratory Medicine and Pathology, Memorial Medical Center, Springfield, Illinois 5 St. John s Hospital, Radiation Therapy Department, Springfield, Illinois Accepted 27 April 2010 Published online 24 August 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Abstract: Background. The submandibular gland is commonly removed during neck dissection involving sublevel IB. However, removal reduces basal salivary secretion and therapeutic options for minimizing xerostomia. The purpose of this study was to determine whether all lymph nodes in sublevel IB can be extirpated without removing the submandibular gland. Methods. Twenty consecutive patients undergoing 33 neck dissections were prospectively enrolled. Sublevel IB dissection was performed by 3 sequential steps: (1) removal of targeted lymph node groups (preglandular and postglandular, prevascular and postvascular), (2) removal of submandibular gland, and (3) removal of residual lymphoadipose tissue in the surgical bed. Results. Complete removal of lymph nodes in sublevel IB was achieved before excising the submandibular gland in all of the 30 eligible neck dissections. The submandibular gland and the surgical bed contained no residual lymph nodes. Conclusion. In suitable cases, it is technically feasible to remove all lymph nodes in sublevel IB and preserve the submandibular gland. VC 2010 Wiley Periodicals, Inc. Head Neck 33: , 2011 Keywords: submandibular gland; level I lymph nodes; neck dissection; xerostomia; organ preservation Sublevel IB is a defined anatomic region in the neck known as the submandibular triangle in which lies the submandibular gland and surrounding lymph nodes. The lymph nodes within this level typically serve as the first echelon station for metastasis from Correspondence to: K. T. Robbins This work was presented at the Annual Meeting of the American Head and Neck Society, Phoenix, Arizona, May 29, Muthuswamy Dhiwakar and Ohad Ronen contributed equally to this project and should be considered co first authors. VC 2010 Wiley Periodicals, Inc. oral cavity cancer. Therefore, it is important to remove all the lymph nodes within sublevel IB when neck dissection is undertaken for oral cavity cancer. It is standard practice for the submandibular gland to be removed as part of the neck dissection procedure encompassing sublevel IB. 1,2 This practice is likely based on the belief that sublevel IB lymph nodes cannot be effectively extirpated unless the submandibular gland is also removed. 1 Furthermore, the submandibular gland itself is considered to be at risk for involvement by metastasis. 1 An important consideration in removing the submandibular gland during neck dissection, particularly when it is done bilaterally, is the potential negative impact on salivary flow. The submandibular gland is a key contributor to the basal flow of mucinous saliva collectively producing as much as 60% to 70% of the total volume. 3 Studies have shown that removal of even 1 gland can predispose the patient to xerostomia 3,4 and dental caries. 3 Furthermore, current radiation treatment protocols for oral cavity cancer include the submandibular glands in their fields and result in xerostomia in up to 100% of patients. 5 This is a distressing side-effect that results in difficulty in chewing and swallowing particles of food and the continuous sensation of parchment and burning within the oral cavity. Chewing dry foods such as crackers may be very painful, and patients often carry water bottles with them at all times. Chronic mucosal dryness can lead to angular cheilitis, fissuring of the tongue and lips, dental caries, oropharyngeal candidiasis, loss of appetite, and weight loss. It is well documented that radiation-induced xerostomia has a major negative impact on quality of life. 6 In consideration of the importance of submandibular gland function, we hypothesized that it is Submandibular Gland Preservation HEAD & NECK DOI /hed May

2 technically feasible to remove all lymph nodes within sublevel IB without routinely sacrificing the gland. Therefore, in this prospective study, we assessed the feasibility of systematically removing all of the visible lymph nodes in sublevel IB, whereas preserving the submandibular gland in situ. To evaluate if this approach achieved complete nodal clearance, the remaining tissue from the region, including the submandibular gland itself, was removed for pathologic examination. PATIENTS AND METHODS Eligible patients for the study were those with biopsy-proven carcinoma of the head and neck in whom a neck dissection encompassing sublevel IB was indicated. Excluded were those with a previous head and neck cancer, previous treatment for the index cancer (surgery, chemotherapy, radiation therapy, or biological therapy), medical comorbidity preventing surgical treatment, or age <18 years. Local ethics committee and institutional review board approval were obtained, and eligible patients underwent an informed consent process before surgery. Treatment planning was performed for all patients in the multidisciplinary head and neck oncology forum, where a detailed analysis and correlation of clinical findings, pathology of biopsy material, and radiology (CT scans, with additional MRI and/or positron emission tomography scans when indicated) were performed before recruitment into the trial. Surgical Steps and Technique. For oral cavity cancer, 5 to 15 minutes before the start of sublevel IB dissection, 1 ml of lymphazurin blue dye was injected in each quadrant around the periphery of the primary tumor. This was to facilitate identification and removal of all lymph nodes in sublevel IB that had lymphatic drainage from the oral cavity (ie, exhibited uptake of dye), and also to assess whether the submandibular gland itself showed any dye uptake. In all cases, subplatysmal flaps were elevated as the initial step to afford exposure to sublevel IB. The marginal mandibular nerve was then identified before administering any muscle relaxant. A hand-held nerve stimulator (Vari-stim III, Medtronics, Minneapolis, MN) was used to locate the nerve in the soft tissues within a 2-cm diameter centered on the angle of the mandible or more anteriorly at the inferior border of the mandible. Once the nerve was identified, it was skeletonized proximally and distally by releasing it from the surrounding soft tissues, mobilized superiorly, and kept protected during the rest of the surgery. At this juncture, the feasibility of removing all visible lymph nodes and fibrofatty tissue within sublevel IB while at the same time preserving the submandibular gland in an oncologically safe manner was reassessed. This was performed by carefully inspecting and palpating the surgically exposed sublevel IB for any grossly enlarged or metastatic lymph node. Similarly for tumors involving the floor of mouth, the extent of mucosal involvement and deep invasion were evaluated initially and during the subsequent extirpation, which afforded better 3-dimensional exposure of macroscopic tumor margins. Cases that had deep tumor invasion of the floor of mouth in close proximity to the ipsilateral submandibular gland, or grossly enlarged or metastatic lymph node within sublevel IB, were excluded from the study protocol and further analysis. For eligible cases, sublevel IB dissection was done by a defined procedure that included 3 distinct steps that were conducted sequentially. In step 1, all lymphoadipose tissue within the boundary of sublevel IB was removed, while at the same time preserving the submandibular gland. This was accomplished by skeletonizing the inferior border of the body of the mandible, the anterior and posterior bellies of the digastric muscle, and systematically removing the fibroadipose tissue encompassing the 4 lymph node groups within the boundaries of the submandibular triangle. The component of fibroadipose tissue that was attached to the anterior, lateral, superior, inferior, and posterior surfaces of the submandibular gland was removed by carefully stripping the investing fascia (capsule) that lay closely applied to the parenchyma of the gland. The intent of this initial step was to remove all of the fibroadipose tissues in sublevel IB except the parenchyma of the submandibular gland, its blood supply (facial artery, facial vein, and visible branches supplying and draining the parenchyma of the gland), and any possible fibroadipose tissue lying deep to the gland. Whenever possible, all of the fibroadipose tissue in sublevel IB was removed as a single contiguous specimen (Figure 1). After removal, it was divided into the following 4 separate compartments and submitted to the pathology laboratory for analysis in 4 individual containers labeled as follows: preglandular (anterior to the anterior surface of the gland), prevascular (anterior to the facial artery up to the anterior surface of the gland), postvascular (posterior to the facial artery up to the posterior surface of the gland), and postglandular (posterior to the posterior aspect of the gland; Figure 2). In step 2, the submandibular gland itself was removed and sent in a fifth container to pathology. Finally, in step 3, the surgical bed was inspected, and any fibroadipose tissue remaining in sublevel IB was removed and sent to pathology in a sixth container. For the subset of patients who had lymphazurin dye injected in the peritumoral mucosa before surgery, the dissected surgical bed of sublevel IB was examined by gross inspection and recorded for evidence of any residual dye staining. In the pathology laboratory, the number of lymph nodes harvested and involved by metastasis in each of the 4 compartments of sublevel IB was analyzed. 604 Submandibular Gland Preservation HEAD & NECK DOI /hed May 2011

3 Table 1. Patient demographics. Category No. (%) FIGURE 1. Dissection of sublevel IB toward completion of step 1. All visible soft tissues have been dissected en bloc, with preservation of submandibular gland (SMG) and facial vessels (*) in situ. The marginal mandibular nerve has been skeletonized and mobilized superiorly for its protection (arrow). The inferior border of mandible (M) and anterior and posterior bellies of the digastric (ad & pd, respectively) have also been skeletonized. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The submandibular gland itself was inked, fixed in formalin, and serially sectioned in parallel slices 3 mm in thickness. The cut sections were grossly examined for any intraglandular lymph node or tumor and then entirely embedded for histologic processing and microscopic examination. An average of 6.5 hematoxylin and eosin stained sections were examined per gland. The presence of any lymph node or focus of metastatic carcinoma within the parenchyma of the gland was documented. An assessment of facial nerve function was performed within 48 hours postoperatively and graded according to the House Brackmann grade. 7 If the House Brackmann grade was 2 or worse, further recording was continued until the grade improved to 1 or until 6 months postoperatively, whichever was earlier. FIGURE 2. At the completion of step 1, the single contiguous specimen has been divided into the 4 respective compartments for pathology. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Age (mean): 56.5 y Sex Male 13 (65) Female 7 (35) Primary (sub)site Oral tongue 8 (40) Floor of mouth 7 (35) Buccal mucosa 1 (5) Retromolar trigone 1 (5) Alveolus 1 (5) Lip 1 (5) Unknown 1 (5) ct classification Tx 1 (5) T1 3 (15) T2 4 (20) T3 6 (30) T4 6 (30) cn classification (targeted neck) N0 26 (79) N1 1 (3) N2a 2 (6) N2b 4 (12) RESULTS Twenty consecutive patients (33 heminecks) were consented and enrolled in the trial. The time period of enrollment was June 2008 to September Table 1 details the demographics of the patients included. All patients had squamous cell carcinoma, and all patients had oral cavity primaries, except 1 in whom the primary was unknown. In all 33 neck dissections, the marginal mandibular nerve was identified, skeletonized, and preserved, as mentioned above. Two patients had large (T4) primary tumors that deeply infiltrated the floor of mouth in close proximity to the ipsilateral submandibular gland. In 1 other patient with a preoperative stage of N2b for the targeted neck, there were multiple enlarged nodes in the prevascular compartment of sublevel IB that seemed grossly metastatic and were close to the gland. To ensure the best oncologic outcomes, the study protocol was abandoned in these 3 cases: an en bloc extirpation of the primary tumor together with the ipsilateral sublevel IB was performed in the former 2 cases, whereas sublevel IB was similarly resected as a single specimen in the latter case. These 3 cases were excluded from further analysis. The remaining 30 cases were eligible to proceed with the sublevel IB dissection according to the study protocol (Figure 3). Four of these 30 cases required inclusion of the distal submandibular duct within the wide mucosal resection undertaken for floor of mouth carcinoma. In all 4 cases, however, sufficient length of the proximal duct was preserved for potential re-routing. In step 1 of the study protocol, the 4 soft tissue compartments in sublevel IB were dissected en bloc in most cases and then subsequently separated into the respective specimen for pathology. In all 30 cases, Submandibular Gland Preservation HEAD & NECK DOI /hed May

4 FIGURE 3. Study flow chart. the submandibular gland was successfully preserved in situ during this portion of the procedure. The facial artery and vein, including branches supplying the gland, were preserved in 28 cases (93%; Figure 1). In the remaining 2 cases (7%), due to the close anatomic relationship between the lymphofatty soft tissue within sublevel IB and the facial vessels, and the necessity to include all of the former content in the extirpation, the facial vessels could not be preserved and were ligated and divided close to the surface of the gland. Retrograde flow from the distal stump of the divided facial artery was not assessed in either case. With the marginal mandibular nerve protected superiorly, care was taken to include all perifacial nodal tissue in the specimen. This included any nodes identified lateral to the body of the mandible that usually lie in close proximity to the marginal mandibular nerve. Subsequent pathologic examination of the specimen removed revealed an average harvest of 5.7 (range, 1 15) lymph nodes per case (average of 1.9 preglandular, 1.7 prevascular, 1.1 postvascular, and 1.0 postglandular nodes). Foci of metastatic carcinoma was found in 4 of 30 specimens (Figure 4), among which 1 had evidence of extracapsular spread. Final pathologic examination revealed that complete lymph node extirpation in sublevel IB had been accomplished at the conclusion of step 1 in all 30 cases. The submandibular gland, removed in step 2, was confirmed not to contain any subcapsular or intraparenchymal lymph node or focus of metastatic carcinoma. In step 3, after removal of the gland, the FIGURE 4. Distribution of lymph nodes harvested in each of the 4 compartments of sublevel IB. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary. com.] 606 Submandibular Gland Preservation HEAD & NECK DOI /hed May 2011

5 deep surgical bed was found not to have any visible fibroadipose tissue in the majority of cases. There were 3 cases in which a scanty amount of fibroadipose tissue was removed, all of which were confirmed on pathology not to contain lymph node or carcinoma. Lymphazurin dye was injected in the peritumoral mucosa in the first 8 patients (15 heminecks). Of these, only 2 patients (4 heminecks) exhibited dye staining in sublevel IB. In all 4 heminecks, the preglandular and prevascular nodes stained blue, without corresponding staining of the submandibular gland. Further, no case exhibited dye staining of the surgical bed in step 3 after completion of sublevel IB dissection. Overall, dye injection did not confer any significant benefit in evaluating the pathways of lymphatic drainage or in identifying lymph nodes for removal. In view of the low staining percentage and high cost-benefit ratio on interim analysis, dye injection was discontinued for subsequent patients. In 2 cases, marginal mandibular nerve function was not evaluated as the oral commissure or cheek skin close to the commissure was resected for oncological purposes. Of the remaining cases, nerve function was grade 1 (normal) in the immediate postoperative period in 26 cases, and grade 2 or worse in 5 cases, of who 3 showed spontaneous recovery to grade 1 within 4 weeks. Thus, only 2 (6%) cases had grade 2 or worse function persisting beyond 6 months. Thirteen patients (65%) received postoperative radiation at a median dose of 56 (range, 54 60) Gy to the primary and high-risk nodal levels. This resulted in 18 of 30 (60%) dissected sublevel IB beds receiving radiation. Over a median follow-up of 12 months (range, 4 20), 18 patients (90%), including 1 who died of an unrelated cause, remained free of disease. Two patients (10%) developed a local recurrence and died. In the final analysis, 30 eligible cases underwent successful extirpation of all lymph node groups in sublevel IB with in situ preservation of the submandibular gland. In 25 of these cases (83%), anatomic preservation of the entire gland with intact facial vessels was also accomplished (Figure 3). DISCUSSION The primary objective of this prospective anatomicpathologic study was to assess the technical feasibility of extirpating all lymph node groups within sublevel IB, whereas preserving the submandibular gland in situ. A small percentage of cases (9%) recruited to this trial were found on intraoperative assessment to have gross disease in close proximity to the submandibular gland, precluding compartmentalized dissection of sublevel IB according to the study protocol. The rest (91%) proceeded with extirpation of all visible lymph nodes and lymphofatty tissue within sublevel IB, with in situ anatomic preservation of the submandibular gland. Subsequent pathology in these cases confirmed successful extirpation of all lymph node groups along with foci of metastases within sublevel IB at this stage of the dissection. Neither the submandibular gland nor the deep surgical bed after removal of the gland contained any residual lymph node or focus of metastatic disease. These results challenge the current philosophy of routinely extirpating the submandibular gland in all neck dissections that involve sublevel IB, regardless of the extent of disease. Contrary to the common perception that the parenchyma of the submandibular gland is at risk of tumor seeding by metastases, several retrospective series 8 10 support the observation in the current study of the absence of involvement of the gland by metastatic foci. Of a pooled total of 650 submandibular glands studied in these 3 series, only 12 (2%) had tumor involvement. In every instance, this was due to direct infiltration of the gland, either from a large oral cavity primary, or from metastatic lymph nodes in sublevel IB outside the gland The absence of lymph nodes, which are targets for tumor seeding and metastases elsewhere in the head and neck region, within the substance of the submandibular gland probably explains the resistance of this organ to involvement by metastases. Unlike the parotid gland, which is well known to contain intraglandular lymph nodes, the histoanatomy of the submandibular gland has not been well studied. Many assume that the gland contains lymph nodes, and hence is at risk for metastatic involvement from a head and neck primary. The term deep node is also sometimes vaguely used in association with the submandibular gland, 1,2 without a clear description of its anatomic position in relation to the gland. Such lack of robust anatomic data, combined with the use of confusing terminology, may have led to the widespread belief that effective clearance of sublevel IB lymph nodes is not possible unless the gland is removed. However, the submandibular glands removed in the current prospective trial were subject to a careful, predefined histopathologic analysis and shown to have no lymph nodes within the parenchyma. Our findings support the embryologic concept that the lymphatic system develops after the submandibular gland has been encapsulated, and, therefore, lymph nodes and lymphatic channels do not get entrapped within the parenchyma of the gland and remain separate. 11,12 Our data further confirm the absence of lymph nodes in sublevel IB deep to the gland, suggesting that submandibular gland preservation may be a sound oncological procedure. Additionally, lymphazurin staining patterns from 4 cases in the current study suggests that lymphatic drainage from the primary tumor does indeed bypass the gland. Of the 30 cases in which the study hypothesis was proved, 25 (83%) also had successful anatomic preservation of the entire gland with intact facial vessels (Figure 3). If the study findings were to be extrapolated to and implemented in clinical practice, it could Submandibular Gland Preservation HEAD & NECK DOI /hed May

6 be argued that only these select 25 submandibular glands would have been suitable for in situ preservation and be functional in the postoperative period. In the remaining cases, however, at least the proximal portion of the duct was preserved in every case. These ducts, with frozen section control of the cut ends if necessary, would have been available for potential rerouting. Furthermore, although the facial vessels were ligated and divided in 2 instances, it has been previously shown that retrograde flow through the distal facial artery stump is consistent and robust and that the submandibular gland is not solely reliant on the facial vein for venous outflow. 13 The potential benefits of preserving the submandibular gland are manifold. First, in patients with oral cavity tumors who do not receive postoperative radiation, a large reservoir of saliva is preserved. This provides undiminished basal salivary flow that is predominantly mucinous, and is responsible for the sensation of mucosal lubrication. Furthermore, basal salivary flow is important for protection of the teeth and general oral hygiene. 6 Second, in patients who do receive postoperative radiation (60% in the current study), submandibular gland preservation widens the therapeutic options aimed at minimizing xerostomia. There may be improved response to sialagogues both during and after radiation therapy. 14 The strategy of preserving as many salivary glands as possible, even though they may ultimately receive radiation, may allow more targets for agents that either protect salivary function or maximize its stimulatory effects. Finally, preserving the gland avoids an external contour defect in the upper neck, and lowers the risk of injury to the lingual and hypoglossal nerves. 9 The necessity for elective neck dissection in patients with early oral cavity tumors that are clinically staged T1/2N0 is currently unclear and has been questioned. 15 Others, however, report a significant risk of occult nodal disease even for such early tumors. 16 Until more robust data are available, the feasibility of submandibular gland preservation with complete nodal clearance in sublevel IB, as has been demonstrated in this report, may weigh decision-making in favor of an elective neck dissection for these tumors. Furthermore, a special case can be made for patients with carcinoma of the oropharynx who initially undergo neck dissection as part of their treatment plan. Under these circumstances, dissection of sublevel IB can be performed with preservation of the gland, either ipsilateral or contralateral to the side of the primary disease site, and then subsequently transposed to the submental triangle. 13 Although intensity-modulated radiation treatment may allow similar preservation of submandibular function for the contralateral submandibular gland, it is generally not feasible for the ipsilateral gland. A similar strategy has been advocated for patients undergoing radiation therapy for nasopharyngeal carcinoma. 17 To our knowledge, the oncological outcomes of sublevel IB dissection with submandibular gland preservation has been demonstrated in only 1 previous report of 21 neck dissections for lip cancer. 11 Therefore, further prospective, preferably randomized studies with postoperative evaluation of salivary flow, incidence of radiation-induced xerostomia with and without sialagogues, quality of life scores, and regional and overall disease control are needed to validate this new conservative approach as oncologically sound and functionally superior to the traditional radical sublevel IB extirpation. Based on the experience in the current study, it may be prudent for such future trials to be more selective in patient recruitment. Oral cavity tumors that are clinically staged T1/2N0 and have no or limited involvement of the floor of mouth seem to be the most appropriate candidates. CONCLUSION With the surgical technique described here, it is possible to preserve the submandibular gland yet ensure complete removal of all lymph nodes in sublevel IB. However, this strategy may not be feasible when there is a need to expose a large oral cavity tumor through the submandibular triangle, or when there is direct extension of the primary and/or regional lymph nodes into the submandibular gland. Future trials measuring oncological and functional outcomes are needed to validate the anatomic-pathologic correlation established in this study. REFERENCES 1. DiNardo LJ. Lymphatics of the submandibular space: an anatomic, clinical, and pathologic study with applications to floor-of-mouth carcinoma. Laryngoscope 1998;108: Lim YC, Kim JW, Koh YW, et al. Perivascular-submandibular lymph node metastasis in squamous cell carcinoma of the tongue and floor of mouth. Eur J Surg Oncol 2004;30: Jacob RF, Weber RS, King GE. Whole salivary flow rates following submandibular gland resection. 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