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 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 8  |  Issue : 6  |  Page : 100-105

Utility of frozen section in assessment of margins and neck node metastases in patients undergoing surgery for carcinoma of the tongue


1 Department of Head and Neck Surgery, Tata Memorial Hospital, EB Road, Parel, Mumbai - 400 012, India
2 Department of Pathology, Tata Memorial Hospital, EB Road, Parel, Mumbai - 400 012, India

Date of Web Publication24-Jan-2012

Correspondence Address:
Pankaj Chaturvedi
45, Head and Neck Service, Tata Memorial Hospital, EB Road, Parel, Mumbai - 400 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.92222

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 > Abstract 

Objective: The aims of this study are to evaluate the impact of frozen section in achieving adequate surgical margin and to study the accuracy of frozen section in detection of occult metastases.
Materials and Methods: This was a retrospective review of prospectively collected data of 877 patients with squamous cell carcinoma of the tongue who underwent surgery and intra-operative frozen section at our center from January 2007 to June 2010.
Results: Frozen section was found to have very high accuracy in assessment of margin as well nodal status. On frozen section, 2% of our patients had positive margins and 21% had close margins. Most of these underwent intra-operative revision and at final pathology, 1.2% patients had positive margins and 11% were close. Of the 651 supraomohyoid neck dissections performed, one third were found to have occult metastases on frozen section. Of those reported positive on frozen section, 68% got additional removal of level 4 ± 5. Interestingly, 11% of these additionally removed nodes harbored metastases at final pathology. However, 7% of the patients were wrongly declared negative on frozen section. Tumor thickness was predictor of margin positivity as well as occult metastases. Tumor volume did not correlate with occult metastases or margin status.
Conclusions: Frozen section nearly halves the rates of positive margin and close margins which certainly translates into clinical benefits. The incidence of 11% positive nodes in the frozen section guided removal of lower levels is an important finding in our study that questions the ability of supraomohyoid neck dissection to completely eradicate the nodal burden in such patients.

Keywords: Frozen section, supraomohyoid neck dissection, surgical margin, tongue cancer


How to cite this article:
Chaturvedi P, Singh B, Nair S, Nair D, Kane SV, D'cruz A, Datta S, Pawar P, Vaishampayan S. Utility of frozen section in assessment of margins and neck node metastases in patients undergoing surgery for carcinoma of the tongue. J Can Res Ther 2012;8, Suppl S2:100-5

How to cite this URL:
Chaturvedi P, Singh B, Nair S, Nair D, Kane SV, D'cruz A, Datta S, Pawar P, Vaishampayan S. Utility of frozen section in assessment of margins and neck node metastases in patients undergoing surgery for carcinoma of the tongue. J Can Res Ther [serial online] 2012 [cited 2019 Dec 5];8:100-5. Available from: http://www.cancerjournal.net/text.asp?2012/8/6/100/92222


 > Introduction Top


Frozen section is an essential component of a surgical theater complex. It is routinely used by surgeons across specialties for rapid assessment of presence of tumor in any tissues and most common being the surgical margins. Surgical margin is an established predictor of loco-regional failure. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10] The status of margin alone may warrant additional adjuvant treatment when none was required or may dictate the addition of chemotherapy in a patient where radiotherapy alone would have sufficed. [11],[12] At the time of frozen section, apart from surgical margins, the surgeon also has the opportunity to know the precise T size and the tumor thickness that are known predictors of the occult lymph node metastases. [13] The above information may allow the surgeons to make a critical decision of undertaking a supraomohyoid neck dissection whenever in dilemma. [14,[15],[16] We routinely utilize frozen section facility for detection of occult metastases in supraomohyoid neck dissection specimens for clinically N0 necks. In case the frozen section detects nodal metastases, we convert the supraomohyoid neck dissection into Type III modified neck dissection. This offered us an opportunity to evaluate the accuracy of frozen section in assessment of occult nodal metastases which to our knowledge has not been previously reported. The aims of the study were to evaluate the role of frozen section in reducing surgical margin positivity in a high volume teaching hospital in India and to study its accuracy in detection of occult metastases in clinically negative neck. We also studied the incidence of positive/close margin at our center and the factors influencing it. We do not aim to correlate the status of surgical margin or frozen assisted nodal dissection with outcome following treatment of these cancers as this is already well established. Oral cavity is a complex site in itself and clubbing various sub sites within oral cavity, as done in most studies, may lead to heterogeneity. Therefore, we restricted our study to surgically treated tongue cancers alone.


 > Materials and Methods Top


All patients with pathologically proven squamous cell carcinoma of the tongue operated between 1st January 2007 and 30 th June 2010 in our institute were included in the study. We excluded those with prior history of oral cancers, prior treatment (such as excision biopsy, nodal biopsy, radiotherapy) and lack of positive histopathology. As per our institutional policy, all the excised tongue specimens are assessed for adequacy of tumor free margin on frozen section. We classify the margins as "positive" when margin showed tumor deposits (invasive and in-situ), "close" when it is less than 5 mm and "negative" when it is equal to or more than 5 mm. As a policy, we prefer supraomohyoid neck dissection (selective neck dissection, level 1-3) in clinically N0 neck. This supraomohyoid neck dissection specimen is sent for frozen section analysis by majority of our surgeons. In case frozen section detects lymph node metastases, large majority of our patients undergo removal of level 4 ± level 5 or a Type III modified neck dissection. This study involves 877 patients of tongue cancer who underwent frozen section for adequacy of margins and 651 patients with clinically N0 neck who underwent frozen section for detection of occult lymph node metastases. [Table 1] The statistical analysis was done using SPSS software and Chi-square test was done as test of significance. Multivariate analysis was done with binary logistic regression.
Table 1: A summary of the important procedures / numbers included in our study

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 > Results Top


The Clinical T Stage breakup for the 877 tongue cancers patients undergoing surgery was T1-18%, T2-45%, T3-18%, T4-19%. The N stage break up for these patients was N0-65.7%, N1-19.8%, N2a-3.2%, N2b-7.1%, N2c-3.8%, N3- 0.5%. The median age of this cohort was 48 years (range 20 - 104) with nearly three fourth being males (72.5%). Majority of our patients had per oral excision of the tumor (74.6%), the pull through approach was undertaken in 17% and 8% had composite resections with mandible. As per our institutional criteria, 2% (17/877) of our patients had positive margins on frozen section and 21% (187/877) were found to have close margins. Majority of the time when the margin was declared as positive or close, it was the lateral mucosal margin (42%) or margin at the base of the tumor (41%). Based on the frozen section report, 16 out of 17 patients with positive margins underwent revision and the margin remained positive in 3 patients at paraffin section too [Table 1]. More than half (59%) of those with close margins underwent revision. Nearly 87% of these close margins were labeled "4 mm" and the 79% times revision was not done because of the presence of mandible at the margin. Finally, at paraffin section, 1% (11) patient had positive margin and 11% (96) had close margin [Table 1]. We did not have any false positive frozen section report. Therefore, the positive predictive value of the frozen section in assessment of margins is 100% and the negative predictive value of frozen section is 99.4%.

We performed 651 supraomohyoid neck dissections in 581 patients with cancers of the tongue. Of these 581 patients, four hundred and seventy clinically N0 patients underwent ipsilateral neck dissection for a lateralized disease, 70 clinically N0 necks underwent bilateral neck dissection for midline disease and 41 patients with clinically N+ neck underwent contralateral supraomohyoid neck dissection for the disease crossing the midline. The T stage breakup of this group of patients was T1-13%, T2-48%, T3- 19% and T4-20%. To evaluate the accuracy of frozen section in detecting metastases, we have used 651 neck dissections in 581 patients. If the frozen section detected metastases, patient underwent standard type III modified neck dissection (Levels 1-4 ± 5). Nearly one third (188/651) of the supraomohyoid neck dissections were found to have lymph node metastases. Based on this report, 68% (129/188) underwent further dissection of level 4 ± 5 and 11% of these additionally dissected nodes showed metastases in the final pathology. At final pathology, while there was no instance of false positive [Table 1]. However, 7% (47/651) patients were falsely reported as negative on frozen section. Hence, the positive predictive value of frozen section in detecting occult metastases is 100% and negative predictive value is 90%.

Amongst these 651 neck dissections, 343 unilateral supraomohyoid neck dissections were done for lateralized T1 (153) and T2 (190) lesions. There was no significant difference between T 1 and T2 lesions with regard to occult metastases in final pathology (24 and 26% respectively). Of the 343 unilateral supraomohyoid neck dissections, 25% (86) were reported positive on frozen section. Nearly 60% (51/86) of these underwent completion neck dissection for removal of level 4 ± 5. On final pathology, 14% (7/51) of this additionally removed level 4 ± 5 showed nodal metastases. Of the 261 declared negative on frozen section, 11% (29) were found to have positive lymph node in final HPR. Since we did not have any false positive frozen section, the positive predictive value of frozen section for detection of occult metastases is 100%. Considering that 232 necks were truly negative and 29 were falsely negative, the negative predictive value of frozen section for the detection of metastases in T1/T2 N0 is 88%. We looked for influence of various factors (available during frozen section) leading to nodal metastases in T1/T2 clinically N0 neck such as age, sex, thickness, maximum tumor dimension, tumor volume (product of all three dimensions).


 > Discussion Top


Achievement of an adequate tumor free margin is the aim of head and neck squamous cell carcinoma surgery, as it is a well known predictor of local failure and distant failures. [1],[7],[17] Frozen section is a widely used method of rapid intra-operative adequacy of surgical margins. [18] Apart from margins, the role of intra-operative frozen section in head and neck carcinoma is to ascertain diagnosis of a doubtful primary or a node with a reported accuracy of 96% to 99%. [19],[20],21],[22] Considering that there may be shrinkage of surgical margin (31% to 46%) at the time of paraffin section, most surgeons aim at 8 to 10 mm of margins during surgery to achieve a 5 mm tumor free margin. [23],[24] There is a wide variation in margin positivity as per the published literature and up to 47% patients may have positive margin on paraffin section. [Table 2] Amongst all the head and neck sub sites, oral cancer is reported to have the highest likelihood (15%) of having positive surgical margins. [28] Within oral cavity, the incidence of margin positivity is highest in tongue cancers with a negative impact on oncologic outcomes. [9],[29] If we use surgical volume (total number of patients in the study divided by the duration of study) as a surrogate marker of the surgical experience, there is a lack of clear cut correlation between surgical experience and margin positivity [Figure 1] and [Table 2].
Figure 1: A diagrammatic depiction of relationship between surrogate of surgical experience and margin status in the published literature

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Table 2: A summary of incidence of inadequate margins as reported in published literature

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In our study, the frozen section detected close margins in 21% patients (187/877) and 59% (110/187) of them were revised. The main reason for non-revision despite a close margin was proximity to bone and majority of the time it was labeled "4 mm" on frozen section. There was 97% concordance between the margins (positive + close) reported on frozen section and those reported at the final histopathology i.e the frozen margin close/positive were the same as that reported on histopathology. The frozen section detected positive margin in 2% (17/877) and 16 of these had intra-operative revisions. At final pathology 1.2% (11/877) of the patients were reported to have positive margin. Amongst the patients with positive margin at paraffin section, 1 was not revised after positive frozen section, 3 were revised but not sent for repeat frozen section and 7 were declared negative on frozen section. Therefore, only 7 out of eleven patients were wrongly declared negative on frozen section. Of the seven that were falsely negative on frozen section, 2 had carcinoma in situ, 1 had a small focus of carcinoma, 1 had sub mucosal disease, 1 had peri-neural invasion, 1 had positivity of bony margin and one was positive in another margin. It is accepted that above mentioned issues are challenging even for an experienced pathologist performing the frozen section. The positive predictive value of frozen section in detecting a positive margin was 100% and the negative predictive value was 99.4%. Several studies in the past have reported similar high accuracy of frozen section in assessment of margin status. [5],[23],[30],[31],[32] We also studied several factors influencing surgical margin (positive and close) such as age, sex, grade, PNI, tumor size, thickness, maximum tumor dimension and tumor volume (assuming tumor as a cube and calculated as product of length, breadth and height) [Table 3]. The multivariate analysis in our study showed that the tumor thickness as the most important predictor of positive /close margin (P<0.0001). It is anticipated that thicker tumor are more likely to be positive at the deeper margin or the base. Using 4 mm as cut off, we did not find any correlation between thickness and the chances of close/positive base (P < 0.60). The age, sex, grade, PNI, T stage, maximum tumor size, tumor volume did not influence the margin status in multivariate analysis [Table 3]. Had the frozen section not been done, our final margin positivity rate would have been 2.7% (24/877). Therefore, frozen section reduced the overall incidence of positive margins by half (2.7% vs 1.2%). Although revision was done in only 59% of those where frozen section reported close margins, at final pathology only 11% were reported to have close margins. Hence, frozen section halved the incidence of the close margin in our study (21% at frozen section vs 11% at PS). Finally, intra-operative frozen section led to nearly 50% reduction in positive and close margin which does have important clinical implications.
Table 3: Multivariate analysis of factors available at the time of frozen section that may infl uence margin status

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Byers reported that the outcome of patients who achieve a negative margin with re-excision following positive frozen section is the same as those who were negative on frozen section. The two-year survival was 10% for margin positive, 77% for negative margin after revision (following positive frozen) and 86% for those that were negative on frozen as well as paraffin. [29] A 50% reduction in positive/close margins by frozen section, as demonstrated in our study, supports the above observation. However, DiNardo et al, have reported that intra-operative frozen section assessment of margin is costly and may not reliably eradicate positive final margin at paraffin section. [22] Their conclusions cannot be entirely relied upon in the surgical management of oral cancers because of several factors. The study had only 23 patients with oral cancers; the study was not restricted to squamous cell carcinomas (14% were non squamous pathologies), all surgeries were done by a single surgeon that is not truly representative of a teaching hospital setting; numbers of specimens sent for margin was very high (5.25 per patient) and the cost of frozen section may vary between different health care systems in the world. Spiro et al, did not find the status of margins as an independent predictor of survival. In their series, though the incidence of local recurrence was significantly higher in margin positive cases than margin negative cases, there was no significant difference in overall survival between the two groups. [9] It is well expected that status of margin may warrant additional adjuvant treatment when none was required or may dictate the addition of chemotherapy in a patient where radiotherapy alone would have sufficed. Therefore, aggressive adjuvant treatment may dilute the effect of surgical margin status on overall outcome.

Another recent study evaluated the prognostic and therapeutic implication of initially positive margin in frozen section, that were subsequently revised to negative. They concluded that patients revised to negative margin had higher local recurrence, but only when regional disease was also present. [30] Kumar et al compared the outcome of surgically treated 416 oral cancers treated over a period of 30 years who underwent intra-operative frozen section vis-à-vis no frozen section. [17] The authors reported similar cause-specific survival and primary failure rate in both groups at five years. However, primary failure was independently influenced by status of margin, with involved margin failing twice more often than those with tumor free margin. The lack of overall difference in the two groups could be attributed to a high margin positivity rate (15.4%) at paraffin section despite frozen section and the lack of significant difference in the number of patients with positive margins in both groups (those with frozen section and those without frozen section). Ideally, an impeccable frozen section should have significantly reduced the number of positive margins that would have translated into clear survival benefit in the group that underwent frozen section.

The management of N0 neck in T1-T2 tongue cancer is an issue of great debate. [14] In case a surgeon decides to undertake a neck dissection in early lesions, supra-omohyoid neck dissection is not only the most effective staging technique but also has therapeutic value. [15],[16] There is more or less unanimity in management of clinically N+ neck with most authors advocating modified neck dissection (MND) (Type 1-3) depending upon the levels of nodal involvement. Considering chances of level IV involvement in clinically N+ neck, supraomohyoid neck dissection in these patients is an issue of debate. [16] Considering that up to 20% clinically N0 neck are actually pathologically N+ (pN+), we believe that Type 3 modified neck dissection is better than a supraomohyoid neck dissection in patients with metastatic nodes detected on frozen section. Therefore, we routinely utilized frozen section facility for detection of occult metastases in supraomohyoid neck dissections being done for clinically N0 necks. This offered us an opportunity to evaluate the accuracy of frozen section in assessment of occult nodal metastases. Only a limited number of studies focusing on the role of frozen section in determining cervical nodal status in head and neck squamous cell carcinoma are available. [31],[32],[33],[34],[35],[36],[37] The specificity of frozen section is 100% in almost every study and the sensitivity varies between 42% and 73%. The interest in frozen section has gained momentum in the last decade following increasing usage of sentinel node biopsy in the management of oral squamous cell carcinoma. [38] Currently, supraomohyoid neck dissection is the most accurate staging tool for the clinically N0 Neck with an additional advantage of being therapeutic too. The accuracy supraomohyoid neck dissection is superior to the reported sensitivity of MRI, USG, USG guided FNAC and PET Scan. [39],[40],[41],[42]

Of the 651 supraomohyoid neck dissections, nearly one third were found to have occult metastases on frozen section. Of those reported positive on frozen section, 68% had additional removal of level 4 ± 5. Interestingly, 11% of these additionally removed nodes harbored metastases at final pathology. This impressive gain was diluted by 7% false negative frozen sections. When we restrict our study to 343 unilateral supraomohyoid neck dissections done for clinically N0 necks for lateralized T1/T2 lesions, 25% were detected to harbor metastases on frozen section. Of these necks positive on frozen section, 60% of them underwent additional removal of level 4 ± 5. Surprisingly, 14% of these additionally removed nodes showed the presence of metastases. We analyzed the factors predicting occult metastases on frozen section in our series. A recent meta analysis found statistically significant difference using 4-mm and 5-mm tumor thickness as cut off with a respective rate of 4.5 and 16.6% for incidence of occult nodal metastases. [13] At the time of frozen section, surgeon has an opportunity to know the precise tumor size and thickness that are independent predictors of occult metastases in a clinically N0 neck. [43],[44],[45],[46],[47],[48] On multivariate analysis, tumor thickness (with 4 mm cut off) was the most important predictor of occult metastases detected on frozen section (P<0.004) [Table 3]. With the available tumor dimensions, we calculated the rough tumor volume (product of the length, breadth and thickness - considering the tumor as a cube) with a hope that it may have greater accuracy in predicting LN metastases. However, there was no significant correlation between incidence of lymph node metastases on frozen section and the tumor volume.


 > Conclusions Top


Frozen section certainly has an important role to play in intra-operative assessment of margins. Our study shows that it nearly halves the rates of positive margin and close margin. With current standards of care, this certainly translates into clinical benefit to the patients in terms of loco-regional failure and overall survival. In T1/T2 lesions, the incidence of 14% positive nodes in the frozen guided removal of lower levels is a surprising finding in our study. The high incidence of metastases in the lower levels questions the ability of supraomohyoid neck dissection to completely eradicate the nodal burden clinically in such patients. No neck with occult metastases detected on frozen section. Frozen section, with a negative predictive value of 88%, may allow us to select patients with occult metastases who are benefited most by the additional removal of lower levels of neck nodes. We accept that, in the absence of survival data, these gains or findings may not have important clinical relevance. A randomized clinical trial comparing supraomohyoid neck dissection alone and supraomohyoid neck dissections with frozen guidance in clinically N0 neck may be the best way to solve this dilemma.

 
 > References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]


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