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Significance of post-resection tissue shrinkage on surgical margins of oral squamous cell carcinoma
Accepted Manuscript Significance of post-resection tissue shrinkage on surgical margins of oral squamous cell carcinoma Hossam Abd El-Kader El-Fol, MBBCh, MSc, MD, Samer Abduljabar Noman, BDS, MSc, PhD, DDS, Mohamed Galal Beheiri, BDS, MSc, PhD, DDS, Abdalla M. Khalil, MBBCh, MSc, MD, Mahmoud Mohamed Kamel, MBBCh, MSc, MD PII:
S1010-5182(15)00019-0
DOI:
10.1016/j.jcms.2015.01.009
Reference:
YJCMS 1959
To appear in:
Journal of Cranio-Maxillo-Facial Surgery
Received Date: 31 October 2014 Revised Date:
9 December 2014
Accepted Date: 15 January 2015
Please cite this article as: El-Kader El-Fol HA, Noman SA, Beheiri MG, Khalil AM, Kamel MM, Significance of post-resection tissue shrinkage on surgical margins of oral squamous cell carcinoma, Journal of Cranio-Maxillofacial Surgery (2015), doi: 10.1016/j.jcms.2015.01.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Significance of post-resection tissue shrinkage on surgical
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margins of oral squamous cell carcinoma
Hossam Abd El-Kader El-Fol, MBBCh, MSc, MD1 Samer Abduljabar Noman, BDS, MSc, PhD, DDS 2 Abdalla M. Khalil, MBBCh, MSc, MD 4
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Mahmoud Mohamed Kamel, MBBCh, MSc, MD 5
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Mohamed Galal Beheiri, BDS, MSc, PhD, DDS 3
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Author Affiliation:
Department of Surgical Oncology, Faculty of Medicine, Menofia University, Egypt
2
Department of Oral & Maxillofacial Surgery, Faculty of Oral & Dental Medicine, Sana’a University, Yemen
3
Department of Oral & Maxillofacial Surgery, Faculty of Oral & Dental Medicine, Cairo University, Egypt
4
Department of Pathology, Faculty of Medicine, Cairo University, Egypt
5
Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt
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Corresponding Author: Samer Abduljabar Noman E-mail: [email protected] Mob: 00201111366619
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Summary
Background: Resecting oral squamous cell carcinoma (SCC) with an appropriate
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margin of uninvolved tissue is critical in preventing local recurrence and in making decisions regarding postoperative radiation therapy. This task can be difficult due to the discrepancy between margins measured intraoperatively and those measured
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microscopically by the pathologist after specimen processing.
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Material and Methods: A total of 61 patients underwent resective surgery with curative intent for primary oral SCC were included in this study. All patients underwent resection of the tumor with a measured 1-cm margin. Specimens were then submitted for processing and reviewing, and histopathologic margins were measured. The closest histopathologic margin was compared with the in situ margin (1 cm) to determine the
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percentage discrepancy.
Results: The mean discrepancy between the in situ margins and the histopathological margins of all close and positive margins were 47.6% for the buccal mucosa (with a P
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value corresponding to 0.05 equaling 2.1), which is statistically significant, 4.8% for the
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floor of mouth, 9.5% for the mandibular alveolus, 4.8% for the retromolar trigon, and 33.3% for the tongue.
Conclusion: There is a significant difference among resection margins based on tumor anatomical location. Margins shrinkage after resection and processing should be considered at the time of the initial resection. Tumors located in the buccal mucosa show significantly greater discrepancies than tumors at other sites. These findings suggest that it is critical to consider the oral site when outlining margins to ensure adequacy of resection. Buccal SCC is an aggressive disease, and should be considered
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ACCEPTED MANUSCRIPT as an aggressive subsite within the oral cavity, requiring a radical and aggressive
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resective approach.
Keywords: oral squamous cell carcinoma, margins shrinkage, resection margins
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INTRODUCTION
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Surgery is the most well-established mode of initial definitive treatment for a majority of oral cancers, and has been the accepted method of treatment for well over a century (Shah and Gil, 2009).
The surgeon’s objective is, ideally, to eliminate disease by resecting as little
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tissue as possible and to obtain a margin clear of tumor. Margin status in oral squamous cell carcinoma (SCC) has been found to be an independent predictor for recurrence and
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patient survival (Yahalom et al., 2008).
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One of the most important but difficult aspects of cancer surgery is ensuring complete removal of the tumor at the primary site. It has been shown that failure to achieve a clear surgical margin results in increased risk of local recurrence and a subsequent reduced chance of survival (Kurita et al., 2008).
Assessment of the resection margins forms an important part of the pathological examination of surgical specimens in patients undergoing surgery with curative intent for most forms of malignant disease, including oral SCC. Although the histopathologic
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ACCEPTED MANUSCRIPT status of the resection margins has long been used as a potential indicator of local recurrence and survival, there is still considerable uncertainty concerning many aspects of resection margins. including their nomenclature and definition, and the influence of
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anatomical and histological factors (Woolgar and Triantafyllou, 2005).
The optimal width of the surgical margin for oral cancer has always been an
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issue of debate. Microscopic tumor at the inked resection margin increases the chance of local recurrence by a factor of 2 or more in most series. The term “positive margin”
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should be reserved for patients with microscopic tumor at the inked resection margin (Nason et al., 2009).
There are 2 explanations for the positive margin phenomenon. The first is that
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microscopic tumor may extend beyond the clinically visible and palpable tumor. Resection of a 1-cm margin of clinically normal tissue around the tumor is carried out to achieve at least 5 mm of histopathologically normal tissue; however, this is not always
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sufficient. Finger extensions or islands of tumor may invade out of the main mass of tumor, resulting in a margin that is closer than anticipated. Alternatively, tissue
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retraction that occurs after resection and pathologic processing of the specimen may cause the margin of tissue to decrease in size. A combination of these phenomena may also occur (Cheng et al., 2008).
Boonstra et al. (Boonstra et al., 1983) evaluated cervical tissue shrinkage by formaldehyde fixation, paraffin wax embedding, cutting, and mounting. They concluded that shrinkage did not differ significantly in the different directions and resulted in an
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ACCEPTED MANUSCRIPT average shrinkage of respectively 2.7% and 12.6% of the original dimensions. In the calculation of the total shrinkage, these alterations can be neglected, since the changes, although not consistent, are small. It follows that in morphometric studies, a total
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shrinkage of about 15% of the original dimensions has to be taken into consideration.
Chen et al. (Chen et al., 2012) conducted a study to investigate whether formalin
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fixation is associated with the shrinkage of head and neck cancer specimens. They found that the average decreases in length, width, and depth after formalin fixation were
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1.50 mm (4.40%), 1.52 mm (6.18%), and 0.67 mm (4.10%), respectively. There was no significant difference in the shrinkage percentages associated with gender, age, tumor site, tumor size, or histology.
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The pathological margins are reported to be much smaller than the pre-resection margins; this is largely attributed to the margin shrinkage following resection, and less commonly to the presence of microscopic neoplastic foci beyond the palpable and
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visual margins. The problem of margin shrinkage has been dealt with at other sites, but
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has not been analyzed and quantified in oral cavity cancers (Mistry et al., 2005).
Cheng et al. (Cheng et al., 2008) found a significant difference between margins
measured at the time of surgical resection of oral SCC and the margins measured after histopathologic review.
The aim of this prospective study was to evaluate the surgical resection of oral SCC and the possible difference and discrepancy between in situ margins (measured at
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ACCEPTED MANUSCRIPT the time of surgical resection) and post-resection margins at the time of pathological
MATERIAL AND METHODS
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processing and interpretation.
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This prospective study was performed in the Oral and Maxillofacial Surgery Department, Faculty of Oral and Dental Medicine, Cairo University, and the Surgical
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Oncology Department, Faculty of Medicine, Menofia University, between September 2006 and January 2014 after approval by the hospital’s Ethics Committees. It involved surgical resection of primary oral SCC in 61 patients.
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Following a thorough clinical examination and routine preoperative laboratory tests, a search of locoregional and distant metastases were done with computed tomography (CT), magnetic resonance imaging (MRI), bone scanning, and abdominal
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ultrasonography. Inclusion criteria included primary oral SSC with no previous treatment and good general condition allowing a major surgical procedure. Patients with
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locoregional recurrence or distant metastases were excluded from the study.
The studied groups were 61 patients: 39 males (63.9%) and 22 females (36.1%),
with a male to female ratio 1.8:1. The age of the patients ranged from 35 to 69 years, with a mean of 51.6 ± 7.07 years. The tumor site was the tongue in 20 cases (32.8%), mucosa of alveolar margin of the mandible in 13 (21.3%), buccal mucosa in 15 (24.6%),
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ACCEPTED MANUSCRIPT retromolar in 6 (9.8%), floor of mouth in 3 (4.9%), and mucosa of alveolar margin of the maxilla in 4 (6.6%) (Table 1).
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The borders of the tumor were determined by visual inspection and palpation and were then marked with marking ink. Adequate surgical margin of at least 10 mm from the tumor margin was marked circumferentially for subsequent resection using a
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metric ruler and/or caliper at 10 mm from the clinically detectable tumor, as illustrated in Figure 1. These measurements were used to guide tissue resection. Care was taken to
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flatten the surrounding mucosa without stretching it. Two sterile black silk sutures were placed over the tumor margin and the proposed resection margin. The distance between the 2 sutures was measured using a measuring caliper and recorded as the in situ resection margin. The specimen was resected using electrocautery with 3-dimensional
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clearance, and carefully incorporating both the sutures in the resected specimen. After resection, the specimen was examined, and the distance was measured again and
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recorded (Mistry et al. 2005).
In cases in which the primary site was the buccal mucosa invading the
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buccinator muscle, with or without clinical palpable LN, the excision included the skin, buccinator muscle, and buccal fat pad, together with the marginal mandibular branch en bloc with radical neck dissection (Figure 2).
Frozen section biopsy samples were taken intraoperatively to assess resection adequacy. In the case of positive margins of frozen section analysis, additional tissue
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ACCEPTED MANUSCRIPT was taken. However, this additional tissue was not included in the margin discrepancy analysis.
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For regional control, neck management includes radical neck dissection (RND), modified radical neck dissection (FND), and/or supraomohyoid neck dissection, depending on the primary tumor size and location, clinical presentation, and
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involvement of cervical lymph nodes. Postoperatively, patients with unfavorable pathologic features including involved margin, nodal extracapsular extension, more than
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2 positive cervical nodes, perineural invasion, or lymphovascular permeation were scheduled to receive adjuvant radiotherapy and/or chemotherapy.
Specimens were then
submitted
for processing and
reviewing,
and
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histopathologic margins were measured. The closest histopathologic margin was compared with the in situ margin (10 mm) to determine the percentage discrepancy. The histopathologic examination of the primary tumor site and the neck lymph nodes was
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performed separately to verify the differentiation grade and the nodal micrometastasis. Routine examination of all components of the specimen was done using hematoxylin
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and eosin–stained sections after fixation in neutral buffered formalin. Verification of the tumor type, tumor grade, and degree of keratinization were recorded histologically.
For the clear margins of the resected specimens and negative neck L.Ns,
immunohistochemical staining using the streptovidin-biotin-perioxidase method and the primary antibodies against cytokeratins 34BE12, AE3, and AE1/AE3 was done. All reagents were supplied by Dako, with a dilution of 1:50 of the primary antibodies. The
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ACCEPTED MANUSCRIPT main tumor lesion was stained for these antibodies and was taken as a positive immunohistochemical control. The pattern of immunostaining in both the primary tumor and in the nodal metastases, the intensity of the stain, and the percentage of
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stained neoplastic cells were recorded.
Statistical analysis was performed using the SPSS for Windows program. The
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study contained binary, categorical, and continuous variables. Binary and categorical variables were represented as frequencies and percentages.
Continuous data were
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represented as mean ± SD. A chi-square test of independence was used to show relationships between binary or categorical variables. A test result was considered statistically significant if the P value was equal to or less than 0.05. To identify the variable that caused the significant change, a positive chi-square test was followed by
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obtaining the critical value for standardized residual (converted to a z score). The critical value that corresponds to 0.05 is ±1.96, and the variable was considered
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significant if its critical value was more than 1.96 or less than −1.96.
RESULTS
The studied groups were 61 patients: 39 males (63.9%) and 22 females (36.1%),
with a male to female ratio 1.8:1. The age of the patients ranged from 35 to 69 years, with a mean of 51.6 ± 7.07 years. Tumor site was the tongue in 20 cases (32.8%), mucosa of alveolar margin of the mandible in 13 (21.3%), buccal mucosa in 15 (24.6%),
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ACCEPTED MANUSCRIPT retromolar in 6 (9.8%), floor of mouth in 3 (4.9%), and mucosa of alveolar margin of the maxilla in 4 (6.6%) (Table 1).
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Histopathological examination of the specimens of the resected primary tumor sites showed that the mean discrepancy between the in situ margins and the histopathological margins of all close and positive margins were 47.6% for buccal
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mucosa with a P value that corresponds to 0.05 equaling 2.1, which is statistically significant, 4.8% for the floor of mouth, 9.5% for the mandibular alveolus, 4.8% for the
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retromolar trigon, and 33.3% for the tongue (Table 2 and Figure 1).
The mean discrepancy between the in situ margins and the histopathological margins in relation to the site were 66.7% for buccal mucosa with a P value that
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corresponds to 0.05 equaling 2.1, which is statistically significant, 33.3% for floor of mouth, 15.4% for mandibular alveolus, 16.7% for retromolar trigon, and 35% for
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tongue (Table 2 and Figure 2).
The follow up data show that close and positive margins associated with
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increased incidents of recurrence. The standardized residual (SR) that corresponds to 0.05 for margin condition in relation to recurrence equals 2.8, which is statistically significant value for close and positive margins (Table 3 and Figures 5 and 6).
DISCUSSION
In the current study, we found a difference between margins measured at the time of surgical resection of oral SCC and the margins measured after histopathological
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ACCEPTED MANUSCRIPT review. Furthermore, we found a significant difference among margin discrepancies based on tumor anatomical location.
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An ultimate goal of any oncologic surgeon treating SCC is to remove all tumor cells from the body on both macro- and microscopic levels. One of the main goals of treatment of oral SCC is resection with a minimum of a 0.5-cm cuff of surrounding
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histopathologically normal tissue—the violation of this principle being consistently
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correlated with a poorer prognosis.
Because of the compact and complex anatomy of the oral cavity, achieving a tumor-free margin remains a challenge. This is endorsed by Lee (Lee, 1974). In a study of 1,522 cases of aerodigestive tract carcinoma, Lee discovered that the oral cavity was likely
site
to
have
margins
involved
with
residual
tumor.
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most
The rate of positive margins in the same study for oral cancers was 15%. He recommended intraoperative control of margins with frozen section and prompt re-
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excision for optimal result.
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Many authors have reported on the significance of a tumor-free margin in the final outcome of patients with oral cavity cancers. Looser et al. (Looser et al., 1978) published a landmark study on the significance of positive margins in head and neck carcinoma. They observed that close histologic margins, that is, within 5 mm of the tumor, resulted in approximately the same local recurrence rate and 5-year survival (73.3% and 21.1%) as did macroscopically involved margins (64% and 28%). In comparison, the group with negative margins had a 31.7% local recurrence rate and
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ACCEPTED MANUSCRIPT 35.9% 5-year survival. Even patients with carcinoma in situ and premalignant features at the surgical margins had higher rates of local recurrences compared to those with a clear margin of 5 mm or greater. The investigators also observed an increased rate of
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positive margins in carcinoma of oral cavity and recommended re-excision of the involved site whenever feasible, since postoperative radiotherapy was inadequate to
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control close or positive margins.
Vikram et al. (Vikram et al., 1984), in their retrospective analysis of upper
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aerodigestive tract tumors treated by multimodality therapy, observed that adjuvant radiotherapy effectively reduced the local recurrence rate. However, when the margins were unsatisfactory (margins <5 mm or frankly positive), the recurrence rate was still 5 times higher (10.5%) than when surgical margin were clear (2%). Although it was
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suggested that high doses of radiation might reduce the recurrence rate when the margins are unsatisfactory, these authors also recommended and emphasized the need
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on the part of the surgeon to secure adequate margins.
Loree et al. (Loree et al., 1990) found twice the rate of local recurrence in the
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oral cavity when margins were positive, compared to that in a group with negative margins (36%–18%). Ravasz et al. (Ravasz et al., 1991) reported a 29% incidence of local recurrence with close margins (<5 mm), compared to a 12.5% local recurrence rate with negative margins.
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ACCEPTED MANUSCRIPT Cook et al. (Cook et al., 1993) and Slootweg et al. (Slootweg et al., 2002) reported an increased risk of local and nodal recurrence and reduced 5-year survival in
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patients with positive resection margins.
Kreppel et al. (Kreppel et al., 2013) reported a 5-year overall survival rate of 45.5%. The margin status revealed statistical significance on overall survival and
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showed an independent prognostic impact.
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Local recurrence of disease in advanced carcinomas of the head and neck is strongly correlated with the presence of positive or close resection margins after operative treatment. Feichtinger et al. (Feichtinger et al., 2010) introduced a new method of assessing resection margins intraoperatively by using image-guided surgery.
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Intraoperative navigation of the ablative defect showed an unsafe resection margin in 4 patients. The results suggest that intraoperative control of the surgical margins using a 3-dimensional navigation system based on positron emission tomography (PET) /
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computed tomography (CT) image fusion can be a useful tool to assess and improve
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local control in advanced cancer of the head and neck.
In attempting to obtain adequate margins on a wide excision, it is a common
observation that the pathological margin distances are much smaller than the clinical in situ measurements prior to resection. In addition, malignant changes in molecular level may be present even when there are histopathologically normal margins. (Tabor et al., 2004; Van Houten et al., 2004).
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ACCEPTED MANUSCRIPT However, the discrepancy in the clinical and pathological margins is most often due to shrinkage. Many surgeons have observed the problem of margin shrinkage at other sites. In a study on cutaneous malignant melanoma, Silverman et al. (Silverman et
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al., 1993) reported 15%–25% shrinkage in the margins, depending on patient age. In a study by Siu et al. (Siu et al., 1986), the investigators noticed shrinkage of the entire specimen of 40% after resection for esophageal cancer. Interestingly, Siu et al. found
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the tumor itself shrinking only 10%, probably due to the replacement of contractile
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esophageal musculature with noncontractile tumor tissue.
The results of our study show a significant difference between margins measured at the time of surgical resection of oral SCC and the margins measured after histopathological review. Furthermore, we found a significant difference among margin
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discrepancies based on tumor anatomical location.
The mean discrepancy between the in situ margins and the histopathological
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margins of all positive margins were 47.6% for buccal mucosa with a P value equaling 2.1), which is statistically significant, 4.8% for the floor of mouth, 9.5% for the
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mandibular alveolus, 4.8% for the retromolar trigon, and 33.3% for the tongue. The site most affected by this phenomenon was the buccal mucosa (47.6%), followed by the tongue (33.3%).
The mean discrepancy between the in situ margins and the histopathological margins in relation to the site were 66.7% for buccal mucosa with a P value equaling 2.1), which is statistically significant, 33.3% for the floor of mouth, 15.4% for the
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ACCEPTED MANUSCRIPT mandibular alveolus, 16.7% for the retromolar trigon, and 35% for the tongue. The site most affected by this phenomenon was the buccal mucosa (66.7%), followed by the
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tongue (35%).
Boonstra et al. (Boonstra et al., 1983) evaluated cervical tissue shrinkage by: formaldehyde fixation, paraffin wax embedding, cuttin, and mounting. They concluded
SC
that shrinkage did not differ significantly in the different directions, and resulted in an average shrinkage of respectively 2.7% and 12.6% of the original dimensions. In the
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calculation of the total shrinkage these alterations can be neglected, since the changes, although not consistent, are small. It follows that, in morphometric studies, a total shrinkage of about 15% of the original dimensions has to be taken into consideration.
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Chen et al. (Chen et al., 2012) conducted a study to investigate whether formalin fixation is associated with the shrinkage of head and neck cancer specimens. They found that the average decreases in length, width, and depth after formalin fixation were
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1.50 mm (4.40%), 1.52 mm (6.18%), and 0.67 mm (4.10%), respectively. There was no significant difference in the shrinkage percentage associated with gender, age, tumor
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site, tumor size, or histology.
In our results of margin discrepancy by location, we found significant
differences according to anatomical site of the tumor (buccal mucosa, 66.7%, followed by the tongue, 35%) which is not in agreement with the results of Chen et al. (Chen et al., 2012) study to investigate whether formalin fixation is associated with the shrinkage of head and neck cancer specimens, as they concluded that there was no significant
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ACCEPTED MANUSCRIPT difference in the shrinkage percentage associated with tumor site. One explanation for significant differences based on tumor site is that specimens of different tissue composition have varying amounts of dimensional change (Cheng et al., 2008). An
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additional explanation that has been suggested is that different subsites likely have variable susceptibility to invasion (Woolgar et al., 1999; Batasakis 1999). A third explanation is that tumors from different locations are simply biologically
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heterogeneous. As an example, an oral SCC arising in the buccal mucosa might be more invasive than SCC of the hard palate, which might explain why the buccal mucosa has a
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much larger discrepancy than other oral sites (Parsons et al., 1984).
Because of specimen shrinkage after tumor resection and specimen processing, it is unavoidable that a surgical margin will change from its distance in situ to its
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distance under the microscope after resection and processing. This unpredictable discrepancy between surgical margins and histopathologic margins has resulted in the reported rates of clear margins being fairly low, from 48% to 70% (Woolgar et al.,
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1999; McMahon et al., 2003; Weijers et al., 2004). However, the results of the present study are in agreement with those of Cheng et al. (Cheng et al., 2008), as they stated in
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their discussion about the idea that shrinkage causes an otherwise clear margin to be reported as positive or close by a pathologist is incorrect. This is because the main body of literature on the prognostic relevance of margin status refers to pathologic margins, after shrinkage has already occurred. The magnitude of the in situ margin is clinically irrelevant to prognosis.
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ACCEPTED MANUSCRIPT What margin discrepancies do indicate is that, based on current thinking for surgical treatment of oral SCC, the 1-cm margin of resection used was inadequate in the areas where the discrepancy led to a close or positive margin. There are several
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explanations for the discrepancy between in situ margins and histopathologic margins. One conclusion is that specimens contract significantly after resection and pathologic processing, so that clinically 1-cm margins become close when reviewed by the
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pathologist. Tissue under tension would be expected to decrease in dimension on surgical release from the surrounding tissue. Another explanation is that the invasive
current methods can measure.
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character of oral sec leads to occult microscopic margins that extend beyond what our
Our results are consistent with those by Johnson et al. (Johnson et al., 1997), as
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they reported on 1 of the early studies on margin shrinkage in oral cavity. This was an animal experiment in 10 normal mongrel dogs. The investigators noticed a 24.8% mean shrinkage of tongue mucosal margins, and a 38.3% mean shrinkage of the buccal
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margin postresection. In the recent study on oral mucosal shrinkage by Mistry et al. (Mistry et al., 2005), the investigators noticed a 23.5% shrinkage for the tongue and
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21.2% for the buccal mucosa. They also noticed a further loss of 7.6% of the tongue and 10.5% of the buccal mucosa on formalin fixation. Johnson et al. concluded that significant (30%–50%) margin shrinkage occurs in the oral cavity and that the maximum shrinkage occurs immediately after resection. This shrinkage they attributed to the unopposed contractility of underlying muscles and release from the surrounding supporting structures. The investigators concluded that significant shrinkage in mucosal margin occurs after resection of oral cavity cancers. Tumors of lower stage (T1 and T2)
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ACCEPTED MANUSCRIPT show significantly higher mucosal shrinkage compared to higher-stage tumors (T3 and T4). Margins shrinkage after resection and processing should be considered at the time of the initial resection to prevent the discontent resulting from close or involved
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margins, especially in low-stage tumors.
The findings of the present study support the work done by Cheng et al. (Cheng
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et al., 2008) that shows that the mean discrepancy for all patients was a statistically significant 59.02% (P < .0001). The mean discrepancy was 71.90% for group 1 (buccal
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mucosa, retromolar and mandibular alveolus), 53.33% for group 2 (maxilla and hard palate), and 42.14% for group 3 (tongue). The investigators concluded that oral SCC margin discrepancies after resection and specimen processing are highly significant. Tumors located in the buccal mucosa show significantly greater discrepancies than
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tumors of the maxilla or the oral tongue. These findings suggest that it might be prudent to consider the oral site when outlining margins to ensure adequacy of resection.
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In our results of margin discrepancy by location, we found significant differences according to anatomical location of the tumor (buccal mucosa, 66.7%,
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followed by the tongue, 35%). One explanation for significant differences in discrepancies based on tumor site is that specimens of different tissue composition have varying amounts of dimensional change (Cheng et al., 2008). An additional explanation that has been suggested is that different subsites likely have variable susceptibility to invasion (Woolgar et al., 1999; Batasakis 1999). A third explanation is that tumors from different locations are simply biologically heterogeneous. As an example, an oral SCC arising in the buccal mucosa might be more invasive than an SCC of the hard palate,
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ACCEPTED MANUSCRIPT which might explain why the buccal mucosa has a much greater discrepancy than other oral sites (Parsons et al, 1984).
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The current study found a trend toward margin discrepancy and positive involvement of the resected buccal mucosal tumor. In the study by Diaz et al. (Diaz et al., 2003), they stated that, in developing the clinical classification of SCC of buccal
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mucosa, they considered the buccinator muscle to be the most important layer, due to the potential role of this muscle as a barrier against tumor invasion. It has also been
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pointed out that when the tumor invasion goes beyond the mucosa to include the buccinator and then spreads further to the buccal fat, there is no longer any good anatomic barrier beyond which to spread. Also there is a report that when patients with local recurrence of stage I and II buccal SCC without tumor cells in the mucosal margin
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were examined histopathologically, no buccinator was found in the resected specimens (Strome et al., 1999). This supports the idea that local recurrence resulted because the
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buccinator was not included in the resection.
Yoshihide et al (Yoshihide et al, 2009) observed that even in those buccal
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mucosal tumors classified as being of early-stage disease, the tumor might invade into the deep layers, including the buccinator and buccal fat. These authors propose that this could account for why, when resection has been performed based on tumor size, the tumor may still remain in the deep surgical margin, thus frequently resulting in local failure.
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ACCEPTED MANUSCRIPT Sieczka et al (Sieczka et al, 2001) found that local excisions of T1 and T2 buccal mucosa cancers with pathologically negative margins had a high rate of local recurrence. Low T-stage and negative margins are not adequate predictors of local
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control. Even patients with early buccal tumors may benefit from adjuvant therapy to enhance local control.
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Similar to our findings, in the recent study by Lubek et al. (Lubek et al., 2013), the authors concluded that buccal SCC is an aggressive disease, and they considered it
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as an aggressive subsite within the oral cavity, with high rates of locoregional disease recurrence independent of surgical margin status. Elective neck dissection and adjuvant therapy should be considered for early-stage disease. Successful salvage is rare in cases
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of early recurrence.
The results of our study are in agreement with the findings published by Sieczka et al (Sieczka et al, 2001) and Lubek et al. (Lubek et al., 2013), which justify the more
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radical and aggressive resective approach for treatment of SCC of the buccal mucosa.
CONCLUSION
There is a significant difference among resection margins based on tumor anatomical location. Margins shrinkage after resection and processing should be considered at the time of initial resection. Tumors located in the buccal mucosa show significantly greater discrepancies than tumors at other sites. These findings suggest that
19
ACCEPTED MANUSCRIPT it is critical to consider the oral site when outlining margins to ensure adequacy of resection. Buccal SCC is an aggressive disease, and should be considered as an aggressive subsite within the oral cavity, requiring a radical and aggressive resective
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approach.
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ACCEPTED MANUSCRIPT Acknowledgments The authors thank Dr. Amr Maher for his contribution to the statistical analysis.
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No potential conflicts of interests were involved in this research.
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Diaz EM Jr., Holsinger FC, Zuniga ER, Roberts DB, Sorensen DM: Squamous cell carcinoma of the buccal mucosa: one institution’s experience with 119 previously untreated patients. Head Neck. 25: 267-273, 2003.
Chen CH, Hsu MY, Jiang RS, Wu SH, Chen FJ, Liu SA: Shrinkage of head and neck cancer specimens after formalin fixation. J Chin Med Assoc 75: 109-13, 2012.
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Feichtinger M, Pau M, Zemann W, Aigner RM, Kärcher H: Intraoperative control of resection margins in advanced head and neck cancer using a 3D-navigation system based on PET/CT image fusion. J Craniomaxillofac Surg. 38: 589-94, 2010.
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Johnson RE, Sigman JD, Funk GF, et al: Quantification of surgical margin shrinkage in the oral cavity. Head Neck 19: 281-286, 1997.
Kreppel M, Dreiseidler T, Rothamel D, et al: The role of clinical versus
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histopathological staging in patients with advanced oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy followed by radical surgery. J
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Kurita H, Sakai H, Kamata T, Koike T, Kobayashi H, Kurashina K: Accuracy of intraoperative tissue staining in delineating deep surgical margins in oral carcinoma surgery. Oral Oncol 44: 935-940, 2008.
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Lee JG: Detection of residual carcinoma of the oral cavity oropharynx, hypopharynx, and larynx: a study of surgical margins. Trans Am Acad Opthal Otolaryngol 78: 49-53, 1974.
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Looser KG, Shah JP, Strong EW: The significance of “positive” margins in
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surgically resected epidermoid carcinomas. Head Neck Surg 1: 107-111, 1978.
Loree TR, Strong EW: Significance of positive margins in oral cavity squamous carcinoma. Am J Surg 160: 410, 1990.
Lubek JE, Dyalram D, Perera EH, Liu X, Ord RA: A retrospective analysis of squamous carcinoma of the buccal mucosa: an aggressive subsite within the oral cavity. J Oral Maxillofac Surg 71: 1126-31, 2013.
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ACCEPTED MANUSCRIPT 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.; 41:224, 2003.
Mistry RC, Qureshi SS, Kumaran C: Post-resection mucosal margin shrinkage in
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Nason R, Binahmed A, Pathak K, Abdoh A, Sándor A: What is the adequate margin of surgical resection in oral cancer? Oral Surg Oral Med Oral Pathol Oral Radiol
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Endod 107: 625-629, 2009.
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Parsons JT, Cassisi NJ, Million RR: Results of twice-a-day irradiation of squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 10: 2041, 1984.
Ravasz LA, Slootweg PJ, Hordijk GJ, et al: The status of resection margin as a prognostic factor in the treatment of head and neck carcinoma. J Cranio-Max-Fac
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Surg 19: 314-318, 1991.
Shah JP, Gil Z: Current concepts in management of oral cancer surgery. Oral Oncol 45: 394-401, 2009.
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Sieczka E, Datta R, Singh A, Loree T, Rigual N, Orner J, and Hicks W Jr: Cancer of the buccal mucosa: are margins and T-stage accurate predictors of local control? Am
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J Otolaryngol 22: 395-399, 2001.
Silverman MK, Golomb FM, Kopf AW, et al: Verification of a formula for determination of preexcision surgical margins from fixed-tissue melanoma specimens. J UOEH 15: 277–286, 1993.
Siu KF, Cheung HC, Wong J: Shrinkage of the esophagus after resection for carcinoma. Ann Surg 203: 173-176, 1986.
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ACCEPTED MANUSCRIPT Slootweg PJ, Hordijk GJ, Schade Y, et al: Treatment failure and margin status in head and neck cancer critical view on the potential value of molecular pathology. Oral Oncol 38: 500-503, 2002.
Strome SE, To W, Strawderman M, Gersten K, Devaney KO, Bradford CR, et al:
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Squamous cell carcinoma of the buccal mucosa. Otolaryngol Head Neck Surg 120: 375-379, 1999.
Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, et al: Genetically altered fields as
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origin of locally recurrent head and neck cancer: a retrospective study. Clin Cancer
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Res 10: 3607-3613, 2004.
Van Houten VM, Leemans CR, Kummer JA, et al: Molecular diagnosis of surgical margins and local recurrence in head and neck cancer patients: a prospective study. Clin Cancer Res 10: 3614-3620, 2004.
Vikram B, Strong EW, Shah JP, et al: Failure at the primary site following
723, 1984.
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multimodality treatment in advanced head and neck cancer. Head Neck Surg 6: 720-
Weijers M, Snow GB, Bezemer DP, et al: The status of the deep surgical margins in
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tongue and floor of mouth squamous cell carcinoma and risk of local recurrence: an
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analysis of 68 patients. Int J Oral Maxillofac Surg 33:146, 2004.
Woolgar JA, Rogers S, West CR, et al: Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol 35: 257, 1999.
Woolgar J, Triantafyllou A: A histopathological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens. Oral Oncol 41: 1034-1043, 2005.
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ACCEPTED MANUSCRIPT Yahalom R, Dobriyan A, Vered M, Talmi YP, Teicher S, Bedrin L: A prospective study of surgical margin status in oral squamous cell carcinoma: a preliminary report. J Surg Oncol 98: 572-578, 2008.
Yoshihide O, Takayuki A, Kazunari K, Mitsunobu O, Hirotaka K, Masashi S,
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Naoya NM, Hiroshi K: Determination of deep surgical margin based on anatomical architecture for local control of squamous cell carcinoma of the buccal mucosa.
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Oral Oncol 45, 605-609, 2009.
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Table (1): Patients demographic characters
Studied Variable
n
%
Mean Range
61 39 63.9% 22 36.1%
Tumor Site Buccal Mucosa Tongue Mandible alveolus Retromolar trigon Floor of mouth Maxillary alveolus
15 20 13 6 3 4
24.6% 32.8% 21.3% 9.8% 4.9% 6.6%
Tumor stage T1 T2 T3 T4
4 47 5 5
6.6% 77% 8.2% 8.2%
55 6
90.2% 9.8%
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Nodal stage N0 N1
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Total patients Male Female
35-69
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51.6
Age
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Table (2): Mean percentage of margin discrepancies between Insitu margins and histopathological margins. Clear Margins
Close Margins
% within Site
% within Margin
P value*
Count
% within Site
% within Margin
P value*
Buccal Mucosa
5
33.3%
12.5%
-1.5
Floor of mouth
2
66.7%
5.0%
0
10
66.7%
47.6%
2.1*
1
33.3%
4.8%
0
Mandibular alveolus
11
84.6%
27.5%
Maxillary alveolus
4
100%
10.0%
0.8
2
15.4%
9.5%
-1.2
0.9
0
0%
0%
-1.2
Retromolar trigon
5
83.3%
12.5%
0.5
1
16.7%
4.8%
-0.7
Tongue
13
65%
32.5%
0
7
35%
33.3%
0
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Count
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* The critical value for standardized residual (converted to z score) that corresponds to 0.05 is +1.96 and the variable was considered significant if its critical value was more than 1.96 or less than -1.96.
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Table (3): Detailed count and conditions of the resected tumors T1
T2
T3
T4
Total N+ N0 N1
1
1
12
1
1
13
1
0
0
5
0
1
11
1
1
1
10
2
0
4
4
0
0
0
3
0
1
Tongue
20
13
6
1
2
17
Floor of mouth
3
2
1
0
0
2
15
5
9
Retromolar trigone
6
5
Mandibular alveolus
13
Maxillary alveolus
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2
Recurrence Local Neck
4
2
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Buccal Mucosa
Stage
5
1
1
0
13
0
2
0
4
0
1
0
1
0
18
2
3
1
0
1
2
1
0
1
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Clear
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Margin Status Close Positive
Number
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Figure (1): A brief of the procedure with intraoperative measurements and immediate post resection
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measurements in a case of T1N0 tongue SCC
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(b) Clinically palpable SFLN
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(a) SCC of buccal mucosa invading the buccinator muscle
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(d) Cervicofacial division of the facial nerve
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(c) Skin, SFLN, MMB of facial nerve, buccal mucosa and mandible excised en block
(e) Post-resection appearance (f) Post resection Specimen Figure (2): A brief of the procedure in a case of buccal SCC and clinically palpable LN
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Figure (3): Graph representing mean percent margin discrepancy between intraoperative margins
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measured in situ & histopathological margins.
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Figure (4): Graph representing the percentage of margin discrepancy between intraoperative margins
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measured in situ & histopathological margins according to tumor location.
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Figure (5): Graph representing recurrence in the study.
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Figure (6): Graph representing recurrence in relation to margin condition.
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• There is a significant difference among resection margins based on tumor anatomical location.
considered at the time of initial resection.
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• Margins shrinkage following resection and processing should be
discrepancies than tumors of other sites.
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• Tumors located in the buccal mucosa show significantly greater
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• These findings suggest that it might be prudent to consider oral site when outlining margins to ensure adequacy of resection. • Buccal squamous cell carcinoma is an aggressive disease, and should be considered as an aggressive subsite within the oral cavity requiring
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radical and aggressive resective approach.
S1010-5182(15)00019-0
DOI:
10.1016/j.jcms.2015.01.009
Reference:
YJCMS 1959
To appear in:
Journal of Cranio-Maxillo-Facial Surgery
Received Date: 31 October 2014 Revised Date:
9 December 2014
Accepted Date: 15 January 2015
Please cite this article as: El-Kader El-Fol HA, Noman SA, Beheiri MG, Khalil AM, Kamel MM, Significance of post-resection tissue shrinkage on surgical margins of oral squamous cell carcinoma, Journal of Cranio-Maxillofacial Surgery (2015), doi: 10.1016/j.jcms.2015.01.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Significance of post-resection tissue shrinkage on surgical
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margins of oral squamous cell carcinoma
Hossam Abd El-Kader El-Fol, MBBCh, MSc, MD1 Samer Abduljabar Noman, BDS, MSc, PhD, DDS 2 Abdalla M. Khalil, MBBCh, MSc, MD 4
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Mahmoud Mohamed Kamel, MBBCh, MSc, MD 5
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Mohamed Galal Beheiri, BDS, MSc, PhD, DDS 3
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Author Affiliation:
Department of Surgical Oncology, Faculty of Medicine, Menofia University, Egypt
2
Department of Oral & Maxillofacial Surgery, Faculty of Oral & Dental Medicine, Sana’a University, Yemen
3
Department of Oral & Maxillofacial Surgery, Faculty of Oral & Dental Medicine, Cairo University, Egypt
4
Department of Pathology, Faculty of Medicine, Cairo University, Egypt
5
Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt
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Corresponding Author: Samer Abduljabar Noman E-mail: [email protected] Mob: 00201111366619
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Summary
Background: Resecting oral squamous cell carcinoma (SCC) with an appropriate
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margin of uninvolved tissue is critical in preventing local recurrence and in making decisions regarding postoperative radiation therapy. This task can be difficult due to the discrepancy between margins measured intraoperatively and those measured
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microscopically by the pathologist after specimen processing.
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Material and Methods: A total of 61 patients underwent resective surgery with curative intent for primary oral SCC were included in this study. All patients underwent resection of the tumor with a measured 1-cm margin. Specimens were then submitted for processing and reviewing, and histopathologic margins were measured. The closest histopathologic margin was compared with the in situ margin (1 cm) to determine the
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percentage discrepancy.
Results: The mean discrepancy between the in situ margins and the histopathological margins of all close and positive margins were 47.6% for the buccal mucosa (with a P
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value corresponding to 0.05 equaling 2.1), which is statistically significant, 4.8% for the
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floor of mouth, 9.5% for the mandibular alveolus, 4.8% for the retromolar trigon, and 33.3% for the tongue.
Conclusion: There is a significant difference among resection margins based on tumor anatomical location. Margins shrinkage after resection and processing should be considered at the time of the initial resection. Tumors located in the buccal mucosa show significantly greater discrepancies than tumors at other sites. These findings suggest that it is critical to consider the oral site when outlining margins to ensure adequacy of resection. Buccal SCC is an aggressive disease, and should be considered
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ACCEPTED MANUSCRIPT as an aggressive subsite within the oral cavity, requiring a radical and aggressive
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resective approach.
Keywords: oral squamous cell carcinoma, margins shrinkage, resection margins
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INTRODUCTION
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Surgery is the most well-established mode of initial definitive treatment for a majority of oral cancers, and has been the accepted method of treatment for well over a century (Shah and Gil, 2009).
The surgeon’s objective is, ideally, to eliminate disease by resecting as little
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tissue as possible and to obtain a margin clear of tumor. Margin status in oral squamous cell carcinoma (SCC) has been found to be an independent predictor for recurrence and
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patient survival (Yahalom et al., 2008).
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One of the most important but difficult aspects of cancer surgery is ensuring complete removal of the tumor at the primary site. It has been shown that failure to achieve a clear surgical margin results in increased risk of local recurrence and a subsequent reduced chance of survival (Kurita et al., 2008).
Assessment of the resection margins forms an important part of the pathological examination of surgical specimens in patients undergoing surgery with curative intent for most forms of malignant disease, including oral SCC. Although the histopathologic
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ACCEPTED MANUSCRIPT status of the resection margins has long been used as a potential indicator of local recurrence and survival, there is still considerable uncertainty concerning many aspects of resection margins. including their nomenclature and definition, and the influence of
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anatomical and histological factors (Woolgar and Triantafyllou, 2005).
The optimal width of the surgical margin for oral cancer has always been an
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issue of debate. Microscopic tumor at the inked resection margin increases the chance of local recurrence by a factor of 2 or more in most series. The term “positive margin”
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should be reserved for patients with microscopic tumor at the inked resection margin (Nason et al., 2009).
There are 2 explanations for the positive margin phenomenon. The first is that
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microscopic tumor may extend beyond the clinically visible and palpable tumor. Resection of a 1-cm margin of clinically normal tissue around the tumor is carried out to achieve at least 5 mm of histopathologically normal tissue; however, this is not always
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sufficient. Finger extensions or islands of tumor may invade out of the main mass of tumor, resulting in a margin that is closer than anticipated. Alternatively, tissue
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retraction that occurs after resection and pathologic processing of the specimen may cause the margin of tissue to decrease in size. A combination of these phenomena may also occur (Cheng et al., 2008).
Boonstra et al. (Boonstra et al., 1983) evaluated cervical tissue shrinkage by formaldehyde fixation, paraffin wax embedding, cutting, and mounting. They concluded that shrinkage did not differ significantly in the different directions and resulted in an
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ACCEPTED MANUSCRIPT average shrinkage of respectively 2.7% and 12.6% of the original dimensions. In the calculation of the total shrinkage, these alterations can be neglected, since the changes, although not consistent, are small. It follows that in morphometric studies, a total
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shrinkage of about 15% of the original dimensions has to be taken into consideration.
Chen et al. (Chen et al., 2012) conducted a study to investigate whether formalin
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fixation is associated with the shrinkage of head and neck cancer specimens. They found that the average decreases in length, width, and depth after formalin fixation were
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1.50 mm (4.40%), 1.52 mm (6.18%), and 0.67 mm (4.10%), respectively. There was no significant difference in the shrinkage percentages associated with gender, age, tumor site, tumor size, or histology.
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The pathological margins are reported to be much smaller than the pre-resection margins; this is largely attributed to the margin shrinkage following resection, and less commonly to the presence of microscopic neoplastic foci beyond the palpable and
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visual margins. The problem of margin shrinkage has been dealt with at other sites, but
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has not been analyzed and quantified in oral cavity cancers (Mistry et al., 2005).
Cheng et al. (Cheng et al., 2008) found a significant difference between margins
measured at the time of surgical resection of oral SCC and the margins measured after histopathologic review.
The aim of this prospective study was to evaluate the surgical resection of oral SCC and the possible difference and discrepancy between in situ margins (measured at
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ACCEPTED MANUSCRIPT the time of surgical resection) and post-resection margins at the time of pathological
MATERIAL AND METHODS
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processing and interpretation.
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This prospective study was performed in the Oral and Maxillofacial Surgery Department, Faculty of Oral and Dental Medicine, Cairo University, and the Surgical
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Oncology Department, Faculty of Medicine, Menofia University, between September 2006 and January 2014 after approval by the hospital’s Ethics Committees. It involved surgical resection of primary oral SCC in 61 patients.
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Following a thorough clinical examination and routine preoperative laboratory tests, a search of locoregional and distant metastases were done with computed tomography (CT), magnetic resonance imaging (MRI), bone scanning, and abdominal
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ultrasonography. Inclusion criteria included primary oral SSC with no previous treatment and good general condition allowing a major surgical procedure. Patients with
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locoregional recurrence or distant metastases were excluded from the study.
The studied groups were 61 patients: 39 males (63.9%) and 22 females (36.1%),
with a male to female ratio 1.8:1. The age of the patients ranged from 35 to 69 years, with a mean of 51.6 ± 7.07 years. The tumor site was the tongue in 20 cases (32.8%), mucosa of alveolar margin of the mandible in 13 (21.3%), buccal mucosa in 15 (24.6%),
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The borders of the tumor were determined by visual inspection and palpation and were then marked with marking ink. Adequate surgical margin of at least 10 mm from the tumor margin was marked circumferentially for subsequent resection using a
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metric ruler and/or caliper at 10 mm from the clinically detectable tumor, as illustrated in Figure 1. These measurements were used to guide tissue resection. Care was taken to
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flatten the surrounding mucosa without stretching it. Two sterile black silk sutures were placed over the tumor margin and the proposed resection margin. The distance between the 2 sutures was measured using a measuring caliper and recorded as the in situ resection margin. The specimen was resected using electrocautery with 3-dimensional
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clearance, and carefully incorporating both the sutures in the resected specimen. After resection, the specimen was examined, and the distance was measured again and
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recorded (Mistry et al. 2005).
In cases in which the primary site was the buccal mucosa invading the
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buccinator muscle, with or without clinical palpable LN, the excision included the skin, buccinator muscle, and buccal fat pad, together with the marginal mandibular branch en bloc with radical neck dissection (Figure 2).
Frozen section biopsy samples were taken intraoperatively to assess resection adequacy. In the case of positive margins of frozen section analysis, additional tissue
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For regional control, neck management includes radical neck dissection (RND), modified radical neck dissection (FND), and/or supraomohyoid neck dissection, depending on the primary tumor size and location, clinical presentation, and
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involvement of cervical lymph nodes. Postoperatively, patients with unfavorable pathologic features including involved margin, nodal extracapsular extension, more than
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2 positive cervical nodes, perineural invasion, or lymphovascular permeation were scheduled to receive adjuvant radiotherapy and/or chemotherapy.
Specimens were then
submitted
for processing and
reviewing,
and
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histopathologic margins were measured. The closest histopathologic margin was compared with the in situ margin (10 mm) to determine the percentage discrepancy. The histopathologic examination of the primary tumor site and the neck lymph nodes was
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performed separately to verify the differentiation grade and the nodal micrometastasis. Routine examination of all components of the specimen was done using hematoxylin
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and eosin–stained sections after fixation in neutral buffered formalin. Verification of the tumor type, tumor grade, and degree of keratinization were recorded histologically.
For the clear margins of the resected specimens and negative neck L.Ns,
immunohistochemical staining using the streptovidin-biotin-perioxidase method and the primary antibodies against cytokeratins 34BE12, AE3, and AE1/AE3 was done. All reagents were supplied by Dako, with a dilution of 1:50 of the primary antibodies. The
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ACCEPTED MANUSCRIPT main tumor lesion was stained for these antibodies and was taken as a positive immunohistochemical control. The pattern of immunostaining in both the primary tumor and in the nodal metastases, the intensity of the stain, and the percentage of
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stained neoplastic cells were recorded.
Statistical analysis was performed using the SPSS for Windows program. The
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study contained binary, categorical, and continuous variables. Binary and categorical variables were represented as frequencies and percentages.
Continuous data were
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represented as mean ± SD. A chi-square test of independence was used to show relationships between binary or categorical variables. A test result was considered statistically significant if the P value was equal to or less than 0.05. To identify the variable that caused the significant change, a positive chi-square test was followed by
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obtaining the critical value for standardized residual (converted to a z score). The critical value that corresponds to 0.05 is ±1.96, and the variable was considered
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significant if its critical value was more than 1.96 or less than −1.96.
RESULTS
The studied groups were 61 patients: 39 males (63.9%) and 22 females (36.1%),
with a male to female ratio 1.8:1. The age of the patients ranged from 35 to 69 years, with a mean of 51.6 ± 7.07 years. Tumor site was the tongue in 20 cases (32.8%), mucosa of alveolar margin of the mandible in 13 (21.3%), buccal mucosa in 15 (24.6%),
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Histopathological examination of the specimens of the resected primary tumor sites showed that the mean discrepancy between the in situ margins and the histopathological margins of all close and positive margins were 47.6% for buccal
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mucosa with a P value that corresponds to 0.05 equaling 2.1, which is statistically significant, 4.8% for the floor of mouth, 9.5% for the mandibular alveolus, 4.8% for the
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retromolar trigon, and 33.3% for the tongue (Table 2 and Figure 1).
The mean discrepancy between the in situ margins and the histopathological margins in relation to the site were 66.7% for buccal mucosa with a P value that
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corresponds to 0.05 equaling 2.1, which is statistically significant, 33.3% for floor of mouth, 15.4% for mandibular alveolus, 16.7% for retromolar trigon, and 35% for
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tongue (Table 2 and Figure 2).
The follow up data show that close and positive margins associated with
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increased incidents of recurrence. The standardized residual (SR) that corresponds to 0.05 for margin condition in relation to recurrence equals 2.8, which is statistically significant value for close and positive margins (Table 3 and Figures 5 and 6).
DISCUSSION
In the current study, we found a difference between margins measured at the time of surgical resection of oral SCC and the margins measured after histopathological
9
ACCEPTED MANUSCRIPT review. Furthermore, we found a significant difference among margin discrepancies based on tumor anatomical location.
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An ultimate goal of any oncologic surgeon treating SCC is to remove all tumor cells from the body on both macro- and microscopic levels. One of the main goals of treatment of oral SCC is resection with a minimum of a 0.5-cm cuff of surrounding
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histopathologically normal tissue—the violation of this principle being consistently
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correlated with a poorer prognosis.
Because of the compact and complex anatomy of the oral cavity, achieving a tumor-free margin remains a challenge. This is endorsed by Lee (Lee, 1974). In a study of 1,522 cases of aerodigestive tract carcinoma, Lee discovered that the oral cavity was likely
site
to
have
margins
involved
with
residual
tumor.
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most
The rate of positive margins in the same study for oral cancers was 15%. He recommended intraoperative control of margins with frozen section and prompt re-
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excision for optimal result.
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Many authors have reported on the significance of a tumor-free margin in the final outcome of patients with oral cavity cancers. Looser et al. (Looser et al., 1978) published a landmark study on the significance of positive margins in head and neck carcinoma. They observed that close histologic margins, that is, within 5 mm of the tumor, resulted in approximately the same local recurrence rate and 5-year survival (73.3% and 21.1%) as did macroscopically involved margins (64% and 28%). In comparison, the group with negative margins had a 31.7% local recurrence rate and
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ACCEPTED MANUSCRIPT 35.9% 5-year survival. Even patients with carcinoma in situ and premalignant features at the surgical margins had higher rates of local recurrences compared to those with a clear margin of 5 mm or greater. The investigators also observed an increased rate of
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positive margins in carcinoma of oral cavity and recommended re-excision of the involved site whenever feasible, since postoperative radiotherapy was inadequate to
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control close or positive margins.
Vikram et al. (Vikram et al., 1984), in their retrospective analysis of upper
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aerodigestive tract tumors treated by multimodality therapy, observed that adjuvant radiotherapy effectively reduced the local recurrence rate. However, when the margins were unsatisfactory (margins <5 mm or frankly positive), the recurrence rate was still 5 times higher (10.5%) than when surgical margin were clear (2%). Although it was
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suggested that high doses of radiation might reduce the recurrence rate when the margins are unsatisfactory, these authors also recommended and emphasized the need
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on the part of the surgeon to secure adequate margins.
Loree et al. (Loree et al., 1990) found twice the rate of local recurrence in the
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oral cavity when margins were positive, compared to that in a group with negative margins (36%–18%). Ravasz et al. (Ravasz et al., 1991) reported a 29% incidence of local recurrence with close margins (<5 mm), compared to a 12.5% local recurrence rate with negative margins.
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ACCEPTED MANUSCRIPT Cook et al. (Cook et al., 1993) and Slootweg et al. (Slootweg et al., 2002) reported an increased risk of local and nodal recurrence and reduced 5-year survival in
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patients with positive resection margins.
Kreppel et al. (Kreppel et al., 2013) reported a 5-year overall survival rate of 45.5%. The margin status revealed statistical significance on overall survival and
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showed an independent prognostic impact.
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Local recurrence of disease in advanced carcinomas of the head and neck is strongly correlated with the presence of positive or close resection margins after operative treatment. Feichtinger et al. (Feichtinger et al., 2010) introduced a new method of assessing resection margins intraoperatively by using image-guided surgery.
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Intraoperative navigation of the ablative defect showed an unsafe resection margin in 4 patients. The results suggest that intraoperative control of the surgical margins using a 3-dimensional navigation system based on positron emission tomography (PET) /
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computed tomography (CT) image fusion can be a useful tool to assess and improve
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local control in advanced cancer of the head and neck.
In attempting to obtain adequate margins on a wide excision, it is a common
observation that the pathological margin distances are much smaller than the clinical in situ measurements prior to resection. In addition, malignant changes in molecular level may be present even when there are histopathologically normal margins. (Tabor et al., 2004; Van Houten et al., 2004).
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ACCEPTED MANUSCRIPT However, the discrepancy in the clinical and pathological margins is most often due to shrinkage. Many surgeons have observed the problem of margin shrinkage at other sites. In a study on cutaneous malignant melanoma, Silverman et al. (Silverman et
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al., 1993) reported 15%–25% shrinkage in the margins, depending on patient age. In a study by Siu et al. (Siu et al., 1986), the investigators noticed shrinkage of the entire specimen of 40% after resection for esophageal cancer. Interestingly, Siu et al. found
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the tumor itself shrinking only 10%, probably due to the replacement of contractile
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esophageal musculature with noncontractile tumor tissue.
The results of our study show a significant difference between margins measured at the time of surgical resection of oral SCC and the margins measured after histopathological review. Furthermore, we found a significant difference among margin
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discrepancies based on tumor anatomical location.
The mean discrepancy between the in situ margins and the histopathological
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margins of all positive margins were 47.6% for buccal mucosa with a P value equaling 2.1), which is statistically significant, 4.8% for the floor of mouth, 9.5% for the
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mandibular alveolus, 4.8% for the retromolar trigon, and 33.3% for the tongue. The site most affected by this phenomenon was the buccal mucosa (47.6%), followed by the tongue (33.3%).
The mean discrepancy between the in situ margins and the histopathological margins in relation to the site were 66.7% for buccal mucosa with a P value equaling 2.1), which is statistically significant, 33.3% for the floor of mouth, 15.4% for the
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ACCEPTED MANUSCRIPT mandibular alveolus, 16.7% for the retromolar trigon, and 35% for the tongue. The site most affected by this phenomenon was the buccal mucosa (66.7%), followed by the
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tongue (35%).
Boonstra et al. (Boonstra et al., 1983) evaluated cervical tissue shrinkage by: formaldehyde fixation, paraffin wax embedding, cuttin, and mounting. They concluded
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that shrinkage did not differ significantly in the different directions, and resulted in an average shrinkage of respectively 2.7% and 12.6% of the original dimensions. In the
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calculation of the total shrinkage these alterations can be neglected, since the changes, although not consistent, are small. It follows that, in morphometric studies, a total shrinkage of about 15% of the original dimensions has to be taken into consideration.
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Chen et al. (Chen et al., 2012) conducted a study to investigate whether formalin fixation is associated with the shrinkage of head and neck cancer specimens. They found that the average decreases in length, width, and depth after formalin fixation were
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1.50 mm (4.40%), 1.52 mm (6.18%), and 0.67 mm (4.10%), respectively. There was no significant difference in the shrinkage percentage associated with gender, age, tumor
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site, tumor size, or histology.
In our results of margin discrepancy by location, we found significant
differences according to anatomical site of the tumor (buccal mucosa, 66.7%, followed by the tongue, 35%) which is not in agreement with the results of Chen et al. (Chen et al., 2012) study to investigate whether formalin fixation is associated with the shrinkage of head and neck cancer specimens, as they concluded that there was no significant
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ACCEPTED MANUSCRIPT difference in the shrinkage percentage associated with tumor site. One explanation for significant differences based on tumor site is that specimens of different tissue composition have varying amounts of dimensional change (Cheng et al., 2008). An
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additional explanation that has been suggested is that different subsites likely have variable susceptibility to invasion (Woolgar et al., 1999; Batasakis 1999). A third explanation is that tumors from different locations are simply biologically
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heterogeneous. As an example, an oral SCC arising in the buccal mucosa might be more invasive than SCC of the hard palate, which might explain why the buccal mucosa has a
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much larger discrepancy than other oral sites (Parsons et al., 1984).
Because of specimen shrinkage after tumor resection and specimen processing, it is unavoidable that a surgical margin will change from its distance in situ to its
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distance under the microscope after resection and processing. This unpredictable discrepancy between surgical margins and histopathologic margins has resulted in the reported rates of clear margins being fairly low, from 48% to 70% (Woolgar et al.,
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1999; McMahon et al., 2003; Weijers et al., 2004). However, the results of the present study are in agreement with those of Cheng et al. (Cheng et al., 2008), as they stated in
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their discussion about the idea that shrinkage causes an otherwise clear margin to be reported as positive or close by a pathologist is incorrect. This is because the main body of literature on the prognostic relevance of margin status refers to pathologic margins, after shrinkage has already occurred. The magnitude of the in situ margin is clinically irrelevant to prognosis.
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ACCEPTED MANUSCRIPT What margin discrepancies do indicate is that, based on current thinking for surgical treatment of oral SCC, the 1-cm margin of resection used was inadequate in the areas where the discrepancy led to a close or positive margin. There are several
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explanations for the discrepancy between in situ margins and histopathologic margins. One conclusion is that specimens contract significantly after resection and pathologic processing, so that clinically 1-cm margins become close when reviewed by the
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pathologist. Tissue under tension would be expected to decrease in dimension on surgical release from the surrounding tissue. Another explanation is that the invasive
current methods can measure.
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character of oral sec leads to occult microscopic margins that extend beyond what our
Our results are consistent with those by Johnson et al. (Johnson et al., 1997), as
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they reported on 1 of the early studies on margin shrinkage in oral cavity. This was an animal experiment in 10 normal mongrel dogs. The investigators noticed a 24.8% mean shrinkage of tongue mucosal margins, and a 38.3% mean shrinkage of the buccal
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margin postresection. In the recent study on oral mucosal shrinkage by Mistry et al. (Mistry et al., 2005), the investigators noticed a 23.5% shrinkage for the tongue and
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21.2% for the buccal mucosa. They also noticed a further loss of 7.6% of the tongue and 10.5% of the buccal mucosa on formalin fixation. Johnson et al. concluded that significant (30%–50%) margin shrinkage occurs in the oral cavity and that the maximum shrinkage occurs immediately after resection. This shrinkage they attributed to the unopposed contractility of underlying muscles and release from the surrounding supporting structures. The investigators concluded that significant shrinkage in mucosal margin occurs after resection of oral cavity cancers. Tumors of lower stage (T1 and T2)
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ACCEPTED MANUSCRIPT show significantly higher mucosal shrinkage compared to higher-stage tumors (T3 and T4). Margins shrinkage after resection and processing should be considered at the time of the initial resection to prevent the discontent resulting from close or involved
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margins, especially in low-stage tumors.
The findings of the present study support the work done by Cheng et al. (Cheng
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et al., 2008) that shows that the mean discrepancy for all patients was a statistically significant 59.02% (P < .0001). The mean discrepancy was 71.90% for group 1 (buccal
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mucosa, retromolar and mandibular alveolus), 53.33% for group 2 (maxilla and hard palate), and 42.14% for group 3 (tongue). The investigators concluded that oral SCC margin discrepancies after resection and specimen processing are highly significant. Tumors located in the buccal mucosa show significantly greater discrepancies than
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tumors of the maxilla or the oral tongue. These findings suggest that it might be prudent to consider the oral site when outlining margins to ensure adequacy of resection.
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In our results of margin discrepancy by location, we found significant differences according to anatomical location of the tumor (buccal mucosa, 66.7%,
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followed by the tongue, 35%). One explanation for significant differences in discrepancies based on tumor site is that specimens of different tissue composition have varying amounts of dimensional change (Cheng et al., 2008). An additional explanation that has been suggested is that different subsites likely have variable susceptibility to invasion (Woolgar et al., 1999; Batasakis 1999). A third explanation is that tumors from different locations are simply biologically heterogeneous. As an example, an oral SCC arising in the buccal mucosa might be more invasive than an SCC of the hard palate,
17
ACCEPTED MANUSCRIPT which might explain why the buccal mucosa has a much greater discrepancy than other oral sites (Parsons et al, 1984).
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The current study found a trend toward margin discrepancy and positive involvement of the resected buccal mucosal tumor. In the study by Diaz et al. (Diaz et al., 2003), they stated that, in developing the clinical classification of SCC of buccal
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mucosa, they considered the buccinator muscle to be the most important layer, due to the potential role of this muscle as a barrier against tumor invasion. It has also been
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pointed out that when the tumor invasion goes beyond the mucosa to include the buccinator and then spreads further to the buccal fat, there is no longer any good anatomic barrier beyond which to spread. Also there is a report that when patients with local recurrence of stage I and II buccal SCC without tumor cells in the mucosal margin
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were examined histopathologically, no buccinator was found in the resected specimens (Strome et al., 1999). This supports the idea that local recurrence resulted because the
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buccinator was not included in the resection.
Yoshihide et al (Yoshihide et al, 2009) observed that even in those buccal
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mucosal tumors classified as being of early-stage disease, the tumor might invade into the deep layers, including the buccinator and buccal fat. These authors propose that this could account for why, when resection has been performed based on tumor size, the tumor may still remain in the deep surgical margin, thus frequently resulting in local failure.
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ACCEPTED MANUSCRIPT Sieczka et al (Sieczka et al, 2001) found that local excisions of T1 and T2 buccal mucosa cancers with pathologically negative margins had a high rate of local recurrence. Low T-stage and negative margins are not adequate predictors of local
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control. Even patients with early buccal tumors may benefit from adjuvant therapy to enhance local control.
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Similar to our findings, in the recent study by Lubek et al. (Lubek et al., 2013), the authors concluded that buccal SCC is an aggressive disease, and they considered it
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as an aggressive subsite within the oral cavity, with high rates of locoregional disease recurrence independent of surgical margin status. Elective neck dissection and adjuvant therapy should be considered for early-stage disease. Successful salvage is rare in cases
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of early recurrence.
The results of our study are in agreement with the findings published by Sieczka et al (Sieczka et al, 2001) and Lubek et al. (Lubek et al., 2013), which justify the more
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radical and aggressive resective approach for treatment of SCC of the buccal mucosa.
CONCLUSION
There is a significant difference among resection margins based on tumor anatomical location. Margins shrinkage after resection and processing should be considered at the time of initial resection. Tumors located in the buccal mucosa show significantly greater discrepancies than tumors at other sites. These findings suggest that
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ACCEPTED MANUSCRIPT it is critical to consider the oral site when outlining margins to ensure adequacy of resection. Buccal SCC is an aggressive disease, and should be considered as an aggressive subsite within the oral cavity, requiring a radical and aggressive resective
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approach.
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ACCEPTED MANUSCRIPT Acknowledgments The authors thank Dr. Amr Maher for his contribution to the statistical analysis.
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No potential conflicts of interests were involved in this research.
References
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Pathol 6:140, 1999.
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ACCEPTED MANUSCRIPT 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.; 41:224, 2003.
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Parsons JT, Cassisi NJ, Million RR: Results of twice-a-day irradiation of squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 10: 2041, 1984.
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Sieczka E, Datta R, Singh A, Loree T, Rigual N, Orner J, and Hicks W Jr: Cancer of the buccal mucosa: are margins and T-stage accurate predictors of local control? Am
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ACCEPTED MANUSCRIPT Slootweg PJ, Hordijk GJ, Schade Y, et al: Treatment failure and margin status in head and neck cancer critical view on the potential value of molecular pathology. Oral Oncol 38: 500-503, 2002.
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ACCEPTED MANUSCRIPT Yahalom R, Dobriyan A, Vered M, Talmi YP, Teicher S, Bedrin L: A prospective study of surgical margin status in oral squamous cell carcinoma: a preliminary report. J Surg Oncol 98: 572-578, 2008.
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Table (1): Patients demographic characters
Studied Variable
n
%
Mean Range
61 39 63.9% 22 36.1%
Tumor Site Buccal Mucosa Tongue Mandible alveolus Retromolar trigon Floor of mouth Maxillary alveolus
15 20 13 6 3 4
24.6% 32.8% 21.3% 9.8% 4.9% 6.6%
Tumor stage T1 T2 T3 T4
4 47 5 5
6.6% 77% 8.2% 8.2%
55 6
90.2% 9.8%
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Nodal stage N0 N1
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Total patients Male Female
35-69
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51.6
Age
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Table (2): Mean percentage of margin discrepancies between Insitu margins and histopathological margins. Clear Margins
Close Margins
% within Site
% within Margin
P value*
Count
% within Site
% within Margin
P value*
Buccal Mucosa
5
33.3%
12.5%
-1.5
Floor of mouth
2
66.7%
5.0%
0
10
66.7%
47.6%
2.1*
1
33.3%
4.8%
0
Mandibular alveolus
11
84.6%
27.5%
Maxillary alveolus
4
100%
10.0%
0.8
2
15.4%
9.5%
-1.2
0.9
0
0%
0%
-1.2
Retromolar trigon
5
83.3%
12.5%
0.5
1
16.7%
4.8%
-0.7
Tongue
13
65%
32.5%
0
7
35%
33.3%
0
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Count
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* The critical value for standardized residual (converted to z score) that corresponds to 0.05 is +1.96 and the variable was considered significant if its critical value was more than 1.96 or less than -1.96.
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Table (3): Detailed count and conditions of the resected tumors T1
T2
T3
T4
Total N+ N0 N1
1
1
12
1
1
13
1
0
0
5
0
1
11
1
1
1
10
2
0
4
4
0
0
0
3
0
1
Tongue
20
13
6
1
2
17
Floor of mouth
3
2
1
0
0
2
15
5
9
Retromolar trigone
6
5
Mandibular alveolus
13
Maxillary alveolus
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2
Recurrence Local Neck
4
2
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Buccal Mucosa
Stage
5
1
1
0
13
0
2
0
4
0
1
0
1
0
18
2
3
1
0
1
2
1
0
1
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Clear
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Margin Status Close Positive
Number
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Figure (1): A brief of the procedure with intraoperative measurements and immediate post resection
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measurements in a case of T1N0 tongue SCC
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(b) Clinically palpable SFLN
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(a) SCC of buccal mucosa invading the buccinator muscle
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(d) Cervicofacial division of the facial nerve
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(c) Skin, SFLN, MMB of facial nerve, buccal mucosa and mandible excised en block
(e) Post-resection appearance (f) Post resection Specimen Figure (2): A brief of the procedure in a case of buccal SCC and clinically palpable LN
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Figure (3): Graph representing mean percent margin discrepancy between intraoperative margins
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measured in situ & histopathological margins.
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Figure (4): Graph representing the percentage of margin discrepancy between intraoperative margins
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measured in situ & histopathological margins according to tumor location.
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Figure (5): Graph representing recurrence in the study.
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Figure (6): Graph representing recurrence in relation to margin condition.
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• There is a significant difference among resection margins based on tumor anatomical location.
considered at the time of initial resection.
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• Margins shrinkage following resection and processing should be
discrepancies than tumors of other sites.
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• Tumors located in the buccal mucosa show significantly greater
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• These findings suggest that it might be prudent to consider oral site when outlining margins to ensure adequacy of resection. • Buccal squamous cell carcinoma is an aggressive disease, and should be considered as an aggressive subsite within the oral cavity requiring
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radical and aggressive resective approach.