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Extent of Extracapsular Spread A Critical Prognosticator in Oral Tongue Cancer
Jayson S. Greenberg, M.D.1 Robert Fowler, M.D.2 Jose Gomez, M.D.3 Vivian Mo2 Dianna Roberts, Ph.D.2 Adel K. El Naggar, M.D., Ph.D.3 Jeffrey N. Myers, M.D., Ph.D.2
BACKGROUND. Extracapsular spread (ECS) of metastatic squamous cell carcinoma of the head and neck to regional lymph nodes is the most reliable predictor of poor treatment outcomes. Recently, the authors have shown that ECS is significantly associated with higher rates of locoregional recurrence, distant metastasis, and decreased survival in patients with squamous cell carcinoma of the oral tongue (SCCOT). The purpose of this review was to determine if the degree of ECS impacts distant metastasis rates and survival. METHODS. Two hundred sixty-six patients treated for SCCOT with surgery ⫹/⫺
1
The Bobby R. Alford Department of Otorhinolaryngology and Communicative Sciences, Baylor College of Medicine, Houston, Texas.
2
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
3
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
adjuvant radiotherapy from 1980 –1995 were reviewed. The setting was a tertiary referral center. The extent of ECS on histopathologic review of involved lymph nodes was measured from the capsular margin to the farthest perinodal extension in mm. Extent of ECS and the number of pathologic lymph nodes with or without ECS were analyzed for disease-free interval, survival rates, and distant metastases. RESULTS. No differences in the survival of patients with ECS of ⱕ 2 mm or ⬎ 2 mm was found (P ⫽ 0.92). Patients with both ECS and multiple positive lymph nodes had decreased overall survival (P ⫽ 0.0003), disease-specific survival (P ⫽ 0.0005), and a shorter disease-free interval (P ⫽ 0.019) when compared with those with a single positive lymph node with ECS. Those with multiple ECS⫹ lymph nodes had the worst prognosis (P ⫽ 0.001). CONCLUSIONS. Based on these findings, the authors recommended that all patients with SCCOT with ECS or multiple positive lymph nodes with or without ECS on pathologic review be considered for clinical trials that intensify regional and systemic adjuvant therapy. Cancer 2003;97:1464 –70. © 2003 American Cancer Society. DOI 10.1002/cncr.11202
KEYWORDS: extracapsular spread, tongue cancer.
S
Address for reprints: Jeffrey N. Myers, M.D., Ph.D., Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 441, Houston, TX 77030-4009; Fax: (713) 794-4662; E-mail:
[email protected] Received August 6, 2002; revision received October 9, 2002; accepted October 23, 2002. © 2003 American Cancer Society
quamous cell carcinoma of the oral tongue (SCCOT) poses a clinical challenge because of its metastatic potential. Several studies have shown a high rate of occult nodal metastases (20 – 40%) in SCCOT patients with no evidence of regional spread on clinical or radiographic evaluation.1–7 Furthermore, pathologic evidence of regional nodal metastases (pN⫹) has been associated with a marked decrease in overall and disease-specific survival.8 The finding of extracapsular spread (ECS) further decreases survival rates and is associated with increased rates of regional recurrence and distant metastases.9 –16 In a recent study of 266 patients treated surgically with or without adjuvant radiotherapy at our institution between the years 1980 – 1995, the 5-year disease-specific and overall survival rates were 88% and 75% for pN0 patients, 65% and 50% for pN⫹/ECS⫺ patients, and 48% and 30% for pN⫹/ ECS⫹ patients. Thirteen percent of pN0
Extracapsular Spread in Oral Tongue Cancer/Greenberg et al.
patients received postoperative radiotherapy in contrast to 70% of pN⫹ patients. The patterns of failure for the pN0, pN⫹/ECS⫺, and pN⫹/ECS⫹ groups showed overall recurrence rates of 19.8%, 34.2%, and 51.1%; regional failure rates of 11.5%, 19.2%, and 28.9%; and distant metastases rates of 3.3%, 8.2%, and 24.4%.16 Since a high percentage of patients in the ECS⫹ groups who received adjuvant radiotherapy (88%) still had a ⬎ 33% regional recurrence rate, an intensified adjuvant therapy including systemic chemotherapy and/or biologic therapy along with radiation is proposed. To distinguish patients who would most likely benefit from this intensified therapy, we further subdivided patients with ECS into higher- and lower-risk groups of treatment failure based on the degree of ECS. In this study, we analyzed the outcomes of overall and disease-specific survival and distant metastasis in ECS⫹ patients based on the extension at or beyond 2.0 mm into the perilymphoid soft tissue, the number of pathologic lymph nodes in ECS⫹ patients, and the number of ECS⫹ nodes per patient.
MATERIALS AND METHODS A retrospective review of medical records of all patients treated at The University of Texas M. D. Anderson Cancer Center for SCCOT with resection of the primary and neck dissection from January 1980 through December 1995 was performed; all patients with synchronous or metachronous lesions were excluded. We identified 266 patients who had undergone surgery that included a neck dissection. In general, patients with N0 or limited N1 disease underwent a supraomohyoid neck dissection. Those patients with more advanced nodal disease underwent a more comprehensive modified radical neck dissection. One hundred five of these patients (39.5%) received postoperative radiotherapy as part of their treatment. Of these patients, 45 were found to have ECS. The slides of 33 of these 45 patients were available for pathologic re-review and were examined independently by two pathologists (A.E.N. and J.G.), who scored the specimens for extent of ECS outside the lymph node. The major variables evaluated were the extent of ECS, either ⱕ 2 mm or ⬎ 2 mm, and number of lymph nodes involved with tumor with or without ECS. The endpoints evaluated included disease-free interval, survival rates, and distant metastases; none of the patients had distant metastasis on presentation. The Kaplan–Meier method was used to create disease-specific survival curves and disease-free interval curves. Differences between the actuarial curves were tested by the log rank test. Follow-up time was calculated from the patient’s initial visit at M. D. Anderson
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Cancer Center for the primary tumor until the date of last contact or death. Differences in the proportions of patients who survived 3 and 5 years and who developed recurrences were tested by the Pearson chisquare test. If there were 10 or fewer patients in a group, the two-tailed Fisher exact test was used. Survival analysis and chi-square tests were performed using the Statistica software application (StatSoft, Inc., Tulsa, OK). Crude odds ratios for death risk were assessed by Cox regression analysis, calculated with the assistance of SPSS for Windows (version 10.0, SPSS, Inc., Chicago, IL) software.
RESULTS Microscopic Distance of Extension beyond the Lymph Node Capsule All lymph node dissection hematoxylin and eosinstained slides were evaluated for the presence and the extent of ECS by head and neck pathologists. Patients were categorized as having ⱕ 2 mm or ⬎ 2 mm of ECS, and were compared with disease-specific survival (Fig. 1A), overall survival (Fig. 1B), and incidence of distant metastasis (Fig. 1C). No significant statistical differences in overall survival (P ⫽ 0.92), disease-specific survival (P ⫽ 0.31), and rate of distant metastases (P ⫽ 0.48) were identified.
Multiple Lymph Nodes with ECS The overall and disease-specific survival of patients with more than one ECS⫹ node had a significantly poorer prognosis with the majority of patients dying within 1 year after treatment compared with those patients with only one lymph node metastasis (Fig. 2). Disease-specific (P ⫽ 0.001) (Fig. 2A) and overall survival (P ⫽ 0.001) (Fig. 2B) also were much worse in the multiple ECS⫹ node group. The disease-free interval of patients with multiple ECS⫹ nodes was found to be extremely brief, with a median time to recurrence of 6 months (Fig. 2C).
Impact of Multiple Nodes As shown in Figure 3, patients with two or more pathologically positive lymph nodes had worse outcomes than those with a single node irrespective of ECS status for both disease-specific (P ⬍ 0.0001) (Fig. 3A) and overall survival (P ⬍ 0.00001) (Fig. 3B). The disease-free interval also was markedly reduced in those patients with multiple positive lymph nodes (P ⫽ 0.001). Furthermore, patients with multiple positive nodes had more ECS (33/62, 53%) than patients with only one positive node (12/58, 21%).
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FIGURE 1. Impact of tumor spread beyond the lymph node capsule (ⱕ 2 mm or ⬎ 2 mm of extracapsular spread [ECS]) on (A) disease-specific survival, (B) overall survival, and (C) incidence of distant metastasis in patients with squamous cell carcinoma of the oral tongue. Impact of Multiple Nodes with or without ECS Figure 4 shows a composite summary of the relative impact of involvement of multiple nodes and ECS on disease-specific survival (Fig. 4A), overall survival (Fig. 4B), and disease-free interval (Fig. 4C). Treatment outcomes of all groups were clearly stratified into three outcome types. Patients with pathologic nodal classi-
FIGURE 2. Impact of number of ECS⫹ lymph nodes on (A) disease-specific survival, (B) overall survival, and (C) disease-free interval in patients with squamous cell carcinoma of the oral tongue.
fications pN1ECS⫺ and pN1ECS⫹ had similar disease-specific survivals as pN0 patients (P ⫽ 0.12 and P ⫽ 0.26, respectively). Patients with pathologic classifications pN2ECS⫺ and pN2ECS⫹ in one node also fared similarly to one another (P ⫽ 0.62) but much worse than those who were pN0 or pN1 (P ⫽ 0.0002 and P ⫽ 0.01, respectively). Patients with multiple
Extracapsular Spread in Oral Tongue Cancer/Greenberg et al.
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FIGURE 3. Impact of number of pathologically positive lymph nodes regardless of extracapsular spread status on (A) disease-specific survival, (B) overall survival, and (C) disease-free interval in patients with squamous cell carcinoma of the oral tongue.
ECS⫹ nodes clearly had the worst prognosis with higher odds ratio of death from disease (Fig. 5A), overall death (Fig. 5B), and increased recurrence (Fig. 5C).
Impact of Type of Treatment on Treatment Outcomes Table 1 categorizes pathologic nodal stage versus treatment including the incidence of adjuvant radia-
FIGURE 4. Impact of involvement of multiple pathologically positive nodes and extracapsular spread on (A) disease-specific survival, (B) overall survival, and (C) disease-free interval in patients with squamous cell carcinoma of the oral tongue.
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CANCER March 15, 2003 / Volume 97 / Number 6 TABLE 1 Pathologic Nodal Stage Versus Treatment Type in Patients with Squamous Cell Carcinoma of the Oral Tongue pN stage
Ratio (no. of XRT/no. in group)
Percent
NO N1ECS⫺ N1ECS⫹ N2ECS⫺ N2ECS⫹ MultiECS⫹
19/144 21/46 10/12 25/29 14/16 11/12
13.2 45.7 83.3 86.2 87.5 91.7
pN: Pathologic nodal stage; XRT: patients who received adjuvant radiation therapy; ECS: extracapsular spread.
tion therapy. Although relatively few pN0 patients (13.2%) received adjuvant radiotherapy, almost all of those with N2ECS⫺ (86.2%), N2ECS⫹ (87.5%), and multiple ECS⫹ nodes (91.7%) were treated with postoperative radiotherapy. Within the N1 group, 45.7% of ECS⫺ and 83.3% ECS⫹ patients received adjuvant radiotherapy (P ⫽ 0.02).
Patterns of Failure within Different Groups Table 2 compares nodal classification and ECS groups (p0,pN1⫹/⫺ ECS, pN2⫹/⫺ ECS, multiple ECS) with patterns of failure. Local failure rates ranged from 8.3–22.2% and were independent of nodal grouping, whereas regional nodal failure increased with advanced nodal classification. Within nodal classification groups, the presence of a single ECS⫹ lymph node was not associated with increased regional failure, as seen in the N1 groups. The presence of multiple ECS⫹ nodes, however, was associated with an extremely high rate of regional failure (58.3%). Distant metastases (DM) were rarely seen in those patients with low pathologic nodal stage in contrast with a 33.3% DM rate for those with multiple ECS⫹ nodes.
DISCUSSION
FIGURE 5. Impact of involvement of multiple pathologically positive nodes and extracapsular spread on odds ratio of (A) disease-specific death, (B) overall death, and (C) recurrence in patients with squamous cell carcinoma of the oral tongue.
We recently reported that tongue cancer patients with ECS had decreased overall and disease-specific survival with higher rates of regional recurrence and distant metastases than patients with no positive nodes or positive nodes without ECS.16 In the current study, we have further investigated the prognostic significance of the perinodal extent of ECS and number of positive lymph nodes on the outcomes of patients treated at a single institution for oral tongue cancer with surgery including neck dissection and, in many cases, adjuvant radiotherapy. The extent of tumor outside the lymph node capsule was not found to be significantly associated with
Extracapsular Spread in Oral Tongue Cancer/Greenberg et al.
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TABLE 2 Pathologic Nodal Stage Versus Patterns of Failure in Patients with Squamous Cell Carcinoma of the Oral Tongue Local
pN stage
Ratio (no. with recurrence/ no. in group)
N0 N1ECS⫺ N1ECS⫹ N2ECS⫺ N2ECS⫹ Multi ECS Total
19/142 7/46 1/12 6/27 3/16 2/12 38/255
Regional
Percent
Ratio (no. with recurrence/ no. in group)
13.4 15.2 8.3 22.2 18.8 16.7 14.9
18/142 8/46 2/12 6/27 4/16 7/12 45/255
DM
Percent
Ratio (no. with recurrence/ no. in group)
12.7 17.4 16.7 22.2 25.0 58.3 17.6
4/142 2/46 0/12 4/27 4/16 4/12 18/255
Any recurrence
Percent
Ratio (no. with recurrence/ no. group)
Percent
28 4.3 0.0 14.8 25.0 33.3 7.1
29/142 13/46 3/12 12/27 7/16 10/12 74/255
20.4 28.3 25.0 44.4 43.8 83.3 29.0
pN: Pathologic nodal stage; DM: distant metastases; ECS: extracapsular spread.
survival outcomes or the rate of distant metastases in the current study. Previously, other investigators have found that greater spread outside the lymph node capsule is associated with worse outcomes in patients treated for laryngeal cancer.13 One explanation for this discrepancy is that different sites in the head and neck have different metastatic patterns. A more likely explanation is the small number of patients in our series in whom extent of tumor outside the capsule could be quantitated due to the retrospective nature of our study. Further studies, particularly prospective analyses, are needed to fully determine the issue of whether extent of tumor outside the lymph node capsule is a significant predictor of survival and distant metastasis. A striking finding of this study is the significantly poorer outcomes of patients with multiple ECS⫹ nodes. Although the concept of ECS as a poor prognosticator is not a new one,9 –16 this study is the first to examine the incidence of ECS in depth and stratify actual numbers of ECS⫹ nodes, nodal classification, and treatment outcomes at a specific head and neck subsite. The finding of multiple ECS⫹ nodes was associated with median survival of ⬍ 1 year and a high rate of distant metastasis. Similarly, multiple lymph nodes with one or more nodes having ECS also was significantly associated with early recurrence and poor survival. However, the presence of a second ECS⫹ node carried the worst prognosis. These findings cannot be explained by treatment differences because the majority received identical therapy including surgical resection of the primary, neck dissection, and postoperative radiation therapy. Previous studies have reviewed the role of adjuvant chemotherapy or concurrent chemoradiation for patients with extracapsular spread. Johnson et al.17 studied adjuvant chemotherapy in patients with extra-
capsular spread and found 58% had 30-month survival versus 40% for those treated with only surgery and postoperative radiation therapy. Although this was a prospective, single arm, nonrandomized study, these results were statistically significant. Bachaud et al.18 studied the effects of concurrent chemoradiation therapy for patients with advanced squamous cell carcinoma from all head and neck sites and histologic evidence of ECS. They also showed improved locoregional control and survival compared with postoperative radiotherapy alone. The poor survival and early recurrence rates of patients with ECS and multiple nodes with or without ECS support the long-held contention that all patients with one or more of these findings is at high risk for treatment failure and suggest that intensification of therapy is warranted. These findings also demonstrate that further studies into the mechanisms of regional metastases in patients with tongue cancer are needed to provide more rational approaches to the treatment of these high-risk patients because the majority of patients who received surgery and radiotherapy develop recurrence after treatment.
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