Significance of Positive Margins in Oral Cavity Squamous Carcinoma Thom R. Loree, MD, Elliot W. Strong, MD, VACS,New York,New York
Three hundred ninety-eight consecutive, previously untreated patients undergoing surgery for epidermoid carcinoma of the oral cavity from 1979 to 1983 were reviewed. One hundred twenty-nine patients were classified as having positive surgical margins. Of these, 8 3 patients had tumor within 0.5 mm of the surgical margin, 9 had premalignant changes at the margin, 9 had in situ carcinoma at the margin, and 28 had invasive cancer at the margin. The remaining 2 6 9 patients had uninvolved margins. The significance of positive margins relating to survival, subsequent clinical course, local recurrence, and patterns of treatment failure was examined, along with the impact of adjuvant postoperative radiotherapy on positive margins. The percentage of patients having positive margins progressively increased with increasing T stage: 2 1 % in T1 versus 55% in T 4 primary cancers. The overall 5-year survival for patients with negative margins was 60%. For patients with positive margins, 5-year survival was 52%. This difference was statistically significant. The incidence of local recurrence in patients having positive surgical margins was twice as much as in those with negative margins ( 3 6 % versus 1 8 % ) . Metastasis rates in the neck and at distant sites were not significantly influenced by the status of the surgical margin. Of the 129 patients with positive margins, 49 received postoperative radiotherapy. In those patients so treated, a trend toward lower recurrence rates was noted. Differences were not statistically significant. This retrospective review confirms the importance of adequate resection of the primary tumor as well as the relative ineffectiveness of adjuvant postoperative radiotherapy in the improvement of local control in patients with positive surgical margins.
From the Departmentof Surgery,Head and Neck Service.Memorial Sloan-KetteringCancer Center.New York. New York. Requestsfor reprintsshouldbe addressedto ElliotW. Strong,MD, 1275 York Avenue,New York, New York 10021-6007. Presented at the 36th Annual Meetingof the Societyof Head and Neck Surgeons,Washington,DC, May 19-22. 1990. 410
he importance of obtaining clear surgical margins T in the treatment of squamous carcinoma of the head and neck is well recognized. The report of a clear margin does not guarantee that local recurrence will not occur, nor does the report of an involved margin imply that development of local recurrence is certain. However, an involved margin on the final pathology report does imply a significantly higher risk of local recurrence and a poorer prognosis. Other reports, including several from our institution, have confirmed this conclusion through analyses of patients with positive margins derived from a variety of head and neck sites [1-6]. Since these reports deal with relatively few patients, it remains difficult to quantify the risk of recurrence in the patient with an involved margin. Another unresolved issue is the value of adjuvant postoperative radiotherapy in the presence of a positive margin. It is often recommended that patients with positive margins undergo postoperative radiotherapy in order to reduce the risk of local recurrence to a level equivalent to that of comparable patients with negative margins. The literature, however, is inconsistent in this regard [2-6]. In an attempt to clarify these issues, this study analyzed the significance of positive margins in a large group of patients having primary tumors of the oral cavity only. PATIENTS AND M E T H O D S A retrospective review of all previously untreated patients with squamous carcinoma of the oral cavity (excluding lip carcinoma) undergoing surgical treatment at our institution from 1979 to 1983 was undertaken. Three hundred ninety-eight patients were studied. Information regarding age, gender, stage, site, surgical and adjuvant therapy, and follow-up was recorded from each chart. Particular attention was paid to the findings recorded on the final pathology reports. No attempt was made to rereview pathologic material. This information was then analyzed to determine the impact of margin status on survival, recurrence, and disease-free interval. The results of postoperative radiotherapy were documented. Observed surviva! curves were estimated using the method of Kaplan and Meier [7] and compared using the log-rank test [8]. Fisher's exact test was used to compare recurrence rates and subgroup populations [9]. In the entire series, there was a 1.55:1 male predominance. Two hundred forty-two of the patients were men and 156 were women. Ages ranged from 19 years to 95 years, with a median age of 59 years for men and 63 years for women, The site distribution of the primary lesions is shown in Table I. Clinical stage was assigned retrospectively to each patient according to the 1988 American Joint Committee on Cancer staging system. One hundred twenty-seven patients had stage I cancer, 127 had stage II Cancer, 78 had stage III cancer, and 66 had stage IV cancer. The margin was classified as positive according to
THE AMERICAN JOURNAL OF SURGERY VOLUME160 OCTOBER 1990
SIGNIFICANCE OF POSITIVE MARGINS
four criteria: (1) close margin (tumor within 0.5 cm), (2) premalignant change in the margin, (3) in situ carcinoma in the margin, and (4) invasive microscopic cancer at the margin. Standard processing of surgical specimens by the pathology department was employed and has been described previously [4]. Using these criteria, 32% of the patients (n -- 129) had positive margins. The incidence of positive margins was directly proportional to increasing T stage (Table II). The distribution of patients in the subcategories of positive margins is indicated in Table III, with the largest subcategory being patients with close margins (64%). Twenty-two percent of the patients with positive margins and only 7% of the total patient population had microinvasive carcinoma in the margin. In only two of the patients in the microinvasive group was the presence of residual tumor at the margin suspected at surgery. Surgical treatment entailed resection of the primary lesion only in 181 patients (181 NO). Resection of the primary tumor with complete (comprehensive) neck dissection was employed in 173 patients (85 NO). Resection of the primary tumor with modified (selective) neck dissection was employed in 44 patients (36 NO). Surgical pathology reports were used to establish a pathologic stage to allow more accurate analysis. Of the 212 patients who underwent neck dissection, the accuracy of clinical node assessment was 80.6%. Two hundred ninety patients were pathologic stage NO. Of this group, 89 patients had positive margins (31%). One hundred eight patients were N+; 40 of these had positive margins (37%). Sixteen percent of the NO group and 46% of the N + group had T3 or T4 lesions. Adjuvant radiotherapy was employed in 106 patients. Of the 108 N + patients, 74 received postoperative radiotherapy, 30 of whom had positive margins. Of the 290 NO patients, 32 received postoperative radiotherapy, 19 of whom had positive margins. In all 106 patients treated with adjuvant radiotherapy, the dosage, portals, and progress of treatment were monitored and recorded by the attending surgeon during outpatient follow-up and consultation with the radiotherapist. Therapy was altered when deemed necessary. Dosage was less than 5,000 cGy in 12 patients (11%), 5,000 to 6,000 cGy in 36 patients (34%), and 6,000 cGy or greater in 41 patients (39%). In the remaining 17 patients, dosage was not recorded. Of the 94 patients in whom the information was available, 33% completed the course of radiotherapy within 12 weeks postoperatively, 71% within 16 weeks postoperatively, and 93% within 20 weeks postoperatively. Five-year follow-up was available in 76% of patients, and 2-year follow-up was available in 90%. Follow-up time was between 6 months and 2 years in 21 patients (5%). Less than 6-month follow-up was available in the remaining 18 patients (4.5%). RESULTS Five-year survival for all patients was 57%. By clinical stage, 5-year survival was 71% for stage I patients, 61% for stage II patients, 56% for stage III patients, and 31% for stage IV patients. Positive margins increased the risk of local recurrence.
TABLE I Primary Site and Margin Status
Site
NO. of Lesions ~
No. of Positive Margins (%)
Tongue Floor of mouth Lower gingiva Retromolar trigone Upper gingiva Hard palate Buccal mucosa
137 137 57 25 19 17 12
37 (27) 43 (31) 22 (39) 6 (24) 8 (42) 6 (35) 7 (58)
9 Six patients had two primary oral cavity squamous carcinomas.
TABLE II Local Recurrence and Margin Status In Relation to T Stage
Stage
Positive Margins/Total (%)
T1 T2 T3 T4 Total
No. Local Recurrences/Total (%) Positive Margins Negative Margins
29/140 (21) 59/163 (36) 30/75 (40) 11/20 (55)
6129 (21) 20/59 (34) 13/30 (43) 7111 (64)
14/111 (13) 241104 (23) 10/45 (22) 1/9 (11)
129/396 (32)
46/129 (36)
491269 (18)
TABLE III
Local Recurrence In Relation to Margin Status
Margin
No. of Local Recurrences/Total (%)
5-Year Survival (%)
Negative Positive Premalignant change In situ carcinoma Close (within 0.5 cm) MIcroinvasive
49/269 (18) 461129 (36) 319 (33) 4/9 (44) 29/83 (35) 10/28 (36)
60 52 94 71 51 43
The overall local recurrence rate in the entire positive margin group was twice that of the negative margin group: 36% versus 18%, respectively. Table II shows the rates of local recurrence when the patients are stratified solely by T stage. Within each T stage grouping, the local recurrence rate for patients with positive margins exceeds that of patients with negative margins. These differences in local recurrence rates were statistically significant for the T2, T3, and T4 groups (p -- 0.05, 0.03, and 0.02, respectively). Table IV gives the rates of local recurrence and regional and distant metastases when stratified by pathologic stage and margin status. Margin status had a significant effect on local recurrence in both the T I4,N+ group (p = 0.042) and the NO groups (p -- 0.003 for the T1-2,N0 group and p = 0.042 for the T3-4,N0 group). The status of the surgical margin did not significantly influence the rates of regional and distant metastases. Positive margins adversely affected survival. The 5year survival of the positive and negative margin groups
THE AMERICAN JOURNAL OF SURGERY
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OCTOBER 1990
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LOREE AND STRONG
TABLE IV
Recurrence Rates and Survival In Relation to Pathogenic Stage and Margin Status Percentage Margin Status
No, of Patients
5-year Survival
Local Recurrence
Metastasis
Distal Metastasis
Negative Positive Negative Positive Negative Positive
174 71 27 18 68 40
67 67 71 61 41 21
17 25 22 50 21 48
18 18 19 22 32 43
3 3 4 6 21 30
Stage T1-2, T1-2, T3-4, T3-4, T1-4, T1-4,
NO NO NO NO N-F N+
PROPORTION SURVIVING
0.8
%
p < 0.025
0.4
52%
0,2 ~NegatJve i
0 - 0
_ _
1
(n=269)
--~-Positive
(n-129)]
~
J
i
2
3
4
TIME (years)
Figure 1. Observed survival and margin status.
PROPORTION SURVIVING 1
2:,7 7?. ',727
o,, Z
T3-4,NO O.2
+
nag (n=27)
TS-4,NO pos (n=18) T1-4,N+ hog (n=08) TI-4,N+ po8 (n=40)
0 ~ 0
I 1
I 2
3
4
5
TIME(years)
Figure 2. Observed survival by pathologic stage and margin status.
was 52% and 60%, respectively. This difference in survival was statistically significant (p
Three hundred ninety-eight consecutive, previously untreated patients undergoing surgery for epidermoid carcinoma of the oral cavity from 1979 to 1983 were reviewed. One hundred twenty-nine patients were classified as having positive surgical margins. Of these, 8 3 patients had tumor within 0.5 mm of the surgical margin, 9 had premalignant changes at the margin, 9 had in situ carcinoma at the margin, and 28 had invasive cancer at the margin. The remaining 2 6 9 patients had uninvolved margins. The significance of positive margins relating to survival, subsequent clinical course, local recurrence, and patterns of treatment failure was examined, along with the impact of adjuvant postoperative radiotherapy on positive margins. The percentage of patients having positive margins progressively increased with increasing T stage: 2 1 % in T1 versus 55% in T 4 primary cancers. The overall 5-year survival for patients with negative margins was 60%. For patients with positive margins, 5-year survival was 52%. This difference was statistically significant. The incidence of local recurrence in patients having positive surgical margins was twice as much as in those with negative margins ( 3 6 % versus 1 8 % ) . Metastasis rates in the neck and at distant sites were not significantly influenced by the status of the surgical margin. Of the 129 patients with positive margins, 49 received postoperative radiotherapy. In those patients so treated, a trend toward lower recurrence rates was noted. Differences were not statistically significant. This retrospective review confirms the importance of adequate resection of the primary tumor as well as the relative ineffectiveness of adjuvant postoperative radiotherapy in the improvement of local control in patients with positive surgical margins.
From the Departmentof Surgery,Head and Neck Service.Memorial Sloan-KetteringCancer Center.New York. New York. Requestsfor reprintsshouldbe addressedto ElliotW. Strong,MD, 1275 York Avenue,New York, New York 10021-6007. Presented at the 36th Annual Meetingof the Societyof Head and Neck Surgeons,Washington,DC, May 19-22. 1990. 410
he importance of obtaining clear surgical margins T in the treatment of squamous carcinoma of the head and neck is well recognized. The report of a clear margin does not guarantee that local recurrence will not occur, nor does the report of an involved margin imply that development of local recurrence is certain. However, an involved margin on the final pathology report does imply a significantly higher risk of local recurrence and a poorer prognosis. Other reports, including several from our institution, have confirmed this conclusion through analyses of patients with positive margins derived from a variety of head and neck sites [1-6]. Since these reports deal with relatively few patients, it remains difficult to quantify the risk of recurrence in the patient with an involved margin. Another unresolved issue is the value of adjuvant postoperative radiotherapy in the presence of a positive margin. It is often recommended that patients with positive margins undergo postoperative radiotherapy in order to reduce the risk of local recurrence to a level equivalent to that of comparable patients with negative margins. The literature, however, is inconsistent in this regard [2-6]. In an attempt to clarify these issues, this study analyzed the significance of positive margins in a large group of patients having primary tumors of the oral cavity only. PATIENTS AND M E T H O D S A retrospective review of all previously untreated patients with squamous carcinoma of the oral cavity (excluding lip carcinoma) undergoing surgical treatment at our institution from 1979 to 1983 was undertaken. Three hundred ninety-eight patients were studied. Information regarding age, gender, stage, site, surgical and adjuvant therapy, and follow-up was recorded from each chart. Particular attention was paid to the findings recorded on the final pathology reports. No attempt was made to rereview pathologic material. This information was then analyzed to determine the impact of margin status on survival, recurrence, and disease-free interval. The results of postoperative radiotherapy were documented. Observed surviva! curves were estimated using the method of Kaplan and Meier [7] and compared using the log-rank test [8]. Fisher's exact test was used to compare recurrence rates and subgroup populations [9]. In the entire series, there was a 1.55:1 male predominance. Two hundred forty-two of the patients were men and 156 were women. Ages ranged from 19 years to 95 years, with a median age of 59 years for men and 63 years for women, The site distribution of the primary lesions is shown in Table I. Clinical stage was assigned retrospectively to each patient according to the 1988 American Joint Committee on Cancer staging system. One hundred twenty-seven patients had stage I cancer, 127 had stage II Cancer, 78 had stage III cancer, and 66 had stage IV cancer. The margin was classified as positive according to
THE AMERICAN JOURNAL OF SURGERY VOLUME160 OCTOBER 1990
SIGNIFICANCE OF POSITIVE MARGINS
four criteria: (1) close margin (tumor within 0.5 cm), (2) premalignant change in the margin, (3) in situ carcinoma in the margin, and (4) invasive microscopic cancer at the margin. Standard processing of surgical specimens by the pathology department was employed and has been described previously [4]. Using these criteria, 32% of the patients (n -- 129) had positive margins. The incidence of positive margins was directly proportional to increasing T stage (Table II). The distribution of patients in the subcategories of positive margins is indicated in Table III, with the largest subcategory being patients with close margins (64%). Twenty-two percent of the patients with positive margins and only 7% of the total patient population had microinvasive carcinoma in the margin. In only two of the patients in the microinvasive group was the presence of residual tumor at the margin suspected at surgery. Surgical treatment entailed resection of the primary lesion only in 181 patients (181 NO). Resection of the primary tumor with complete (comprehensive) neck dissection was employed in 173 patients (85 NO). Resection of the primary tumor with modified (selective) neck dissection was employed in 44 patients (36 NO). Surgical pathology reports were used to establish a pathologic stage to allow more accurate analysis. Of the 212 patients who underwent neck dissection, the accuracy of clinical node assessment was 80.6%. Two hundred ninety patients were pathologic stage NO. Of this group, 89 patients had positive margins (31%). One hundred eight patients were N+; 40 of these had positive margins (37%). Sixteen percent of the NO group and 46% of the N + group had T3 or T4 lesions. Adjuvant radiotherapy was employed in 106 patients. Of the 108 N + patients, 74 received postoperative radiotherapy, 30 of whom had positive margins. Of the 290 NO patients, 32 received postoperative radiotherapy, 19 of whom had positive margins. In all 106 patients treated with adjuvant radiotherapy, the dosage, portals, and progress of treatment were monitored and recorded by the attending surgeon during outpatient follow-up and consultation with the radiotherapist. Therapy was altered when deemed necessary. Dosage was less than 5,000 cGy in 12 patients (11%), 5,000 to 6,000 cGy in 36 patients (34%), and 6,000 cGy or greater in 41 patients (39%). In the remaining 17 patients, dosage was not recorded. Of the 94 patients in whom the information was available, 33% completed the course of radiotherapy within 12 weeks postoperatively, 71% within 16 weeks postoperatively, and 93% within 20 weeks postoperatively. Five-year follow-up was available in 76% of patients, and 2-year follow-up was available in 90%. Follow-up time was between 6 months and 2 years in 21 patients (5%). Less than 6-month follow-up was available in the remaining 18 patients (4.5%). RESULTS Five-year survival for all patients was 57%. By clinical stage, 5-year survival was 71% for stage I patients, 61% for stage II patients, 56% for stage III patients, and 31% for stage IV patients. Positive margins increased the risk of local recurrence.
TABLE I Primary Site and Margin Status
Site
NO. of Lesions ~
No. of Positive Margins (%)
Tongue Floor of mouth Lower gingiva Retromolar trigone Upper gingiva Hard palate Buccal mucosa
137 137 57 25 19 17 12
37 (27) 43 (31) 22 (39) 6 (24) 8 (42) 6 (35) 7 (58)
9 Six patients had two primary oral cavity squamous carcinomas.
TABLE II Local Recurrence and Margin Status In Relation to T Stage
Stage
Positive Margins/Total (%)
T1 T2 T3 T4 Total
No. Local Recurrences/Total (%) Positive Margins Negative Margins
29/140 (21) 59/163 (36) 30/75 (40) 11/20 (55)
6129 (21) 20/59 (34) 13/30 (43) 7111 (64)
14/111 (13) 241104 (23) 10/45 (22) 1/9 (11)
129/396 (32)
46/129 (36)
491269 (18)
TABLE III
Local Recurrence In Relation to Margin Status
Margin
No. of Local Recurrences/Total (%)
5-Year Survival (%)
Negative Positive Premalignant change In situ carcinoma Close (within 0.5 cm) MIcroinvasive
49/269 (18) 461129 (36) 319 (33) 4/9 (44) 29/83 (35) 10/28 (36)
60 52 94 71 51 43
The overall local recurrence rate in the entire positive margin group was twice that of the negative margin group: 36% versus 18%, respectively. Table II shows the rates of local recurrence when the patients are stratified solely by T stage. Within each T stage grouping, the local recurrence rate for patients with positive margins exceeds that of patients with negative margins. These differences in local recurrence rates were statistically significant for the T2, T3, and T4 groups (p -- 0.05, 0.03, and 0.02, respectively). Table IV gives the rates of local recurrence and regional and distant metastases when stratified by pathologic stage and margin status. Margin status had a significant effect on local recurrence in both the T I4,N+ group (p = 0.042) and the NO groups (p -- 0.003 for the T1-2,N0 group and p = 0.042 for the T3-4,N0 group). The status of the surgical margin did not significantly influence the rates of regional and distant metastases. Positive margins adversely affected survival. The 5year survival of the positive and negative margin groups
THE AMERICAN JOURNAL OF SURGERY
VOLUME 160
OCTOBER 1990
411
LOREE AND STRONG
TABLE IV
Recurrence Rates and Survival In Relation to Pathogenic Stage and Margin Status Percentage Margin Status
No, of Patients
5-year Survival
Local Recurrence
Metastasis
Distal Metastasis
Negative Positive Negative Positive Negative Positive
174 71 27 18 68 40
67 67 71 61 41 21
17 25 22 50 21 48
18 18 19 22 32 43
3 3 4 6 21 30
Stage T1-2, T1-2, T3-4, T3-4, T1-4, T1-4,
NO NO NO NO N-F N+
PROPORTION SURVIVING
0.8
%
p < 0.025
0.4
52%
0,2 ~NegatJve i
0 - 0
_ _
1
(n=269)
--~-Positive
(n-129)]
~
J
i
2
3
4
TIME (years)
Figure 1. Observed survival and margin status.
PROPORTION SURVIVING 1
2:,7 7?. ',727
o,, Z
T3-4,NO O.2
+
nag (n=27)
TS-4,NO pos (n=18) T1-4,N+ hog (n=08) TI-4,N+ po8 (n=40)
0 ~ 0
I 1
I 2
3
4
5
TIME(years)
Figure 2. Observed survival by pathologic stage and margin status.
was 52% and 60%, respectively. This difference in survival was statistically significant (p
