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From the Departments of *Otolaryngology, Pathology, and Biomathematics, Mount Sinai Medical Center, New York, NY; Department of Otolaryngology, Massachusetts General Hospital, Boston, MA; and kDepartment of Oral Pathology, University of Western Cape, Cape Town, South Africa. Reprints: Margaret Brandwein-Gensler, MD, Albert Einstein College of Medicine, Monteore Medical Center, Moses Division, Department of Pathology, ENT, 111 East 210th Street, Bronx, NY 10467 (e-mail: mgensler@monteore.org). Copyright 2005 by Lippincott Williams & Wilkins
any pathologists have faced the query, But I took the whole tumor out. Why did it recur? One goal of this study was to examine the impact on resection margin status on outcomes for patients with oral squamous cell carcinoma (OSCC). We demonstrate that, even among tumors with extensive histologic documentation of adequate resection margins, local recurrence (LR) develops in a predictable subset of patients. Achieving histologically adequate margins does not constitute the entire picture. Correlating pathologic tumor grade alone with outcome has not been a uniformly satisfying venture. Tumor thickness
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for T1 tongue squamous cell carcinoma (SCC) has strongly associated with propensity for lymph node metastasis and survival17 but is not a predictor for LR.13,25 Multiparameter prognostic histologic assessments have been developed and rened over the last two decades, based on variables that include pattern of invasion, degree of keratinization, nuclear pleomorphism, lymphocytic response, and mitotic rate.15,18,22 Pattern of tumor invasion (POI) refers to the manner in which cancer inltrates tissue at the tumor/host interface. It is intuitive that neoplasia inltrating in a widely dispersed manner is more aggressive than those growing in a bulky pushing fashion. Over the past two decades, POI alone, and as part of weighted scoring systems, has been demonstrated to predict LR and decreased overall survival (OS). In this study, we evaluated multiple histologic variables, analyzing them with respect to patient outcome. We present a novel, simple, highly predictive histologic risk scoring scheme that can serve as a rationale for decision-making viz-a-viz the necessity for adjuvant radiation therapy (RT) at the primary tumor site.
Cohort 2 (n = 203) represents a group culled from Cohort 1, with no neoadjuvant therapy, and conrmed treatment status and clinical follow-up. Seventy-nine patients were uniformly treated by primary surgery alone. A total of 124 patients received primary surgery plus adjuvant radiotherapy. Cohort 3 (n = 168) represents a subset of Cohort 2, satisfying the following requirements: 1) they received their primary surgery at this institution between 1989 and 2002; 2) no neoadjuvant therapy was administered; 3) the specimen was adequately sampled, and all or most of the slides were available for rereview to conrm margin status; 4) postoperative treatment and disease status was conrmed; and 5) all disease-free patients had a minimum of 18 months follow-up. Of these 168 patients, 105 received adjuvant radiotherapy and 63 did not. Cohort 4 refers to a subset of Cohort 3 with tumors of the mobile tongue and oor of mouth.
Stage
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Grade
Keratin
Eosinophilia
Lymphocytic inltrate
Vascular/lymphatic invasion
and sampled generously. This involves entirely sampling all of the closest margins, plus representative sections from the remaining margins. The distances between carcinoma (either inltrating or mucosal carcinoma in situ) and the inked resection margins were microscopically measured using a 43 ocular and a ruler. If the distance is #5 mm at the time of frozen section, then that margin was designated as inadequate. A resection margin map is thus generated. The surgeon is informed of the results and the specic problematic sites and examines either a drawing or the actual remaining specimen. The sites of inadequate margins are then revisited in situ, and additional tissue cuffs are submitted as supplemental margins (guided supplemental margins). The supplemental margins are entirely examined; if cancer-free, then tumor extirpation is complete. Our treatment policy is to continue harvesting supplemental margins until resection adequacy is achieved. For this study, all the permanent and frozen section histologic slides on the primary resection specimens were rereviewed, and microscopic measurements were retaken using a 43 ocular piece and a ruler. Patient margin status was retrospectively classied into four groups based on examination of the formalin-xed parafn embedded histology slides, plus the frozen section slides. The rule of thumb is worst news wins. For example, if a margin measures 3 mm on frozen section and the corresponding permanent section measures 5 mm, the shorter distance was taken as the margin distance. Also, while 5 mm was considered close on intraoperative analysis, a measurement of 5 mm on formalin-xed, parafn-embedded tissue was considered adequate retrospectively. This strategy was used to avoid the scenario of negative margins at frozen section converting to close margins after further sectioning on permanent sections. Interestingly, the impact of tissue shrinkage had limited impact when frozen section margin distances were compared with permanent sections.
Margin Analysis
The four margin groups were classied as follows: group 1 was categorized $5 mm clearance at initial resection; group 2 was categorized as inadequate margins during intraoperative consultation, nal margins $5 mm after harvesting supplemental margins; group 3 was categorized as nal permanent pathology revealing close (,5 mm) margins; and group 4 was categorized as nal permanent pathology revealing frankly positive margins. Cohort 3 was subjected to analyses regarding margin status.
Perineural invasion
a four-tiered grading.5) Perineural invasion (PNI) was dened as carcinoma specically tracking along or within a nerve. PNI was further classied as involving large nerves (diameter $1 mm) or small nerves (diameter ,1 mm) (Fig. 3). Other variables examined were as follows: keratinization (quantied as .50%, ,50%, and ,10%), nuclear grade (well, intermediate, poor), foreign body reaction (1 or more high power eld (HPF) vs. none), eosinophilia (1 or more HPF vs. none), lymphatic or vascular tumor emboli, and carcinoma in situ in mucosal adjacent to tumor (no slides, 1 slide, more than 1 slide).
Analysis Endpoints
Follow-up data were collected through patient visits, hospitalizations, or telephone interviews. First failure was dened as the rst manifestation of disease failure per site. Locoregional disease recurrence was subclassied as either local (at the primary tumor site) or regional (at the site of cervical metastases) or both (local plus regional). This was accomplished by reexamining slides from the resection specimen of the rst recurrence and correlating these ndings with the margins of the previous resection and the clinical impression. The endpoint for Cox regression model and Kaplan-Meier analyses was 1) time to rst LR versus 2)
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FIGURE 1. Pattern of invasion (POI). A, POI type 1: broad pushing front. B, POI type 2: nger-like pushing pattern. C, POI type 2: note the high nuclear grade despite the low-grade POI. D, POI type 3: islands at tumor periphery greater larger than 15 cells/island. E, POI type 4: individual tumor cells inltrating at interface. F, POI type 4: strands of inltrating tumor cells. G, POI type 4: tumor islands composed of 15 cells or less. H, POI type 5: 1 mm or greater of normal tissue between tumor satellite islands at interface.
duration of failure-free follow-up, and 3) time to death versus duration of OS. Distant metastases, or the development of a new primary carcinoma, were less common manifestations of rst failures. The date of death was conrmed with the Social Security Death Index (www.ancestry.com/search/rectype/vital/ssdi/main.htm) rather than death certicates. Our endpoint for OS does not distinguish cause of death; this approach is valid as it assumes that deaths unrelated to cancer are equally distributed between both groups. Signicance level was set at P , 0.05. Spearman rank correlation coefcients were used to examine the interrelationships between the histologic variables of Table 2 with each other and with patient age, gender, tumor site, tumor stage (T), nodal stage (N), and stage grouping. The Cox regression survival model and Kaplan-Meier survival analyses were used to analyze data on the variables margin status,
WPOI, PPOI, tumor grade, multifocal carcinoma in situ, keratin production, foreign body reaction, eosinophilia, lymphocytic inltrate, vascular/lymphatic invasion, perineural invasion, tumor site, and T stage with respect to LR, regional metastasis, and OS.
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manifestation of disease failure for 11 patients after a median of 23 months (range, 3 months to 7 years). SPTs were dened as any malignancy developing at an upper aerodigestive tract site not adjacent to the index tumor. Pulmonary adenocarcinomas, or SCC histologically distinct from the index tumor, were also considered as SPTs. With respect to margin status, there were 46 patients classied as group 1, 73 as group 2, 30 as group 3, and 19 as group 4 (total 168, Cohort 3). Table 3 demonstrates the frequency distributions of all rst failure events for Cohort 3, per tumor site. Table 4 demonstrates the LR rates only, for all sites, across all margin groups for Cohort 3. Table 5 breaks down for 85 patients with tongue/oor of mouth tumors (Cohort 4) with respect to LR rate, margin status, T stage, and adjuvant RT status. Across all tumor sites, T stage did signicantly correlate with LR (Pearson x2, P = 0.028). When stratied for both stage and site (but not margin group), this signicance was seen for T4 tumors. The LR rate was signicantly higher for T4 tumors of the buccal mucosa (75%), sinopalatal (50%), and gingival (100%) as compared with mobile tongue (27%) and oropharynx (13%) (Pearson x2, P = 0.013). Margin status was signicantly associated with perineural spread (Pearson x2, P = 0.003,). Patients with close or positive margins were more likely to have perineural spread than patients with negative margins (Table 6).
regional metastases after a median of 9 months (range, 4.4 months to 5 years). Analyses concerning LR included the sum of LR alone, plus LR with synchronous regional metastases. Distant metastases in all but 1 patient involved the lungs; the remaining patient developed brain metastases. Sixteen patients developed distant metastasis as the rst manifestation of disease failure after a median of 7 months (range, 37 days to 2 years). A second primary tumor (SPT) was the rst
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Kaplan-Meier analyses for the endpoints of local disease-free survival and OS demonstrated no signicant association between margin status and either of these endpoints for Cohort 3 (Figs. 4, 5) or Cohort 4. There was no signicant relationship between margin status and LR, or OS, for all sites and T stages, combined and separate. As an example, there were 12 patients with T1 carcinomas who were resected with adequate margins (group 1). None of them received adjuvant RT. Yet 25% of this group developed local and/or local plus regional recurrence. This is explained by the histologic risk factors reported below (Table 5). To control for the confounding effect of adjuvant RT, we also analyzed within treatment groups of Cohort 3 for the patients treated only with surgery (n = 63), and for those also receiving adjuvant RT (n = 105), across margin groups. No
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(14%)
(5%)
Note: Percentages go across rows per site. *Patients with follow-up more than 18 months.
signicant associations were demonstrated between margin status and LR and OS for uniformly treated groups either.
also associated with N . N0 at diagnosis (two-tailed x2, P , 0.001). With regard to LR, statistical signicance was achieved when WPOI pattern 5 was compared with pattern 4 (Table 8), (Pearson x2, P , 0.001), but no signicance was achieved with PPOI. Both PPOI (x2, P = 0.003; 95% condence interval, 1.68, 19.98) and WPOI (x2, P = 0.000; 95% condence interval, 1.49, 28.00) patterns 4 and 5 were signicantly associated with OS (Table 7). Both PNI and lymphocytic response were strongly associated with OS and LR (Table 8). No associations were found between tumor grade, multifocal carcinoma in situ, keratinization, foreign body reaction, eosinophilia, vascular/lymphatic invasion, as well as age and gender, and LR or OS.
TABLE 4. Local Recurrences (LR) for Cohort 3, Stratified for Tumor Site
Margin Status N Mobile tongue +/or oor of mouth Tonsil, pharynx, retromolar trigone Palatomaxillary Base of tongue Buccal Gingiva Total N total N LR N total N LR N total N LR N total N LR N total N LR N total N LR N total N LR 85 17 34 4 19 5 16 2 10 5 4 4 168 37 Group 1 22 4 8 1 7 3 5 0 3 0 1 1 46 9 Group 2 39 9 15 3 7 1 5 1 4 2 3 3 73 19 Group 3 15 2 7 0 3 0 4 1 1 1 0 0 30 4 Group 4 9 2 4 0 2 1 2 0 2 2 0 0 19 5 N per site per margin Corresponding LR N per site per margin Corresponding LR N per site per margin Corresponding LR N per site per margin Corresponding LR N per site per margin Corresponding LR N per site per margin Corresponding LR N per site per margin Corresponding LR group group group group group group group
N, number of patients; N LR, number of patients with local recurrence. Note: 1. Disease-free patients had a minimum of 18 months follow-up. 2. Patients were excluded if margin status could not be histologically re-reviewed. 3. Local recurrence rates refers to the rst recurrence only and is calculated as number of patients who experienced only local recurrence plus patients developing concomitant local and regional recurrence.
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TABLE 5. Local Recurrences of 85 Mobile Tongue/Floor of Mouth SCC (Cohort 4) Per Margin Status and T Stage, Plus Adjuvant RT Status
Group 1 T1 N N N N N N N N N N N N N N N N N N all RT LR all RT LR (X) all RT LR (X) all RT LR (X) all RT LR all RT LR 12 0 3 6 5 0 1 0 3 2 1 (0) 0 22 7 4 Group 2 15 5 0 15 9 5 (3) 7 5 3 (2) 1 1 0 1 1 1 39 21 9 Group 3 6 3 0 5 4 1 (0) 0 4 2 1 (1) 0 15 9 2 Group 4 2 2 0 3 1 1 0 3 3 1 1 1 0 9 7 2 Total 35 10 3 29 19 17 8 5 3 11 8 3 2 2 1 85 44 17
T2
T3
T4
Tx
Total
N, number of patients; N LR, number of patients with local recurrence; N RT, number of patients receiving adjuvant radiotherapy; (X), number of patients with local recurrence who did not receive adjuvant radiotherapy; Tx, unknown T stage.
assigned a score value to these variables (Table 9). We now propose a novel risk classication that is strongly predictive of LR and OS. We were able to develop risk classication algorithms that generated the best t, and classied patients into low, intermediate, and high risk. The rationale behind the point assignments (0, 1, 3) rather than (0, 1, 2) is that we postulated that certain features (POI type 5 vs. type 4, PNI of large nerve vs. small nerves) represented signicant steps downward viz-a-viz prognosis. Thus, we reasoned that this point assignment would better discriminate intermediate- from high-grade risk. We scored Cohort 1 according to this threetiered risk assessment. Kaplan-Meier survival analysis demonstrated that our risk assessment was predictive of both OS (Fig. 6) and LR (not shown) (log rank, P , 0.0001 and P = 0.0004, respectively). The curve representing intermediate risk is relatively equidistant from the low- and high-risk curves graph (Fig. 6), consistent with the reasoning stated above.
TABLE 6. Frequency Distribution of Perineural Invasion With Margin Status (Chi-square P = 0.003)
Perineural Invasion Margin Status Group Group Group Group 1 2 3 4 None 90% 69% 75% 61% ,1 mm 7% 18% 19% 16% .1 mm 3% 13% 6% 23%
Note: x2 (P = 0.003). Group 1, initially .5 mm intraoperatively; group 2, .5 mm after harvesting supplemental margins intraoperatively; group 3, nal pathology reveals margins ,5 mm; group 4, nal pathology reveals frankly positive margins.
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TABLE 7. Distribution Frequencies of Worst Pattern of Invasion, With Respect to Margin Status (P = 0.0001) and Perineural Invasion (P = 0.003)
WPOI 1, 2, 3 Grouped (%) Group 1 Group 2 Group 3 Group 4 No PNI PNI ,1 mm PNI .1 mm 32 15 17 19 26 5 0 WPOI 4 (%) 65 55 55 42 56 64 38 WPOI 5 (%) 3 30 28 39 17 31 62
Note: Percentages are across rows. Group 1, initially .5 mm intraoperatively; group 2, .5 mm after harvesting supplemental margins intraoperatively; group 3, nal pathology reveals margins ,5 mm; group 4, nal pathology reveals frankly positive margins; PNI, perineural spread; WPOI, worst pattern of inltration.
summarize, many groups have demonstrated the local diseasefree and OS benets of achieving negative resection margins.6,7,11,12,15,16,1922 We could not demonstrate the same survival benets with negative resection margins (Figs. 4, 5). The impact of resection margins was not obfuscated by the confounding factor of adjuvant RT, as we had corrected for this. There are at least two explanations for our ndings. First, the denition of positive margins varies, so that what may be deemed adequate by one group is considered inadequate by another. A perusal of Table 10 reveals that the local recurrence rate (LRR) for patients with positive margins varies widely from 22% to 80%. A trend can also be seen, as the LRR for patients with inadequate resection margins decreases between the 1980s and 1990s. When comparing only the reported studies in which the denition of inadequate margins is similar to our denition, the LRR ranges from 22% to 71%.7,15,16,20,21 The weighted average LRR for inadequate margins for these ve reports is 31%. Our LRR for inadequate margins is 18% (9 of 49 patients, Table 4, all sites, all stages), then compares favorably with corresponding reports. Resection margins from the 1970s were not the same as resection margins nowadays. Advances in free-ap reconstructive techniques have allowed surgeons to remove tumors previously deemed unresectable. So our inability to demonstrate signicant differences between in LRR and OS in patients with adequate versus inadequate resection margins may be due to the overall improved outcome of this later group. Second, the denition of LR may also vary with respect to SPT. Recently, van Es et al reported on a series of 82 patients with adequately resected T1 and T2 oral SCC treated by surgery alone.23 Negative resection margins were dened as at least 5 mm, or greater than the intertumor satellite distance. Their reported LRR was signicantly lower than ours (4% vs. 16%, respectively, for T1 and T2 SCC of tongue) (Table 5). The series reported by van Es et al23 and Slootweg et al21 dened SPT adjacent to the index tumor as any tumor developing 2 years or later after resection (personal communication). Molecular proling studies can conclusively distinguish SPT adjacent to the index tumor from LR. Since these tests were not part of this study, we took a very conservative approach in our diagnoses of SPT; any SCC that subsequently developed adjacent to the rst SCC was considered LR. Our rate of SPT for tongue primary SCC is 4%. If, for instance, we applied the same denition to distinguish LR from SPT (2 years), then our SPT rate would
Local Recurrence NS NS WPOI 4 vs. 5 95% CI 0.86, 5.01 P = 0.015 95% CI 1.47, 9.21 P = 0.005 NS 95% CI 1.43, 7.89 P = 0.005
Regional Metastasis NS NS NS NS NS NS NS
Overall Survival 95% CI 1.07, 3.60 P = 0.024 95% CI 1.78, 8.38 P = 0.001 HR 2.0 95% CI 1.62, 8.77 P = 0.004 HR 6.4 95% CI 2.43, 13.97 P = 0.001 HR 6.2 95% CI 2.88, 14.18 P = 0.001 HR 2.3 95% CI 1.36, 3.95 P = 0.002 HR 1.9 95% CI 1.42, 4.81 P = 0.039
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rise to 8%, while our LRR would fall to 12% for 65 patients with T1 and T2 tongue SCC. We analyzed Cohort 4 (mobile tongue/oor of mouth cancers) patients, as this anatomic region allows for relatively simple harvesting of supplemental margins. We would logically predict that, when stratied for T stage, the LRR for group 1 margins would be lowest, followed by group 2, then group 3, and lastly group 4. The closer the LRR for group 2 margins is to group 1 margins, the more effective our supplemental margins, in response to the intraoperative feedback. We do see this effect when grouping T1/T2 tongue carcinomas. The LRR for group 1 margins is 16% (3 of 18) and for group 2 margins is also 16% (5 of 30). However, this association breaks down when we stratify for T stages. For T1 tongue carcinomas (all margin groups), the likelihood of remaining disease free at the primary site is seen as a function of adjuvant RT (Table 5) (0% LRR for 10 RT+ patients, 13% LRR for 22 RT2 patients) (P = 0.0027). The only recurrences in this group developed in patients within the group 1 margins
who were not treated with adjuvant RT. For T2 tumors, we also see the impact of RT on LRR: 16% for RT+ versus 40% for RT2 patients (P = 0.001) but no direct association between margin status and LRR.
FIGURE 6. Kaplan-Meier OS curves classied by risk assessment (Cohort 1). q 2005 Lippincott Williams & Wilkins
FIGURE 7. Kaplan-Meier local disease-free survival curves for Cohort 2 high-risk patients only (n = 98).
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TABLE 10. Historical Review of Local Recurrence Rates and Definitions for Resection Adequacy
Year 1976 Author Looser N 62 Site Intraoral plus lip T All Denition of Margins Negative .5 mm; close ,5 mm; positive = cut through or CIS Positive = cut-through or CIS Supplemental Margins? No Therapy 17: preop RT; all surgery LR for Positive and Close Margins 71% LR for Negative Margins 32% Survival, Positive Margins 30.6% 5-yr OS Survival, Negative Margins 35.9% 5-yr OS
1978
Byers
216
All sites
All
Yes
Surgery only
80%
10 0% 2-yr OS
1986
Scholl
268
Tongue
All
Positive = cut-through Negative .5 mm; close ,5 mm; positive = cut through or CIS Negative .5 mm; close ,5 mm; positive = cut through
Yes
Mixed regimens Mixed regimens 55% for positive, 40% for close 30%
15%
1987
Chen
270
All sites
All
No
1990
Loree
303
Oral cavity
T1, T2
No
Surgery +/2 RT
5977% 2-yr OS (4686% 2-yr OS for negative supplemental group) 49% 5-yr OS
39% 5-yr DF
1993 1996
Jacobs Van Es
687 82
All T1, T2 Close ,5 mm or intertumor distance . distance to margin; positive = cut through Positive = cut through, or up to margin; close not dened
No No
25% NA
11% 4% (3/76)
1996
Jones
352
All sites
All
No
66% at 5 yr
47% at 5 yr
1998
Yuen
50
Tongue
All
No
1999
Woolgar
200
Intraoral
All
No
All with surgery, 5 with preop RT; some with postop RT Surgery, adjuvant RT for margins ,5 mm
16% (8/49)
NA
Disease-specic survival after recurrence and surgical salvage lower for patients with positive margins as compared to negative margins, however not statistically signicant Not addressed
Not addressed
1999
Spiro
150
Tongue
All
Close = 1 HPF; Positive = cut through Close ,5 mm; positive = cut through Included any dysplasia, plus margins ,5 mm or intertumor distance .distance to margin Close ,5 mm positive = cut through
No
36%
12%
2001
Sieczka
27
Buccal
All
No
66%
50%
Margin status (clear vs. close vs. involved) strongly correlated with disease-free survival (P = .0001), however, no rates supplied 5-yr OS was similar in both groups (60%) 75% 66% 5-year 5-year survival survival
2002
Slootweg
394
All sites
All
No
22% (41/187)
4% (8/207)
2004
Brandwein
168
All sites
All
Yes
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By what mechanism does POI impact upon survival? It is well established that the N status at presentation is the single-most predictive value for OSCC. WPOI has been previously demonstrated as signicantly associated with positive lymph nodes.13,24 We also demonstrate the association between WPOI and initial N status. WPOI (collapsed 1, 2, 3 vs. 4, 5) did associate with initially positive lymph node status as a two-tailed x2 analysis (P , 0.001).
feasible, as our study represents the accrual of data collected over one decade. Other hospital centers can retrospectively apply this risk scoring system to validate its signicance. While our data support the idea that intermediate- and low-risk patients do not benet from adjuvant RT, it should not be implied that inadequate resection margins are acceptable. The relative percentages of frankly positive resection margins in our low-risk and intermediate-risk patients were small (2 of 20 and 6 of 86, respectively). Of the intermediate-risk patients, 5 of 6 with positive margins received adjuvant RT. Of the low-risk patients, 1 of 2 with positive margins received adjuvant RT. Do high-risk patients have disease that obligates them to receive adjuvant RT? Or is there some margin distance (eg, 2 cm) that would obviate this need in high-risk patients. It may be possible that high-risk patients might not have margin-dependent disease. It remains to be seen as to which modality (greater margin distance vs. adjuvant therapy) could be of benet to these patients. Future prospective studies are necessary. One of the immediate practical applications of our data is that we can logically recommend adjuvant RT to a new group: patients with T1/T2 N0/N1 SCC who have negative margins but are classied as high-risk. Perineural spread is a traditional nding that usually merits adjuvant RT. But in our risk classication, one may be classied as high risk without having perineural tumor spread. For instance, limited lymphocytic response, plus any WPOI, would yield a score of 3 or more, which is automatically classied as high risk. On the other hand, there are implications of our data that may, at face value, be more difcult to accept. For instance, our data support the idea that patients with low or intermediate risk do not benet from adjuvant RT. Therefore, low- or intermediate-risk patients with inadequate margins might be better treated by re-resection rather than adjuvant RT. This type of issue is better addressed by future prospective studies. In summary, we advocate a very simple scoring system that can group patients into three categories (low-risk, intermediate-risk, and high-risk) and are predictive of LR and also OS. We demonstrate that high-risk patients can benet from adjuvant RT to the primary site, with respect to local disease-free survival, but no benet is observed for low- and intermediate-risk patients. The optimum tumor clearance distance is not established, but we can conclude that if the patient has a high-risk score, adjuvant RT is indicated despite resection margins of 5-mm clearance. ACKNOWLEDGMENT The authors thank Dr. Dave Marshall, MD, Department of Radiation Oncology, MSSM, for helpful discussions. REFERENCES
1. Anneroth G, Batsakis J, Luna M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinoma. Scan J Dent Res. 1987;95:229249. 2. Bundegaard T, Rossen K, Henriksen SD, et al. Histologic parameters in the evaluation of T1 squamous cell carcinomas of the oral cavity. Head Neck. 2002;24:656660.
Future Directions
From a statistical viewpoint, the burden of validation lies in the application of our risk assessment on a new data set. From a clinicopathologic viewpoint, this is not presently
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3. Bryne M, Koppang HS, Lilleng R, et al. New malignancy grading is a better prognostic indicator than Broders grading in oral squamous cell carcinomas. J Oral Pathol Med. 1989;18:432437. 4. Bryne M, Koppang HS, Lilleng R, et al. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J Pathol. 1992;166:375381. 5. Bryne M, Jenssen N, Boysen M. Histologic grading in the deep invasive front of T1 and T2 glottic squamous cell carcinomas has high prognostic value. Virchows Arch. 1995;427:277281. 6. Byers RM, Bland KI, Borlase B, et al. The prognostic and therapeutic value of frozen section determination in the surgical treatment of squamous cell carcinoma of the head and neck. Am J Surg. 1978;136:525528. 7. Chen TY, Edmrich LJ, Driscoll DL. The clinical signicance of pathological ndings in surgically resected margins of the primary tumor in head and neck carcinoma. Int J Radiat Oncol Biol Phys. 1987;13:833837. 8. Fagan JJ, Collins B, Barnes L, et al. Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 1998;124:637640. 9. Hiratsuka H, Miyakawa A, Nakamori K, et al. Multivariate analysis of occult lymph node metastasis as a prognostic indicator for patients with squamous cell carcinoma of the oral cavity. Cancer. 1997;80:351356. 10. Hosal AS, Unal OF, Ayhan A. Possible prognostic value of histopathologic parameters in patients with carcinoma of the oral tongue. Eur Arch Otolaryngol. 1998;225:216219. 11. Jacobs JR, Ahmad K, Casiano R, et al. Implications of positive surgical margins. Laryngoscope. 1993;103:6468. 12. Jones AS. Prognosis in mouth cancer: tumor factors. Oral Oncol Eur J Cancer. 1994;30B:815. 13. Kim HC, Kusukawa J, Kameyama T. Clinicopathologic parameters in predicting cervical nodal metastasis in early squamous cell carcinoma of the oral cavity. Kurume Med J. 1993;40:183192. 14. Kurokawa H, Yamashita Y, Murata T, et al. Histologic grading of malignancy correlates with regional lymph node metastasis and survival of patients with oral squamous cell carcinoma. Fukuoka Acta Med. 1998;89:225231.
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