Vol. 118 No. 6 December 2014
Risk factors for and consequences of inadequate surgical margins in oral squamous cell carcinoma Mads Lawaetz, MD, and Preben Homøe, MD, PhD, DMsc Rigshospitalet, University Hospital Copenhagen, Copenhagen, Denmark
Objective. The purpose of this study was to examine which factors are associated with inadequate surgical margins and to assess the postoperative consequences. Study Design. A retrospective cohort of 110 patients with oral squamous cell carcinoma treated with surgery during a 2-year period was examined. Clinical, histopathologic, and operative variables were related to the surgical margin status. Furthermore postoperative treatment data were compared with margin status. Results. Univariate statistically significant associations were found between the tumor site in the floor of mouth, more advanced T-stage, increasing tumor thickness, and inadequate margins. Of the patients with involved margins, 87% were treated with postoperative radiotherapy or re-resection, but among patients with close margins, only 35% received either radiotherapy or re-resection. Conclusions. Clinical and histopathologic factors were associated with the inadequate margin. Postoperative treatment for patients with close margins is controversial, and more studies are needed to define clear guidelines. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:642-646)
The most common site of head and neck cancer is the oral cavity, including the floor of mouth, oral tongue, hard palate, gingiva, buccal mucosa, and retromolar trigone, with an overall survival ranging from 28% to 69% in European studies.1 The incidence of oral cancer has been increasing in Denmark over the past decades.2 According to the Danish Head and Neck Cancer Group (DAHANCA), the treatment for oral squamous cell carcinoma depends on stage and histopathologic factors. The recommended treatment for stage I (T1 N0), stage II (T2 N0), and some stage III (T1 N1, T2 N1) is monotherapy, which is either surgery or radiotherapy. Surgery is the preferred monotherapy at the tumor site as long as radical resection is expected to be possible with a functionally and aesthetically acceptable result. One indication for postoperative radiotherapy for these stages is when the tumor is not radically removed (i.e., micro- or macroscopic tumor too close to the margin). Stage III and IV are treated with combination therapy. In the surgical treatment of oral squamous cell carcinoma, the aim is to get an adequate clearance of the tumor. The surgeon attempts to resect a margin of 10 mm normal tissue around the tumor. The adequacy of the surgical margin cannot be confirmed until the tissue has been histopathologically evaluated. In clinical practice there are 2 margins: the surgeon’s (or in situ) margin and the pathologist’s margin of the delivered
tissue. There has been reported shrinkage of the mucosal margin between 21% and 59%.3-6 The most widely accepted definition of an inadequate margin is less than 5 mm to carcinoma,7 and we used this definition in our study. A close or involved margin increases the probability of local recurrence by a factor 2 or more in most reports.5,8-10 More uncertain is the inadequate margin’s effect on overall survival. This has been found in some studies8,9 but not others.5,11 According to national guidelines, the close or involved margin should be treated with postoperative radiotherapy. The clear margin is not only prognostically important. As the close or involved margin is an indication for postoperative radiotherapy, the patient with clear margin and limited N and T-stage disease also avoids the morbidity and reduction in quality of life that comes from postoperative radiotherapy,12 as well as maintaining the options for treating recurrence or new primaries in the head and neck. In some studies, the margin status has been associated with factors that have an effect on outcome in oral cancer, including tumor site,13 T status,8,13 N status,8,13 tumor thickness,14 and the pattern of invasion of the
Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University Hospital Copenhagen, Faculty of Health Sciences. Received for publication Feb 2, 2014; returned for revision Jun 21, 2014; accepted for publication Aug 6, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.08.001
We found that the tumor site in the floor of mouth, more advanced T-stage, and increasing tumor thickness were associated with inadequate margins. Postoperative treatment for patients with close margins is controversial, and more studies are needed to define clear guidelines.
642
Statement of Clinical Relevance
OOOO Volume 118, Number 6
tumor.8,11 The question has been raised as to whether or not the positive margin is an indicator of more aggressive disease.9 Others have suggested that anatomic factors are responsible for a large proportion of the positive margin.15 The purpose of this study was to examine if clinical and histopathologic factors are associated with the close or involved surgical margin and to identify which postoperative consequences a close or involved margin has.
MATERIALS AND METHODS This study examined a retrospective cohort of 178 patients with squamous cell carcinoma of the oral cavity treated at Rigshospitalet, Copenhagen, Denmark, during a 2-year period from January 2010 to December 2011. The patients were extracted using topography codes of the International Classification of Diseases for Oncology, Third Edition, from C02.0 to C06.0 and the NOMESCO (Nordic Medico-Statistical Committee) Classification of Surgical Procedures codes KEJB10, 20, 30, 35, 40, 50, 60, and 99. After excluding patients with recurrence of oral squamous cell carcinoma (n ¼ 38), all tumor material resected in the biopsy (n ¼ 12), carcinoma in situ (n ¼ 5), metastatic disease from other areas (n ¼ 2), or patients previously treated with radiotherapy in the head and neck area (n ¼ 11), there were 110 cases with biopsy-proven and previously untreated oral squamous cell carcinoma managed with surgery with or without postoperative radiotherapy. Clinical, demographic, and operative data were retrieved from the electronic medical records, and pathology data were retrieved from pathology reports. The tumor margins were recorded in millimeters on all edges (i.e., anterior, posterior, lateral, medial, and deep), and the smallest margin was then categorized according to the UK Royal College of Pathologists as “clear,” “close,” or “involved” when the primary tumor was respectively >5 mm, 1 to 5 mm, or .1), and significance level P < .05 and odds ratio (OR) were used to assess the independent effect of the variables on margin status when controlling for covariates.
RESULTS The cohort characteristics and tumor characteristics of the 110 patients with oral squamous cell carcinoma are shown in Table II, including univariate statistics of differences between groups. The median age at the time of diagnosis was 66 years (range, 30-94 years). Most of the tumors were T1 and T2 (91%), and the rest were T3 and T4a. The mean tumor size was 20.3 mm (width) and 14.9 mm (length). The mean tumor thickness was 5.8 mm. Nodal disease (N1 and N2) was reported in 26% of the patients. No distant metastasis was described. The procedures were carried out by 7 different surgeons, of whom 3 were responsible for 73% of the procedures. There were no statistically significant differences in tumor size, tumor thickness, T-stage, or N-stage between men and women or between the 2 age groups (older or younger than 65 years) (data not shown). Of the 110 patients, 40 (36%) had clear margin; 55 (50%), close margin; and 15 (14%), involved margin.
ORAL AND MAXILLOFACIAL SURGERY 644 Lawaetz and Homøe
OOOO December 2014
Table II. Relationship between margin status and clinical, pathologic, and operative data
Table III. Relationship between margin status after primary surgery and postoperative treatment modalities Margin status
Margin status Variable Gender Female Male Age < 65 Age 65 Tumor site Floor of mouth Tongue Other T stage T1 T2 T3 or T4 Perineural spread No Yes Vascular permeation No Yes Character of invasive front Cohesive Noncohesive Surgical instrument Not specified Electric scissors Carbon dioxide laser Total (n ¼ 110)
Clear (>5 mm) 17 23 19 21
Close or involved (5 mm)
P
(45%) (32%) (40%) (34%)
21 49 29 41
.21
11 (23%) 25 (48%) 4 (36%)
36 27 7
.039
30 (46%) 9 (30%) 1 (10%)
37 24 9
.044
29 (43%) 9 (27%)
39 24
.19
37 (37%) 1 (25%)
64 3
.64
20 (46%) 18 (31%)
24 41
.15
23 11 6 40
47 9 14 70
.16
(33%) (55%) (30%) (36%)
Variable
Clear
Close
Involved
Total
Surgery alone Postoperative radiotherapy Margin re-resection Total
38 2 0 40
35 17 2 54
2 12 1 15
75 31 3 109
.56
Significant association was observed between close or involved margin and tumor site (P ¼ .039). Patients with lesions in the floor of mouth were more likely to have inadequate margins than tongue lesions (Table II). The inadequate margin in the floor of mouth tumors was the deep margin in 64% (n ¼ 23), the posterior in 36% (n ¼ 13), the lateral in 36% (n ¼ 13), the anterior in 28% (n ¼ 10), and the medial in 17% (n ¼ 6). The deep margin was significantly more often close or involved (P < .001) than the other 4 margins. Of the 36 patients with a close or involved margin in the floor of mouth, 16 had more than 1 inadequate margin. When controlling for covariates in logistic regression analysis in 96 patients (14 were excluded owing to incomplete or missing data), all included variables disappeared as significant. The last variable in the model was T-stage, with a value of P ¼ .098 and with OR ¼ .17 (95% CI, 0.02-1.46) for T-1 and OR ¼ 0.38 (95% CI, 0.04-3.55) for T-2 compared with T3-4 (data not shown). Data about postoperative treatment were available for 109 patients (Table III). Among the patients with close margins, 19 (35%) received radiotherapy or re-resection, and 35 (65%) had surgery alone without supplementary treatment. In the last subgroup, 16 were offered radiotherapy but rejected it, according
to the medical records. In the remaining 19 patients, no information was available as to why no additional therapy was instituted. Two patients with clear margins received postoperative radiotherapy, one because of advanced T-stage and the other because of extracapsular lymph node spread.
DISCUSSION This cohort of patients is comparable with those of most other retrospective studies of patients with oral squamous cell carcinoma regarding age, sex, and tumor site distribution. The frequency of tumors in stages T3 and T4 was lower than in most other larger studies.9,13,15 Clear margin was found in 36% of the cases, which is consistent with the literature, in which the clear margin in oral squamous cell carcinoma varies between 25% and 85%.8,9,11,15 Some studies include dysplasia and carcinoma in situ in the definition of an inadequate margin. The diversity of the definition of a clear and close margin may explain the variation in frequency reported.8 Only 14% of our population had involved margin, and this lies within the reported range of 3% to 22%16-18 of involved margins after surgery for oral cancer. Tumors in the floor of mouth were found to be associated with close or involved margins, with the deep margin being the most common. A more aggressive resection at the deep margin may therefore be considered to achieve better surgical results. The difference in margin status between tongue and floor of mouth tumors may reflect the increased difficulty of the resection in this anatomic site. One study8 found that retromolar and buccal tumors had the highest frequency of inadequate margins in the oral cavity. We were not able to find this relationship, given that we had only 5 retromolar tumors and no buccal tumors in the cohort. If we had had larger numbers of tumors from areas where resection is difficult (such as the retromolar trigone, the buccal mucosa, and the palate), the results would probably have reflected that. The association between T-stage, tumor thickness, and close or involved margins is likely to reflect the problem that large tumors are a greater surgical challenge. A retrospective study from 201115 suggested that anatomic factors accounted for a substantial proportion
OOOO Volume 118, Number 6
of involved margins and that improved imaging and surgical approaches resulted in higher frequencies of clear margins. But anatomic factors may just be one part of the problem. We could not confirm the univariate associations in a logistic regression analysis controlling for covariates. We believe this is due to the rather small sample size for such an analysis. Our data do not show statistically significant association between histologic indicators of aggressive disease (noncohesive front, perineural spread, and vascular permeation) and close or involved margin. However, significant associations have been found in larger studies.8,11 The treatment consequences for patients with inadequate margins in our study were dependent on whether the margin was involved or close. As expected, almost all patients (87%) with involved margins received postoperative radiotherapy or re-resection, and only a few patients (5%) with clear margins were treated with postoperative radiotherapy. Surprisingly, only 35% with close margins were treated with radiotherapy or reresection. The remaining 65% of the patients with close margin did not receive radiotherapy despite being at intermediate risk of recurrence. Sixteen of them refused postoperative radiotherapy, presumably because of the knowledge given about potential adverse events, but the other half may not have been offered radiotherapy. If the 19 patients with close margins were not offered radiotherapy, it could be because of discrepancy between the surgeon’s margin and the pathologist’s margin. If the surgeon finds the tumor radically resected, albeit the pathologist’s margin is close, the surgeon might have a tendency to recommend a watch-and-wait policy rather than radiotherapy. These data reflect the variation in opinion on using radiotherapy, which is described in the literature. Blackburn et al.,19 in a questionnaire survey sent to members of the British Association of Head and Neck Oncologists, found considerable variation in opinion on using postoperative radiotherapy in the intermediate-risk group. This diversity of opinion could be a result of the controversy in determining which patients at intermediate risk would benefit from radiotherapy. Brown et al.12 and Wong et al.17 compared outcome for relatively large retrospective intermediate-risk groups treated with surgery with or without postoperative radiotherapy. They included respectively 462 and 192 patients with oral squamous cell carcinoma. They found that 56% to 59% of the patients in the intermediate-risk group did not receive radiotherapy; this was comparable with our result. Furthermore, they questioned the benefit of radiotherapy for the intermediate-risk group and found only a small reduction in recurrence after treatment. Wong et al.17 postulated that not all patients with close margins required postoperative therapy and suggested that close margins should be redefined as 1 to 2 mm. Other recent studies
ORIGINAL ARTICLE Lawaetz and Homøe 645
found weak survival benefit12,20,21 from radiotherapy and at the same time increased morbidity accompanied by reduction in quality of life parameters.20 All studies referred to in this article regarding treatment modalities have been retrospective. In the review by Langendijk et al.,22 literature on postoperative strategies after primary surgery of squamous cell carcinoma of the head and neck were examined. They found that there were no large randomized controlled trials confirming the additional value of postoperative radiotherapy after primary surgery compared with surgery alone. Only 1 small randomized controlled trial23 with 42 patients addressed this problem, and this study only included stage III and stage IV tumors, most of them not located within the oral cavity. The current guidelines for postoperative radiotherapy are based primarily on findings from retrospective studies. This study has some limitations. The study is limited to 1 hospital in a 2-year period and has a relatively small study population compared with other similar studies. Furthermore, it was not possible to examine associations between margins and T-site recurrence or survival, owing to a too-short follow-up period. Several surgeons and pathologists documented clinical and histopathologic data, respectively. Many variables including the margin status may vary depending on the individual reporting. The interobserver variation is a known problem of this study design.
CONCLUSION With univariate testing, this study found statistically significant associations between tumor site in the floor of mouth, more advanced T-stage, increasing tumor thickness, and close or involved margins. The deep margin was significantly the most common inadequate margin in floor of mouth tumors. The univariate associations could not be confirmed in logistic regression analysis when controlling for covariates. However, our findings suggest that a larger deep surgical margin should be resected and that floor of mouth tumors are especially technically challenging for the surgeon. The majority of patients with involved margins were treated with postoperative radiotherapy, but among patients with close margins, only 35% received either radiotherapy or re-resection, and uncertainty remains about the basis for this decision. Both the variation in opinion regarding postoperative radiotherapy and the weak survival benefit compared with morbidity indicate the need for high-quality data from prospective, randomized controlled trials to define clear guidelines for postoperative radiotherapy, especially for patients with close margins. REFERENCES 1. Rogers SN, Brown JS, Woolgar JA, et al. Survival following primary surgery for oral cancer. Oral Oncol. 2009;45:201-211.
ORAL AND MAXILLOFACIAL SURGERY 646 Lawaetz and Homøe 2. Blomberg M, Nielsen A, Munk C, Kjaer SK. Trends in head and neck cancer incidence in Denmark, 1978-2007: focus on human papillomavirus associated sites. Int J Cancer. 2011;129: 733-741. 3. Mistry RC, Qureshi SS, Kumaran C. Post-resection mucosal margin shrinkage in oral cancer: quantification and significance. J Surg Oncol. 2005;91:131-133. 4. Johnson RE, Sigman JD, Funk GF, Robinson RA, Hoffman HT. Quantification of surgical margin shrinkage in the oral cavity. Head Neck. 1997;19:281-286. 5. Spiro RH, Guillamondegui O, Paulino AF, Huvos AG. Pattern of invasion and margin assessment in patients with oral tongue cancer. Head Neck. 1999;21:408-413. 6. Cheng A, Cox D, Schmidt BL. Oral squamous cell carcinoma margin discrepancy after resection and pathologic processing. J Oral Maxillofac Surg. 2008;66:523-529. 7. Helliwell TR, Woolgar JA. Datasets for Histopathology Reports on Head and Neck Carcinomas and Salivary Neoplasms. 2nd ed. London, England: Royal College of Pathologists; 2005. 8. Sutton DN, Brown JS, Rogers SN, Vaughan ED, Woolgar JA. The prognostic implications of the surgical margin in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2003;32:30-34. 9. Binahmed A, Nason RW, Abdoh AA. The clinical significance of the positive surgical margin in oral cancer. Oral Oncol. 2007;43:780-784. 10. Slootweg PJ, Hordijk GJ, Schade Y, van Es RJJ, Koole R. Treatment failure and margin status in head and neck cancer: a critical view on the potential value of molecular pathology. Oral Oncol. 2002;38:500-503. 11. Kademani D, Bell RB, Bagheri S, et al. Prognostic factors in intraoral squamous cell carcinoma: the influence of histologic grade. J Oral Maxillofac Surg. 2005;63:1599-1605. 12. Brown JS, Blackburn TK, Woolgar JA, et al. A comparison of outcomes for patients with oral squamous cell carcinoma at intermediate risk of recurrence treated by surgery alone or with post-operative radiotherapy. Oral Oncol. 2007;43:764-773. 13. Woolgar JA, Triantafyllou A. A histopathological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens. Oral Oncol. 2005;41:1034-1043. 14. Yuen AP, Lam KY, Wei WI, et al. A comparison of the prognostic significance of tumor diameter, length, width, thickness, area, volume, and clinicopathological features of oral tongue carcinoma. Am J Surg. 2000;180:139-143. 15. McMahon JD, Devine JC, Hetherington J, et al. Involved surgical margins in oral and oropharyngeal carcinomadan
OOOO December 2014
16.
17.
18.
19.
20.
21.
22.
23.
anatomical problem? Br J Oral Maxillofac Surg. 2011;49: 172-175. McMahon J, O’Brien CJ, Pathak I, et al. Influence of condition of surgical margins on local recurrence and disease-specific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg. 2003;41:224-231. Wong LS, McMahon J, Devine J, et al. Influence of close resection margins on local recurrence and disease-specific survival in oral and oropharyngeal carcinoma. Br J Oral Maxillofac Surg. 2012;50:102-108. Nason RW, Binahmed A, Pathak KA, Abdoh AA, Sándor GKB. What is the adequate margin of surgical resection in oral cancer? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107: 625-629. Blackburn TK, Bakhtawar S, Brown JS, Lowe D, Vaughan ED, Rogers SN. A questionnaire survey of current UK practice for adjuvant radiotherapy following surgery for oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2007;43:143-149. Bekiroglu F, Ghazali N, Laycock R, Katre C, Lowe D, Rogers SN. Adjuvant radiotherapy and health-related quality of life of patients at intermediate risk of recurrence following primary surgery for oral squamous cell carcinoma. Oral Oncol. 2011;47:967-973. Brown JS, Shaw RJ, Bekiroglu F, Rogers SN. Systematic review of the current evidence in the use of postoperative radiotherapy for oral squamous cell carcinoma. Br J Oral Maxillofac Surg. 2012;50:481-489. Langendijk JA, Ferlito A, Takes RP, et al. Postoperative strategies after primary surgery for squamous cell carcinoma of the head and neck. Oral Oncol. 2010;46:577-585. Rodrigo JP, Maseda E, Maldonado M, et al. [Efficacy of postoperative radiation therapy for squamous cell carcinoma of the head and neck: results of a prospective randomised clinical trial]. Acta Otorrinolaringol Esp. 2004;55:415-419.
Reprint requests: Mads Lawaetz Rigshospitalet University Hospital Copenhagen Blegdamsvej 9 2100 Copenhagen East Denmark [email protected]
Risk factors for and consequences of inadequate surgical margins in oral squamous cell carcinoma Mads Lawaetz, MD, and Preben Homøe, MD, PhD, DMsc Rigshospitalet, University Hospital Copenhagen, Copenhagen, Denmark
Objective. The purpose of this study was to examine which factors are associated with inadequate surgical margins and to assess the postoperative consequences. Study Design. A retrospective cohort of 110 patients with oral squamous cell carcinoma treated with surgery during a 2-year period was examined. Clinical, histopathologic, and operative variables were related to the surgical margin status. Furthermore postoperative treatment data were compared with margin status. Results. Univariate statistically significant associations were found between the tumor site in the floor of mouth, more advanced T-stage, increasing tumor thickness, and inadequate margins. Of the patients with involved margins, 87% were treated with postoperative radiotherapy or re-resection, but among patients with close margins, only 35% received either radiotherapy or re-resection. Conclusions. Clinical and histopathologic factors were associated with the inadequate margin. Postoperative treatment for patients with close margins is controversial, and more studies are needed to define clear guidelines. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:642-646)
The most common site of head and neck cancer is the oral cavity, including the floor of mouth, oral tongue, hard palate, gingiva, buccal mucosa, and retromolar trigone, with an overall survival ranging from 28% to 69% in European studies.1 The incidence of oral cancer has been increasing in Denmark over the past decades.2 According to the Danish Head and Neck Cancer Group (DAHANCA), the treatment for oral squamous cell carcinoma depends on stage and histopathologic factors. The recommended treatment for stage I (T1 N0), stage II (T2 N0), and some stage III (T1 N1, T2 N1) is monotherapy, which is either surgery or radiotherapy. Surgery is the preferred monotherapy at the tumor site as long as radical resection is expected to be possible with a functionally and aesthetically acceptable result. One indication for postoperative radiotherapy for these stages is when the tumor is not radically removed (i.e., micro- or macroscopic tumor too close to the margin). Stage III and IV are treated with combination therapy. In the surgical treatment of oral squamous cell carcinoma, the aim is to get an adequate clearance of the tumor. The surgeon attempts to resect a margin of 10 mm normal tissue around the tumor. The adequacy of the surgical margin cannot be confirmed until the tissue has been histopathologically evaluated. In clinical practice there are 2 margins: the surgeon’s (or in situ) margin and the pathologist’s margin of the delivered
tissue. There has been reported shrinkage of the mucosal margin between 21% and 59%.3-6 The most widely accepted definition of an inadequate margin is less than 5 mm to carcinoma,7 and we used this definition in our study. A close or involved margin increases the probability of local recurrence by a factor 2 or more in most reports.5,8-10 More uncertain is the inadequate margin’s effect on overall survival. This has been found in some studies8,9 but not others.5,11 According to national guidelines, the close or involved margin should be treated with postoperative radiotherapy. The clear margin is not only prognostically important. As the close or involved margin is an indication for postoperative radiotherapy, the patient with clear margin and limited N and T-stage disease also avoids the morbidity and reduction in quality of life that comes from postoperative radiotherapy,12 as well as maintaining the options for treating recurrence or new primaries in the head and neck. In some studies, the margin status has been associated with factors that have an effect on outcome in oral cancer, including tumor site,13 T status,8,13 N status,8,13 tumor thickness,14 and the pattern of invasion of the
Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University Hospital Copenhagen, Faculty of Health Sciences. Received for publication Feb 2, 2014; returned for revision Jun 21, 2014; accepted for publication Aug 6, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.08.001
We found that the tumor site in the floor of mouth, more advanced T-stage, and increasing tumor thickness were associated with inadequate margins. Postoperative treatment for patients with close margins is controversial, and more studies are needed to define clear guidelines.
642
Statement of Clinical Relevance
OOOO Volume 118, Number 6
tumor.8,11 The question has been raised as to whether or not the positive margin is an indicator of more aggressive disease.9 Others have suggested that anatomic factors are responsible for a large proportion of the positive margin.15 The purpose of this study was to examine if clinical and histopathologic factors are associated with the close or involved surgical margin and to identify which postoperative consequences a close or involved margin has.
MATERIALS AND METHODS This study examined a retrospective cohort of 178 patients with squamous cell carcinoma of the oral cavity treated at Rigshospitalet, Copenhagen, Denmark, during a 2-year period from January 2010 to December 2011. The patients were extracted using topography codes of the International Classification of Diseases for Oncology, Third Edition, from C02.0 to C06.0 and the NOMESCO (Nordic Medico-Statistical Committee) Classification of Surgical Procedures codes KEJB10, 20, 30, 35, 40, 50, 60, and 99. After excluding patients with recurrence of oral squamous cell carcinoma (n ¼ 38), all tumor material resected in the biopsy (n ¼ 12), carcinoma in situ (n ¼ 5), metastatic disease from other areas (n ¼ 2), or patients previously treated with radiotherapy in the head and neck area (n ¼ 11), there were 110 cases with biopsy-proven and previously untreated oral squamous cell carcinoma managed with surgery with or without postoperative radiotherapy. Clinical, demographic, and operative data were retrieved from the electronic medical records, and pathology data were retrieved from pathology reports. The tumor margins were recorded in millimeters on all edges (i.e., anterior, posterior, lateral, medial, and deep), and the smallest margin was then categorized according to the UK Royal College of Pathologists as “clear,” “close,” or “involved” when the primary tumor was respectively >5 mm, 1 to 5 mm, or .1), and significance level P < .05 and odds ratio (OR) were used to assess the independent effect of the variables on margin status when controlling for covariates.
RESULTS The cohort characteristics and tumor characteristics of the 110 patients with oral squamous cell carcinoma are shown in Table II, including univariate statistics of differences between groups. The median age at the time of diagnosis was 66 years (range, 30-94 years). Most of the tumors were T1 and T2 (91%), and the rest were T3 and T4a. The mean tumor size was 20.3 mm (width) and 14.9 mm (length). The mean tumor thickness was 5.8 mm. Nodal disease (N1 and N2) was reported in 26% of the patients. No distant metastasis was described. The procedures were carried out by 7 different surgeons, of whom 3 were responsible for 73% of the procedures. There were no statistically significant differences in tumor size, tumor thickness, T-stage, or N-stage between men and women or between the 2 age groups (older or younger than 65 years) (data not shown). Of the 110 patients, 40 (36%) had clear margin; 55 (50%), close margin; and 15 (14%), involved margin.
ORAL AND MAXILLOFACIAL SURGERY 644 Lawaetz and Homøe
OOOO December 2014
Table II. Relationship between margin status and clinical, pathologic, and operative data
Table III. Relationship between margin status after primary surgery and postoperative treatment modalities Margin status
Margin status Variable Gender Female Male Age < 65 Age 65 Tumor site Floor of mouth Tongue Other T stage T1 T2 T3 or T4 Perineural spread No Yes Vascular permeation No Yes Character of invasive front Cohesive Noncohesive Surgical instrument Not specified Electric scissors Carbon dioxide laser Total (n ¼ 110)
Clear (>5 mm) 17 23 19 21
Close or involved (5 mm)
P
(45%) (32%) (40%) (34%)
21 49 29 41
.21
11 (23%) 25 (48%) 4 (36%)
36 27 7
.039
30 (46%) 9 (30%) 1 (10%)
37 24 9
.044
29 (43%) 9 (27%)
39 24
.19
37 (37%) 1 (25%)
64 3
.64
20 (46%) 18 (31%)
24 41
.15
23 11 6 40
47 9 14 70
.16
(33%) (55%) (30%) (36%)
Variable
Clear
Close
Involved
Total
Surgery alone Postoperative radiotherapy Margin re-resection Total
38 2 0 40
35 17 2 54
2 12 1 15
75 31 3 109
.56
Significant association was observed between close or involved margin and tumor site (P ¼ .039). Patients with lesions in the floor of mouth were more likely to have inadequate margins than tongue lesions (Table II). The inadequate margin in the floor of mouth tumors was the deep margin in 64% (n ¼ 23), the posterior in 36% (n ¼ 13), the lateral in 36% (n ¼ 13), the anterior in 28% (n ¼ 10), and the medial in 17% (n ¼ 6). The deep margin was significantly more often close or involved (P < .001) than the other 4 margins. Of the 36 patients with a close or involved margin in the floor of mouth, 16 had more than 1 inadequate margin. When controlling for covariates in logistic regression analysis in 96 patients (14 were excluded owing to incomplete or missing data), all included variables disappeared as significant. The last variable in the model was T-stage, with a value of P ¼ .098 and with OR ¼ .17 (95% CI, 0.02-1.46) for T-1 and OR ¼ 0.38 (95% CI, 0.04-3.55) for T-2 compared with T3-4 (data not shown). Data about postoperative treatment were available for 109 patients (Table III). Among the patients with close margins, 19 (35%) received radiotherapy or re-resection, and 35 (65%) had surgery alone without supplementary treatment. In the last subgroup, 16 were offered radiotherapy but rejected it, according
to the medical records. In the remaining 19 patients, no information was available as to why no additional therapy was instituted. Two patients with clear margins received postoperative radiotherapy, one because of advanced T-stage and the other because of extracapsular lymph node spread.
DISCUSSION This cohort of patients is comparable with those of most other retrospective studies of patients with oral squamous cell carcinoma regarding age, sex, and tumor site distribution. The frequency of tumors in stages T3 and T4 was lower than in most other larger studies.9,13,15 Clear margin was found in 36% of the cases, which is consistent with the literature, in which the clear margin in oral squamous cell carcinoma varies between 25% and 85%.8,9,11,15 Some studies include dysplasia and carcinoma in situ in the definition of an inadequate margin. The diversity of the definition of a clear and close margin may explain the variation in frequency reported.8 Only 14% of our population had involved margin, and this lies within the reported range of 3% to 22%16-18 of involved margins after surgery for oral cancer. Tumors in the floor of mouth were found to be associated with close or involved margins, with the deep margin being the most common. A more aggressive resection at the deep margin may therefore be considered to achieve better surgical results. The difference in margin status between tongue and floor of mouth tumors may reflect the increased difficulty of the resection in this anatomic site. One study8 found that retromolar and buccal tumors had the highest frequency of inadequate margins in the oral cavity. We were not able to find this relationship, given that we had only 5 retromolar tumors and no buccal tumors in the cohort. If we had had larger numbers of tumors from areas where resection is difficult (such as the retromolar trigone, the buccal mucosa, and the palate), the results would probably have reflected that. The association between T-stage, tumor thickness, and close or involved margins is likely to reflect the problem that large tumors are a greater surgical challenge. A retrospective study from 201115 suggested that anatomic factors accounted for a substantial proportion
OOOO Volume 118, Number 6
of involved margins and that improved imaging and surgical approaches resulted in higher frequencies of clear margins. But anatomic factors may just be one part of the problem. We could not confirm the univariate associations in a logistic regression analysis controlling for covariates. We believe this is due to the rather small sample size for such an analysis. Our data do not show statistically significant association between histologic indicators of aggressive disease (noncohesive front, perineural spread, and vascular permeation) and close or involved margin. However, significant associations have been found in larger studies.8,11 The treatment consequences for patients with inadequate margins in our study were dependent on whether the margin was involved or close. As expected, almost all patients (87%) with involved margins received postoperative radiotherapy or re-resection, and only a few patients (5%) with clear margins were treated with postoperative radiotherapy. Surprisingly, only 35% with close margins were treated with radiotherapy or reresection. The remaining 65% of the patients with close margin did not receive radiotherapy despite being at intermediate risk of recurrence. Sixteen of them refused postoperative radiotherapy, presumably because of the knowledge given about potential adverse events, but the other half may not have been offered radiotherapy. If the 19 patients with close margins were not offered radiotherapy, it could be because of discrepancy between the surgeon’s margin and the pathologist’s margin. If the surgeon finds the tumor radically resected, albeit the pathologist’s margin is close, the surgeon might have a tendency to recommend a watch-and-wait policy rather than radiotherapy. These data reflect the variation in opinion on using radiotherapy, which is described in the literature. Blackburn et al.,19 in a questionnaire survey sent to members of the British Association of Head and Neck Oncologists, found considerable variation in opinion on using postoperative radiotherapy in the intermediate-risk group. This diversity of opinion could be a result of the controversy in determining which patients at intermediate risk would benefit from radiotherapy. Brown et al.12 and Wong et al.17 compared outcome for relatively large retrospective intermediate-risk groups treated with surgery with or without postoperative radiotherapy. They included respectively 462 and 192 patients with oral squamous cell carcinoma. They found that 56% to 59% of the patients in the intermediate-risk group did not receive radiotherapy; this was comparable with our result. Furthermore, they questioned the benefit of radiotherapy for the intermediate-risk group and found only a small reduction in recurrence after treatment. Wong et al.17 postulated that not all patients with close margins required postoperative therapy and suggested that close margins should be redefined as 1 to 2 mm. Other recent studies
ORIGINAL ARTICLE Lawaetz and Homøe 645
found weak survival benefit12,20,21 from radiotherapy and at the same time increased morbidity accompanied by reduction in quality of life parameters.20 All studies referred to in this article regarding treatment modalities have been retrospective. In the review by Langendijk et al.,22 literature on postoperative strategies after primary surgery of squamous cell carcinoma of the head and neck were examined. They found that there were no large randomized controlled trials confirming the additional value of postoperative radiotherapy after primary surgery compared with surgery alone. Only 1 small randomized controlled trial23 with 42 patients addressed this problem, and this study only included stage III and stage IV tumors, most of them not located within the oral cavity. The current guidelines for postoperative radiotherapy are based primarily on findings from retrospective studies. This study has some limitations. The study is limited to 1 hospital in a 2-year period and has a relatively small study population compared with other similar studies. Furthermore, it was not possible to examine associations between margins and T-site recurrence or survival, owing to a too-short follow-up period. Several surgeons and pathologists documented clinical and histopathologic data, respectively. Many variables including the margin status may vary depending on the individual reporting. The interobserver variation is a known problem of this study design.
CONCLUSION With univariate testing, this study found statistically significant associations between tumor site in the floor of mouth, more advanced T-stage, increasing tumor thickness, and close or involved margins. The deep margin was significantly the most common inadequate margin in floor of mouth tumors. The univariate associations could not be confirmed in logistic regression analysis when controlling for covariates. However, our findings suggest that a larger deep surgical margin should be resected and that floor of mouth tumors are especially technically challenging for the surgeon. The majority of patients with involved margins were treated with postoperative radiotherapy, but among patients with close margins, only 35% received either radiotherapy or re-resection, and uncertainty remains about the basis for this decision. Both the variation in opinion regarding postoperative radiotherapy and the weak survival benefit compared with morbidity indicate the need for high-quality data from prospective, randomized controlled trials to define clear guidelines for postoperative radiotherapy, especially for patients with close margins. REFERENCES 1. Rogers SN, Brown JS, Woolgar JA, et al. Survival following primary surgery for oral cancer. Oral Oncol. 2009;45:201-211.
ORAL AND MAXILLOFACIAL SURGERY 646 Lawaetz and Homøe 2. Blomberg M, Nielsen A, Munk C, Kjaer SK. Trends in head and neck cancer incidence in Denmark, 1978-2007: focus on human papillomavirus associated sites. Int J Cancer. 2011;129: 733-741. 3. Mistry RC, Qureshi SS, Kumaran C. Post-resection mucosal margin shrinkage in oral cancer: quantification and significance. J Surg Oncol. 2005;91:131-133. 4. Johnson RE, Sigman JD, Funk GF, Robinson RA, Hoffman HT. Quantification of surgical margin shrinkage in the oral cavity. Head Neck. 1997;19:281-286. 5. Spiro RH, Guillamondegui O, Paulino AF, Huvos AG. Pattern of invasion and margin assessment in patients with oral tongue cancer. Head Neck. 1999;21:408-413. 6. Cheng A, Cox D, Schmidt BL. Oral squamous cell carcinoma margin discrepancy after resection and pathologic processing. J Oral Maxillofac Surg. 2008;66:523-529. 7. Helliwell TR, Woolgar JA. Datasets for Histopathology Reports on Head and Neck Carcinomas and Salivary Neoplasms. 2nd ed. London, England: Royal College of Pathologists; 2005. 8. Sutton DN, Brown JS, Rogers SN, Vaughan ED, Woolgar JA. The prognostic implications of the surgical margin in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2003;32:30-34. 9. Binahmed A, Nason RW, Abdoh AA. The clinical significance of the positive surgical margin in oral cancer. Oral Oncol. 2007;43:780-784. 10. Slootweg PJ, Hordijk GJ, Schade Y, van Es RJJ, Koole R. Treatment failure and margin status in head and neck cancer: a critical view on the potential value of molecular pathology. Oral Oncol. 2002;38:500-503. 11. Kademani D, Bell RB, Bagheri S, et al. Prognostic factors in intraoral squamous cell carcinoma: the influence of histologic grade. J Oral Maxillofac Surg. 2005;63:1599-1605. 12. Brown JS, Blackburn TK, Woolgar JA, et al. A comparison of outcomes for patients with oral squamous cell carcinoma at intermediate risk of recurrence treated by surgery alone or with post-operative radiotherapy. Oral Oncol. 2007;43:764-773. 13. Woolgar JA, Triantafyllou A. A histopathological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens. Oral Oncol. 2005;41:1034-1043. 14. Yuen AP, Lam KY, Wei WI, et al. A comparison of the prognostic significance of tumor diameter, length, width, thickness, area, volume, and clinicopathological features of oral tongue carcinoma. Am J Surg. 2000;180:139-143. 15. McMahon JD, Devine JC, Hetherington J, et al. Involved surgical margins in oral and oropharyngeal carcinomadan
OOOO December 2014
16.
17.
18.
19.
20.
21.
22.
23.
anatomical problem? Br J Oral Maxillofac Surg. 2011;49: 172-175. McMahon J, O’Brien CJ, Pathak I, et al. Influence of condition of surgical margins on local recurrence and disease-specific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg. 2003;41:224-231. Wong LS, McMahon J, Devine J, et al. Influence of close resection margins on local recurrence and disease-specific survival in oral and oropharyngeal carcinoma. Br J Oral Maxillofac Surg. 2012;50:102-108. Nason RW, Binahmed A, Pathak KA, Abdoh AA, Sándor GKB. What is the adequate margin of surgical resection in oral cancer? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107: 625-629. Blackburn TK, Bakhtawar S, Brown JS, Lowe D, Vaughan ED, Rogers SN. A questionnaire survey of current UK practice for adjuvant radiotherapy following surgery for oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2007;43:143-149. Bekiroglu F, Ghazali N, Laycock R, Katre C, Lowe D, Rogers SN. Adjuvant radiotherapy and health-related quality of life of patients at intermediate risk of recurrence following primary surgery for oral squamous cell carcinoma. Oral Oncol. 2011;47:967-973. Brown JS, Shaw RJ, Bekiroglu F, Rogers SN. Systematic review of the current evidence in the use of postoperative radiotherapy for oral squamous cell carcinoma. Br J Oral Maxillofac Surg. 2012;50:481-489. Langendijk JA, Ferlito A, Takes RP, et al. Postoperative strategies after primary surgery for squamous cell carcinoma of the head and neck. Oral Oncol. 2010;46:577-585. Rodrigo JP, Maseda E, Maldonado M, et al. [Efficacy of postoperative radiation therapy for squamous cell carcinoma of the head and neck: results of a prospective randomised clinical trial]. Acta Otorrinolaringol Esp. 2004;55:415-419.
Reprint requests: Mads Lawaetz Rigshospitalet University Hospital Copenhagen Blegdamsvej 9 2100 Copenhagen East Denmark [email protected]
