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CLINICAL REVIEW David W. Eisele, MD, Section Editor CONTROVERSIES IN THE MANAGEMENT OF RETROMOLAR TRIGONE CARCINOMA Tareck Ayad, MD,1 Louis Guertin, MD,1 Denis Soulières, MD,2 Manon Belair, MD,3 Stéphane Temam, MD,4 Phuc Felix Nguyen-Tân, MD5 1 Department of Otolaryngology–Head and Neck Surgery, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal, Montreal, Quebec, Canada. E-mail: [email protected] 2 Department of Hematology-Oncology, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal, Montreal, Quebec, Canada 3 Department of Radiology, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal, Montreal, Quebec, Canada 4 Department of Otolaryngology–Head and Neck Surgery, Institut Gustave Roussy, Villejuif, France 5 Department of Radiation Oncology, Hôpital Notre-Dame, Centre Hospitalier Universitaire de Montréal, Montreal, Quebec, Canada Accepted 14 July 2008 Published online 20 November 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20956 Abstract: Our objective is to discuss the current controversies that surround the management of retromolar trigone (RMT) cancer. We conducted this literature review to discuss trigone cancer. RTM and anterior pillar cancers should be studied separately. Preoperative clinical and radiographic assessments need to be further investigated to establish their reliability at predicting bone invasion. In the absence of suspicion of bone invasion, surgery and radiotherapy seem to give similar results, but recent reports indicate a greater benefit if they are used in combination. Some authors have advocated systematic segmental resection for all RMT cancers but marginal mandibulectomy is a reasonable option in selected cases. Standard treatment for RMT cancers with N0 necks is selective neck dissection or radiation therapy, depending on the modality of treatment of the primary. Allowing a better understanding of the evolution of RMT cancer and its response to different treatment modalities requires efforts to report different institutional experience with Correspondence to: T. Ayad Contract grant sponsor: Bourse André Lanthier, from Centre Hospitalier Universitaire de Montréal. C V 2008 Wiley Periodicals, Inc. 398 Retromolar Trigone Carcinoma Controversies this rare tumor. 398–405, 2009 C 2008 Wiley Periodicals, Inc. Head Neck 31: V Keywords: retromolar trigone; cancer; oral cavity; surgery; radiotherapy Retromolar trigone (RMT) carcinoma is a relatively rare tumor. Little information has been published concerning their treatment, and questions remain concerning the best management. Available options encompass surgery, radiation therapy, or a combined therapy. In 1959, Barbosa published the first series of patients with RMT carcinoma treated by surgery or radiotherapy (RT).1 Since then, there is still controversy on the best treatment for RMT cancer.2–4 It is well accepted that bone invasion suspicion makes surgery mandatory if a curative treatment is considered. For lower stages, the optimal treatment is still debated. Some cancer institutes favor HEAD & NECK—DOI 10.1002/hed March 2009 surgical treatment; others prefer radiation therapy as primary treatment preserving surgery for locoregional failures. More recently a trend for systematic combination therapy (surgery and radiation therapy) has been seen in some institutions. To date, no randomized controlled study has been published on RMT cancers. Only retrospective studies can be found in the English-language literature. Our objective is to discuss the current controversies in the management of RMT carcinomas according to the literature. The authors have chosen to limit the analysis and discussion to these specific matters of controversies. PRIMARY SITE LOCALIZATION The RMT is in continuity with the anterior pillar in its medial part, the upper gum superiorly, the lower gum inferiorly, and the buccal mucosa laterally. While the RMT is a subsite of the oral cavity, the anterior pillar is a subsite of the oropharynx. Even though they pertain to different anatomic sites, 3 studies group the RMT and anterior pillar cancer together.5–7 Lo et al found no statistically significant difference between RMT and anterior pillar cancers in terms of primary control in a study with 137 patients treated by radiation therapy.6 The differences between these 2 subsites for regional control and survival were not mentioned. The grouping of anterior pillar and RMT cancers can be supported by their geographic proximity that makes identification of the exact primary site often difficult. Confinement of a cancer to the RMT occurs only in 15.5% to 26.3% of the cases. The tumor spreads to the anterior pillar in 80% to 84.5% of the cases and the majority of them invade 3 or more subsites of the oral cavity and oropharynx.8–10 Despite this tendency to spread to the anterior pillar, the majority of the authors study these subsites separately. In fact, RMT cancer is more prone to bone invasion because of its close proximity to the mandible and the maxilla. Moreover, it is considered to have a different growth pattern than anterior pillar cancer. RMT cancers tend to spread upward along the pterygomandibular raphe and deep in the masticator space after an initial superficial growth phase.11 In the published studies, the authors rely on the written and/or drawn description of the tumor to classify it as a RMT cancer instead of an anterior pillar cancer. Because of the retrospective nature of these studies and the difficulty to assess the exact initial subsite of a large tumor, misclassifi- Retromolar Trigone Carcinoma Controversies Table 1. Local control rates (%) according to T classification for retromolar trigone cancers and lateralized lesions of the oral cavity. T1 6 Lo et al Byers et al9 Mendenhall et al15 Ayad et al8 Barker et al7 Richaud et al14 71 92 75 85 82.6 T2 70 88 65 90 81 67.7 T3 76 90 65 85 81.8 T4 60 75 61 75 64 50 cation of anterior pillar cancers as RMT cancers is a concern. As previously mentioned, RMT cancers are considered prone to mandible invasion. Reported rates of pathologically proven bone invasion have been inconsistent, ranging from 12% to 53%.5,9,11,12 In the study by Kowalsky et al, 114 consecutive patients underwent a segmental mandibulectomy as part of their treatment.13 Mandibular invasion was seen in 14% of the cases and maxillary invasion in only 3 cases. Hao et al found a higher rate of bone invasion both in the maxilla (22%) than in the mandible (18%) in a series of 50 patients.11 PRIMARY SITE STAGING The absence of correlation between T staging and local control is a frequent finding in the literature with RMT carcinomas and other lateralized lesions of the oral cavity.14 Only T4 lesions are clearly associated to a worse local control, with bone invasion and masticator space extension established as unfavorable prognostic factors.6–9,14,15 Involvement of adjacent structures such as the masticator space, as opposed to T classification, is more relevant.11 For lower stages, local control does not appear to be influenced by the tumor size (Table 1). This could be explained by the superficial growth of RMT carcinomas. Cancer growth in this area is limited in deeper planes by the periosteum and bone. As a consequence, for each T classification, cancers arising and spreading in this area contain proportionately fewer cells than cancers that grow spherically, such as tongue or tonsillar fossa tumors. As stated by Barker et al ‘‘the stage according to diameter of the lesion (. . .) is not a reflection of the volume of the cancer.’’7 Tumors of the RMT are associated with areas of leukoplakia and erythroplakia in adjacent mucosa. Histopathologically, it has been documented HEAD & NECK—DOI 10.1002/hed March 2009 399 that in oral erythroplakia of the homogenous type, 51% showed invasive carcinoma and 40% carcinoma in situ.16 If underestimated, these lesions could be excluded of the radiation or resection field. Another potential contributing factor to the discrepancies observed in local control and T classification is the erroneous staging of the disease. Small lesions can involve minimal foci of osseous invasion that may be missed by physical examination or imaging. Stage underestimation can result in inappropriate treatment and thus, in erroneous local control rates for a particular stage. PREOPERATIVE ASSESSMENT Bone invasion has a strong impact on the management of RMT cancer. To maximize the cure rate, a marginal or segmental mandibulectomy is required when periosteal or bone invasion is suspected. It is unwise to rely solely on clinical examination to assess bone integrity in oral cavity cancers. In the study by Weisberger and Kimmelman, 33% of patients with histologically proven tumoral bone infiltration showed no clinical sign of bone invasion.17 Tsue et al found that 34% (11 of 32) of patients with clinically free mobile tumors had histologic bone tumoral infiltration and only 44% (14 of 32) of patients with clinical tumor fixation had confirmed histologic bone infiltration.18 However, Jones et al found that clinical assessment is an accurate method of predicting bone invasion with a sensitivity of 91% and negative predictive value (NPV) of 93%. These contradictory results make radiological assessment a useful adjunct to evaluate the need for mandible resection.19 Plain radiography, panorex, orthopantomography, MRI, and CT have all been used to assess mandibular integrity, with the latter 2 being the most commonly used nowadays. The use of CT in the assessment of mandibular invasion in oral cavity cancers is controversial. False-negative rates varying from 0% to 35% have been reported.20–25 In a series of 26 patients, Lane et al evaluated the parameters of accuracy for bone invasion assessment by a CT with 5-mm-thick axial sections. They found the following results: sensitivity 50%, specificity 91%, NPV 61%, positive predictive value (PPV) 87.5%.12 According to these results, CT is reliable when bone invasion is detected (PPV, 87.5%.) but a negative scan is of no use because half the patients with histologic bone invasion show no radiologic sign of bone invasion (NPV, 61%; sensitivity, 50%). As stated by the 400 Retromolar Trigone Carcinoma Controversies authors, these suboptimal results could be explained by the thick section studies (5 mm) and the lack of high-resolution bone algorithm. Accuracy of CT imaging in assessing bone invasion for RMT cancer is still to be established. MRI is a valuable tool in assessing surrounding structures including mandible as shown by Crecco et al. In this retrospective study, the results of MRI findings and pathological data were compared for 22 patients with RMT cancers.26 MRI appeared to be highly accurate to study the T classification and the relationships with the surrounding structures. In assessing bone marrow invasion the sensitivity was 100% but the specificity was 77%. As for CT, further evaluation of MRI accuracy to detect mandibular invasion in RMT cancers is needed. UNIMODAL TREATMENT OR COMBINED THERAPY To date, no clear recommendations have been proposed for the treatment of RMT cancers. Because of the rarity of this tumor at this subsite, retrospective studies reported limited number of patients, and a prospective randomized study is not feasible. We have to rely on retrospective studies with their inherent fallbacks and limitations. Out of 14 studies published on RMT cancer treatment in the English-language literature between 1959 and 2007, only 6 of them compared 2 or more treatment modalities.1,9,10,15,27,28 In the other studies, patients receive 1 treatment modality (surgery or radiation therapy) and the results are compared to historical series. However, patient and tumor characteristics are not comparable between these studies, and the reported outcomes are not uniform. For example, cause-specific survival is not mentioned in 5 of these studies.5,7,9,13,29 The results and conclusions of the 4 most recent comparative studies are summarized in Table 2. We did not include the 2 studies by Barbosa (1959 and 1962) in this table because of the short follow-up period and the evolution of radiation therapy techniques since then.1,28 In 1984, Byers et al reported their experience with 110 patients with RMT cancers treated with surgery (n 5 46), RT (n 5 50) or combined treatment (n 5 14) with minimal 2 years of follow-up.9 Median follow-up is not mentioned. In this study, the local and regional controls were similar between these groups of patients, and Byers concluded that single-mode therapy is equivalent to a combined therapy. Of note, the surgery groups included HEAD & NECK—DOI 10.1002/hed March 2009 Table 2. Studies comparing different treatment modalities for retromolar trigone carcinomas. Authors/year of publication Byers et al,9 1984 Huang et al,10 2001* Mendenhall et al,15 2005* Binahmed et al,27 2007 Local control, % Regional control, % Locoregional control, % CSS, % OS, % 89.5 84 – – – 90 – – 90 26 10 87.5–92 84 – 39 – – 77 63 – 15 64 – 71 – – 56 71 31 69 – 56 35 15 48 – – – 48 – 52 – 40 57 29 20 – – – – – – – – 45 64 Treatment Patients Surgery RT Combined treatment (preoperative RT) Combined treatment (postoperative RT) Radiotherapy alone Combined treatment (pre or postoperative RT) RT Combined treatment (postoperative RT) RT Surgery 110 – Abbreviations: CSS, cause-specific survival; OS, overall survival; RT, radiotherapy. *Studies with statistically significant differences between treatment modalities (p < .05). more T3-T4 cancers and cause-specific survival according to treatment modality is not reported in this study. Binhamed et al reported their experience with RMT cancer treatment in the province of Manitoba, Canada.27 Among 76 patients with RMT cancer, 12 were treated with palliative intent. Surgery was used as the primary treatment modality in 20 patients. Radiotherapy was used as the primary treatment modality in 29 patients with 3 patients having a neck dissection for persistent disease. Fifteen patients received postoperative radiotherapy. Median or minimum follow-up is not mentioned. The 5-year overall survival rates for patients treated with surgery was 64%, with surgery and radiotherapy 57%, and 45% when radiotherapy was elected as a single treatment modality. The difference between these 3 groups was not statistically significant (p 5 .0270). Locoregional control and cause-specific survival according to initial treatment modality have not been studied. Two recent comparative studies favor combined treatment with surgery and RT over RT alone.10,15 Mendenhall et al compared RT alone to RT combined with surgery in the treatment of RMT cancer.15 The data on 99 patients treated with curative intent between June 1966 and August 2003 were included in this study. The median follow-up was 3.3 years and no patient was lost on follow-up. Thirty-five patients were treated by definitive RT. Sixty-four patients had RT and surgery, preoperatively in 9 patients and postoperatively in 55 patients. In this study, multivariate Retromolar Trigone Carcinoma Controversies analysis showed that combined treatment significantly improved local control, local-regional control, distant metastasis-free survival, cause-specific survival, and overall survival. Huang et al studied 65 patients in 3 treatment groups: definitive RT (n 5 15), preoperative RT (n 5 10), and postoperative RT (n 5 39)10. The minimum followup was 5 years. Preoperative RT led to significantly better locoregional control and cause-specific survival (90% and 90%) than postoperative RT (77% and 63%) and RT alone (56% and 31%). These 2 studies share 1 drawback. Within the same institution, similar groups of patients with cancers of similar stage are treated differently and the reasons to do so cannot reliably be established retrospectively. RETROMOLAR TRIGONE SURGICAL MANAGEMENT Clinical or radiological suspicion of bone invasion indicates the need for segmental resection. Normal bone separated from the tumor by normal mucosa can usually be saved. Because RMT cancers lie directly on the anterior ramus of the mandible, bone resection must be systematically considered even if there is no gross bone invasion. A question remains as to whether a segmental or marginal (partial-thickness) mandibular resection is required for these patients. Bone involvement can be assessed intraoperatively even if preoperative clinical and radiological evaluations do not show bone involvement. For an optimal evaluation, the periosteum should be stripped from the mandible cautiously. If medullary bone invasion or perineural spread is confirmed by intraoperative exami- HEAD & NECK—DOI 10.1002/hed March 2009 401 nation, then segmental mandibulectomy is performed. If the bone is normal, periosteum histologic examination is performed. In the absence of infiltrating disease, no resection or marginal resection are reasonable options. In the presence of neoplastic invasion, segmental or marginal resections are both acceptable. Irradiated mandibles do not present the same dilemma. The pattern of invasion is different with tumor extending directly through different points in the cortex instead of the occlusal surface. In these patients marginal mandibulectomy is usually contraindicated because extensive and diffuse invasion of the mandibular body are expected.30 In 1959, Barbosa reported ‘‘the retromolar operation,’’ an original procedure consisting of a hemimandibulectomy with ‘‘en bloc’’ resection of the pterygoid and masseter muscles and ipsilateral radical neck dissection.1 In 2 small series, Barbosa concluded that surgery is superior to radiation therapy.1,28 In the original study Barbosa compares 10 patients treated by surgery to 11 treated by radiation therapy.1 Even though his results seem to favor surgery as the most adequate treatment for RMT cancer, one must restrain from adopting definitively the conclusions of this study. In fact, the variable and short duration of follow-up (less than 2 years), the small number of patients in each group, and the evolution of radiation therapy since 1959 limit the conclusions to be drawn from this study. Still, Barbosa has the merit to be the first to specifically assess the effectiveness of different treatment modalities for this small subsite of the oral cavity. Kowalski et al applied ‘‘the retromolar operation’’ or an extended version of it to 114 patients with RMT cancer in a 31-year period.13 Fortythree percent were classified as T1-T2. Radical neck dissection was performed in 92.1% of the patients. Sixty-six patients received postoperative radiotherapy for positive margins or multiple pathologic nodes. The median follow-up time was 25 months. Five-year disease-free survival and overall survival were 48.9% and 55.3%, respectively. The rate of local recurrences (27.2%) encourage the author to suggest a more extensive resection in appropriate patients and consider radiotherapy in the patients with stages III/IV cancer or when the tumor shows histologic criteria of aggressiveness such as perineural spread and vascular emboli. Petruzzelli et al reviewed their experience with posterior marginal mandibulectomy in the management of SCC of the RMT and orophar- 402 Retromolar Trigone Carcinoma Controversies ynx.31 Sixteen patients were included, with 13 treated for a primary located in the RMT. None of the patients had clinical or radiographic evidence of mandibular invasion. All patients received adjuvant radiation therapy and surgical treatment of the neck. Two of the 16 marginal mandibulectomies demonstrated bone invasion. Median overall survival was 37.5 months. Local control was achieved in 15 of the 16 patients (93.75%). The authors concluded that in the absence of clinical or radiographic evidence of bone invasion, the posterior marginal mandibulectomy provides the necessary bony margin to prevent local recurrence. Pascoal et al compared 20 patients who had a marginal mandibulectomy to 22 who had segmental mandibulectomy for tonsillar or RMT (11 patients) cancer.29 The patients had locally advanced disease without clinical or radiographic evidence of bone invasion. Twenty-eight patients (66.7%) were staged IVa (patients with lesions that invaded deep/extrinsic muscles of the tongue, the pterygoid muscle, or the hard palate) and 14 patients (33.3%) were staged IVb (patients with invasion of the lateral pterygoid muscle, or pterygoid laminae, or the lateral wall of the nasopharynx). All patients underwent postoperative radiotherapy. The main treatment failure in both groups was local and regional recurrence, at rates of 35% in the marginal mandibulectomy group, and 36.4% in segmental mandibulectomies. The survival rate of the group treated by marginal mandibulectomy was 55%.The survival rate of the group treated by segmental mandibulectomy was 45%. The authors believe that the unfavorable prognosis of advanced tumors without preoperative evidence of bone invasion should not encourage segmental resection, as preservation of part of the mandibular arch does not appear to worsen the survival rate and preserves function and aesthetics. In their review of the M. D. Anderson Cancer Center experience with treatment of RMT cancers, Byers et al have used marginal mandibulectomy in 5 patients with no local failures and segmental mandibulectomy in 46 patients with 4 local recurrences (12.5%).9 No preoperative tumor staging for these patients has been provided. In conclusion, marginal mandibulectomy seems to be safe if there is the possibility of bone involvement but no indicator of gross bone invasion. However, functional results and postoperative trismus according to the procedure have not been reported. The indications of postoperative radiotherapy are also unclear. Some institutes HEAD & NECK—DOI 10.1002/hed March 2009 favor postoperative radiotherapy for limited bone invasion with clear surgical margins, whereas others do not. ROLE OF CHEMOTHERAPY Various phase III studies and recent meta-analysis have advocated concurrent chemotherapy and RT for advanced stage III–IV head and neck carcinoma.32–34 Oral cavity lesions constituted only a fraction of the population studied. According to updated data from Notre-Dame hospital, 6 patients with stage III–IV carcinoma of the RMT received concurrent platinum-based chemotherapy and RT from 1999 to 2006.8 Four of these patients had a complete locoregional response. One patient had persistent disease at the primary and the neck and died of his disease. One patient had a complete response at the primary and underwent a neck dissection for a persistent neck node and has been without disease since. MANAGEMENT OF THE N0 NECK Presence of pathologic neck nodes is a bad prognostic factor in RMT cancers. Histologically involved lymph nodes are found in 26% to 80% of the patients.5,9,11 Reports of controlateral neck metastases are anecdotal.8–10 Thus, bilateral neck dissection is recommended only if the lesion crosses the midline anteriorly in the oral cavity or posteriorly in the oropharynx. The modality of treatment of the N1 neck should be the same as the primary. The N0 neck is systematically treated in the published reports. In the study by Byers et al,9 114 consecutive patients underwent surgical treatment of the RMT cancer with systematic neck dissection. N0 cases were treated at least with a supra-omohyoid neck dissection. The rate of occult metastases was 38% (16 of 42). In the study by Antoniades et al, the rate of occult metastases was 63.6% (7 of 11) but the number of patients was limited and the study grouped together the anterior pillar and RMT cancers.5 In the study by Hao et al, 50 patients with RMT squamous cell carcinomas were treated with curative intent by surgery.11 The rate of occult metastases was 8.3%. The rate of occult metastases varies between studies but as long as their frequency is not clearly established, systematic ipsilateral neck treatment is recommended in N0 cases. When surgery is the treatment selected, selective neck dissection should be performed for N0 necks with dissection of the level 2b if the lesion extends Retromolar Trigone Carcinoma Controversies to the oropharynx. Regional control has been similar in the series using surgery (89.5%)9,13 or radiotherapy (84%–90%)6,8,9 as primary treatment. In recent years, sentinel node biopsy (SNB) and SNB-guided elective neck dissection have been used in selected centers to stage N0 necks for T1-T2 cancers of the oral cavity. An increase in the staging sensitivity is expected by localizing the first-echelon nodes, including those with unpredictable drainage patterns, and then applying advanced anatomo-pathologic study techniques to a very reduced number of lymph nodes. In the published studies, patients with cancer of all subsites of the oral cavity are grouped together, with a few having RMT carcinoma. Nevertheless, reliability of the SNB for RMT cancers seems comparable to cancers arising in other subsites of the oral cavity excluding the floor of mouth.35,36 It has been found that SNB is less reliable for floor of mouths cancers than for the other oral cavity subsites.35,36 The close proximity of the floor of mouth to the nodal basin leads to difficulty in identifying and harvesting the sentinel node, which is not the case for RMT cancers. More studies are needed before considering SNB or SNB-guided END as part of a standard treatment for RMT carcinomas. CONCLUSIONS Literature on RMT cancer treatment demonstrates limitations on the establishment of guidelines due to the inherent characteristics of this tumor as well as the lack of uniformity between the studies. For a better understanding of the evolution of RMT cancer and its response to different treatment modalities, efforts should be made to report different institutional experience with this rare tumor. RTM and anterior pillar cancers should be studied separately because cancers arising from the subsites require a different initial assessment and seem to have different behavior and prognosis. Preoperative clinical and radiographic assessments need to be further investigated to establish their reliability at predicting bone invasion for RMT cancers. In the absence of clinical or radiological suspicion of bone invasion, surgery and radiation therapy seem to give similar results, but recent reports indicate a greater benefit if they are used in combination. If there is suspicion of mandibular or maxillary invasion, a primary surgical therapy is the mainstay of treatment. Decision on whether to treat a patient surgically or by radiation therapy based on clinical and radiographic grounds HEAD & NECK—DOI 10.1002/hed March 2009 403 appears to carry a significant amount of uncertainty. For this reason, many advocate systematic surgical treatment with at least a marginal mandibulectomy for RMT cancers. Some authors have advocated systematic segmental resection for all RMT cancers but marginal mandibulectomy is a reasonable option in selected cases. The experience of combined chemotherapy and RT for advanced carcinoma of RMT is scarce, but is most likely a reasonable option when there is no documented bone invasion and the patient is reluctant to surgery. Surgery is then proposed as salvage therapy. Even if SNB has been used recently as a staging procedure for N0 necks in T1-T2 oral cavity cancers, standard treatment for RMT cancers with N0 necks remains selective neck dissection or radiation therapy depending on the modality of treatment of the primary. REFERENCES 1. Barbosa JF. Cancer of the retromolar area: a study of twenty-eight cases with the presentation of a new surgical technique for their treatment. AMA Arch Otolaryngol 1959;69:19–30. 2. 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