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Squamous cell carcinoma of the tongue in young adults: Increasing incidence and factors that predict treatment outcomes
Squamous cell carcinoma of the tongue in young adults: Increasing incidence and factors that predict treatment outcomes JEFFREY N. MYERS, MD, PhD, TINA ELKINS, BS, DIANNA ROBERTS, PhD, and ROBERT M. BYERS, MD, Houston, Texas
OBJECTIVE: This study was designed to determine whether the incidence of squamous cell carcinoma of the oral tongue (SCCOT) in young adults has changed during the past 25 years and to determine prognostic factors for young adult patients (aged < 40 years) with SCCOT. METHODS AND PATIENTS: A retrospective review of young adults with SCCOT who sought treatment at the M. D. Anderson Cancer Center between 1973 and 1995 was undertaken. RESULTS: The percentage of young adult SCCOT patients at M. D. Anderson increased from 4% in 1971 to 18% in 1993. T stage, N stage, perineural invasion, and lymphatic invasion were all associated with decreased survival. Patients who received a neck dissection as part of their primary treatment had a better chance of survival than patients who did not. CONCLUSIONS: The incidence of SCCOT in the young adult population is increasing in the United States. Appropriate surgical management for young adults with SCCOT includes resection of the primary tumor along with a selective node dissection. (Otolaryngol Head Neck Surg 2000;122:44-51.)
T
he recent head and neck literature has given increasing attention to squamous cell cancer of the oral tongue (SCCOT) in young adults, which was not categorized as a distinct clinical entity until 1975.1-6 Authors have speculated that the incidence of SCCOT in young adults is increasing. Atula et al4 in Finland found that the percentage of SCCOT cases occurring in young adults in that nation increased from From the Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center. Presented at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, San Antonio, TX, September 13-16, 1998. Reprint requests: Jeffrey N. Myers, MD, PhD, Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 69, Houston, TX 77030. Copyright © 2000 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2000/$12.00 + 0 23/1/99076 44
3% per year for the decade 1953 to 1962 to 7% per year for the decade 1983 to 1992. Similarly, in our head and neck surgical practice at the University of Texas M. D. Anderson Cancer Center (UTMDACC), we have the general sense that we are seeing increasing numbers of young adults with SCCOT. However, the incidence of SCCOT in young adults at our institution and in the United States has not previously been evaluated. Authors have also suggested that younger patients with SCCOT have a worse prognosis than older patients.6 However, data regarding prognosis are conflicting. Byers6 reported a series of 11 patients aged 30 years or younger with SCCOT who were treated at UTMDACC between 1956 and 1973. Although 9 of these patients had smaller primary lesions (T1 or T2), a high percentage of patients (54%) had regionally metastatic disease at presentation. Overall, 6 of these 11 patients had locoregional control of their disease, and the 2-year survival rate was 45%, compared with a 65% 2-year survival rate in the 407 older patients with SCCOT treated at UTMDACC over the same period. McGregor et al7 reported on 27 patients 40 years or younger with SCCOT who received a variety of primary treatment modalities. The disease-free survival rate at 2 years was 78% (21 of 27 patients), which was actually better than that seen in patients older than 40 years. MartinGranizo et al3 from Spain reviewed their experience with 7 cases of SCCOT in patients younger than 40 years. These authors treated all of their patients with resection of the primary tumor and an elective or therapeutic neck dissection. This group of patients had a 70.8% survival rate at 18 months. Several authors have found similar survival rates for young adults and older patients with SCCOT.1-4 In the series by Atula et al,4 all but 1 of the 31 patients were treated initially with surgery, and 53% underwent neck dissection. These authors documented a 5-year survival rate of 70.6% and believed that there were no differences in clinical course or prognosis between young and older patients. A similar conclusion was drawn by Siegelmann-Danieli et al2 at the Fox Chase Cancer Center, who reviewed the records of 30 patients with SCCOT who were 45 years or younger and compared the results with the findings in 57 patients with SCCOT who were 46 years or older. Likewise, Freidlander et al1
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C
B
D
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Fig 1. Incidence of SCCOT at UTMDACC has increased steadily during the past 25 years (A). In addition, the percentage of patients with SCCOT at UTMDACC who are younger than 40 years at presentation has increased during the past 25 years (B). These increases reflect a national trend, as shown by review of the SEER database for patients of all ages with SCCOT (C) and for patients younger than 40 years with SCCOT (D).
found that younger patients with SCCOT had survival rates similar to those of older patients in their retrospective matched-pair analysis of patients treated at the Memorial Sloan-Kettering Cancer Center. Others have hypothesized that patients without typical risk factors for developing SCCOT do poorly compared with patients with the usual risk factors (ie, an extensive history of tobacco and alcohol use). An analysis of 25 patients younger than 35 years with SCCOT treated in India showed that the rate of tobacco use or betel quid chewing was low in these patients relative to the rate seen in older patients.8 These younger patients also had a much higher failure rate at 11 months compared with patients with SCCOT who were older than 60 years— 51.3% versus 37.8%. Similar results were published by Sarkaria and Harari5 in their review of 152 cases of SCCOT in young adult patients. These authors found that
although 64% of young adult patients had stage I and II disease at presentation, 57% had failures above the clavicle, and 47% ultimately died of their disease. It has been difficult to address questions concerning SCCOT in young adults: the incidence of SCCOT in this population is so low that it is hard to find a single institution with enough young adults with SCCOT to permit meaningful conclusions, even in a retrospective analysis. We decided to evaluate the combined clinical experience of practitioners treating young adults with SCCOT at UTMDACC during the past several decades. This study was conducted to determine whether the incidence of SCCOT in young adults has changed during the past 25 years and to determine treatment outcomes and clinicopathologic factors predictive of survival in a group of young adults (aged < 40 years) with SCCOT treated at UTMDACC.
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Table 1. Characteristics of young adults with SCCOT seen at UTMDACC between 1973 and 1995 Characteristic
Total No. of patients Age (y) Mean Median Range Race White African-American Hispanic Asian Other Follow-up (mo) Mean Median Range Risk factors Exposure to tobacco Exposure to alcohol Cancer in a 1st-degree relative Presenting symptoms Dysphagia Odynophagia Neck mass Weight loss Trismus Periodontal disease Otalgia TNM stage at presentation* T1 or T2 T3 or T4 N0 >N0
No. of patients (%)
64 31.3 32.5 19-39 56 (87.5) 0 (0) 6 (9.4) 0 (0) 2 (3.1) 36.0 27.0 0.1-169 26 (40.6) 35 (54.6) 6 (9.4) 17 (26.5) 8 (12.5) 18 (28.1) 17 (26.6) 5 (7.8) 11 (17.2) 24 (37.5) 35 (54.7) 14 (21.9) 36 (56.3) 18 (28.1)
*Tumor
stage was known for only 49 patients, and nodal stage was known for only 54 patients.
METHODS AND PATIENTS The medical records of all patients younger than 40 years who came to UTMDACC between 1973 and 1995 for evaluation of SCCOT were reviewed for clinicopathologic data and clinical outcomes. To determine whether presenting symptoms were associated with patient survival, data regarding dysphagia, odynophagia, neck mass, trismus, weight loss, history of periodontal disease, and otalgia were recorded and analyzed by univariate analysis. To test the hypothesis that the incidence of SCCOT is increasing, we examined our departmental and institutional databases for all patients evaluated for the diagnosis of SCCOT at UTMDACC between 1948 and 1997. To determine the incidence of SCCOT in the US population at large, we also examined the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. The number of patients younger than 40 years with
SCCOT was compared with the total number of cases of SCCOT for each year between 1973 and 1992. Two- and 5-year disease-specific survival rates were compared between patients with and without specific clinical and pathologic features to determine whether there were significant survival differences between groups. This was accomplished with χ2 analysis and, when the number of observations in a given group fell below 6, Fisher’s exact test, by use of SigmaStat statistical software (SPSS Inc, Chicago, IL). Kaplan-Meier disease-specific survival curves were generated, and log-rank test analysis of the statistical significance of variations between groups was carried out with Statistica for Windows software (StatSoft Inc, Tulsa, OK). RESULTS Incidence of SCCOT
Between 1948 and 1995, the number of patients with SCCOT seen at UTMDACC steadily increased from fewer than 10 patients per year to as many as 52 patients per year (Fig 1A). To determine whether the percentage of SCCOT cases occurring in young adults also increased, we compared the ratio of patients aged 40 years or younger with SCCOT to the total number of patients with SCCOT seen at UTMDACC for each year from 1963 to 1996. As seen in Fig 1B, the percentage of cases of SCCOT occurring in young adults increased dramatically during this period from less than 10% of all cases to 15% to 25% of all cases in the mid-1990s. Curious to know whether these increases were reflective of a shift in referral patterns or a true increase in the incidence of SCCOT in the general population, we examined the National Cancer Institute’s SEER database in a similar fashion. We found a steady increase in the total number of cases of SCCOT, from roughly 300 in 1973 to more than 500 in 1992 (Fig 1C). Also evident from this analysis was an increase in the percentage of cases of SCCOT that occurred in young adults, from 3% in 1973 to nearly 6% in 1993 (Fig 1D). Demographic Data
A total of 64 patients younger than 40 came to UTMDACC between 1973 and 1995 for evaluation of SCCOT. The clinicopathologic data and treatment outcomes for these patients are given in Table 1. Of the 64 patients whose charts were evaluated, 27 (42%) were initially treated elsewhere; 37 patients (58%) received their primary treatment at UTMDACC. Thirty-seven (58%) of the patients were men, and 27 (42%) were women. The patients ranged in age from 19 to 39 years. The mean age was 31.3 years, and the median age was 32.5 years. Follow-up for this group of patients ranged
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Fig 2. Disease-specific survival of all young adults treated for SCCOT at UTMDACC between 1973 and 1995.
Table 2. Effects of presenting symptoms on cumulative survival
Table 3. Effects of clinical stage on cumulative survival
Symptom
P value
Parameter
P value
Dysphagia Odynophagia Neck mass Trismus Weight loss Periodontal disease Otalgia
0.00060 0.00072 0.00232 0.01021 0.04649 0.58220 0.24238
T 1,2 vs 3,4 N>0 Distant metastases
0.09479 0.0035 0.00001
from less than 1 month to 169 months, with a mean follow-up time of 36 months. Fifty-nine percent of the patients were nonsmokers, and 45% used no alcohol. Presenting Symptoms and Clinical Outcomes
Patients treated at UTMDACC who had dysphagia, odynophagia, neck mass, trismus, or weight loss at presentation had significantly decreased survival compared with patients without these presenting symptoms (Table 2). Figure 2 shows the disease-specific survival of 37 patients initially treated for SCCOT at UTMDACC. The 5-year disease-specific survival rate was 77.7%. All patients without dysphagia at presentation for whom follow-up data were available were alive at 5 years, compared with a 5-year survival rate of less than 50% for patients with dysphagia at presentation (data not shown). Similar differences in outcomes were seen for patients with odynophagia or weight loss at presentation versus patients without these symptoms at presentation.
Other information obtained from the patients’ histories, such as age, tobacco and alcohol use, and family history of cancer, did not appear to be predictive of survival (data not shown). Clinical (TNM) Stage and Clinical Outcomes
Clinical stage at presentation and at the time of recurrence was clearly correlated with outcomes. In young adults with SCCOT initially treated at UTMDACC (n = 37), T2 and T3 tumors were the most common, occurring in 15 patients (40.5%) and 10 patients (27%), respectively. The 2-year survival rate was 93% for patients with early lesions (T1 and T2) versus 43% for patients with more advanced lesions (T3 and T4). Twenty-one of the young adults with SCCOT treated at UTMDACC (57%) had clinically negative necks, and 13 (35%) had palpable lymph nodes. In the remaining cases, the clinical nodal status was not specified. Of the patients with palpable nodes, 7 had N1 disease, 3 had N2a disease, 2 had N2b disease, and 1 had N3 disease. For patients with clinically negative necks, the 2- and 5year survival rates were 100% and 85%, respectively. In contrast, in patients with palpable lymph nodes, 2- and 5-year survival rates were only 40% and 14.3%, respectively (Fig 3).
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Fig 3. Disease-specific survival of young adults treated for SCCOT at UTMDACC according to the clinical nodal status (N stage) of their necks.
Fig 4. Effect of surgical margins on disease-specific survival of young adults treated for SCCOT at UTMDACC.
Distant metastases were seen in only 4 patients, and all of these patients died within 4 years. The effect of clinical stage on survival is summarized in Table 3. Pathologic Parameters and Clinical Outcomes
Review of pathologic features and analysis of their relationship to clinical outcomes yielded a number of significant findings. Seventeen (46%) of the 37 patients initially treated at UTMDACC had moderately differentiated squamous cell carcinoma, 12 patients (32%) had well-differentiated squamous cell carcinoma, and 2 patients (5%) had poorly differentiated tumors. Although the outcomes tended to be better in patients with well-differentiated tumors, this finding was not statistically significant because of the small number of patients with poorly differentiated tumors. Although
there is a great deal of literature to support the concept that depth of tumor invasion and tumor thickness correlate with regional metastases and decreased survival, these parameters were not documented well enough in our cohort to permit useful conclusions about the relationship between these features and survival. Clinical outcomes were also evaluated with respect to pathologic nodal stage. Twenty-four patients (65%) had no lymph nodes that were pathologically positive for metastatic tumor or had lymph node metastases in only 1 level of the neck. Level II of the neck was the most common site of nodal spread; level II metastases were seen in 7 patients. Only 4 patients had nodal metastases in more than 1 level of the neck, and there were no “skip” metastases (cases in which nodal spread bypassed upper neck nodes to present in lower neck
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A
B
Fig 5. Effects of regional (A) and local (B) recurrence on the disease-specific survival rate of young adults treated for SCCOT at UTMDACC.
nodes only). Only 4 patients (11%) had extracapsular extension of tumor, and these patients appeared to have shorter survival times, but differences in survival were not statistically significant. As seen for clinical staging of the neck, patients with positive nodes on pathologic review of the neck dissection specimen had decreased survival compared with patients without positive lymph nodes. Perineural invasion was seen in 10 (27%) of the specimens and was correlated with decreased survival: 2- and 5-year survival rates were 50% and 0%, respectively, in patients with perineural invasion, compared with 95% and 87.5%, respectively, in patients without this finding. Vascular and lymphatic invasion were also predictive of decreased survival. Of the 3 patients (8%) with lymphatic invasion, only 1 was alive at 2 years, whereas the 2-year survival rate in patients without this finding was 100%. Of the 3 patients whose specimens had vascular invasion, none was alive at 2 years. Close surgical margins (ie, margins < 5 mm) were also predictive of decreased survival (Fig 4). No
patients had positive margins on final pathologic review, although 2 patients initially had positive frozensection margins. It has been hypothesized that positive margins on frozen-section analysis, despite negative final margins, are associated with worse clinical outcomes because of possible retraction of the lingual muscle fibers with viable tumor cells to sites at a distance from the mucosal margin of resection. However, we did not have enough patients with positive frozen-section margins to evaluate this hypothesis in a statistically meaningful fashion. The data correlating pathologic criteria with diseasespecific survival of young adults with SCCOT are summarized in Table 4. In brief, close surgical margins, perineural invasion, lymphatic invasion, and positive lymph nodes all portended poorer outcomes. Treatment Received and Clinical Outcomes
Regardless of where patients were treated, those who had a neck dissection had a much better outcome.
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Table 4. Effects of pathologic criteria on cumulative survival Parameter
Margins ≤ vs > 5 mm Perineural invasion Lymphatic invasion Positive lymph nodes
P value
0.04706 0.02203 <0.00001 0.04817
Three- and 5-year survival rates were 81% and 72%, respectively, in patients who had neck dissections and 44% (P = 0.025) and 22% (P = 0.018), respectively, in patients whose necks were not dissected. Patients who had a local or regional recurrence had shorter survival times. As shown in Fig 5, patients with regional recurrence fared poorly, and those with local recurrence did even worse. Adjuvant radiotherapy was most often used in cases in which the primary tumor had close margins, when there was evidence of perineural invasion, when the multiple lymph nodes contained metastatic tumor, or when there was extracapsular extension of tumor outside the lymph node. Those patients who were treated with surgery and radiation had decreased survival rates relative to those treated with surgery alone at 3 (P = 0.09) and 5 (P = 0.015) years. Second Primary Tumors
Only 1 of the patients in this study was found to have a second primary tumor of the aerodigestive tract during the follow-up period. Bronchogenic squamous cell carcinoma developed in a 39-year-old patient a year after treatment for his tongue lesion, and he died of this second cancer within the next several months. DISCUSSION
We found that the incidence of SCCOT in young adults has increased not only at our institution but also in the US population at large. In addition, we found that the 77.7% 5-year overall survival rate of young adult patients treated at our hospital was comparable with the survival rates seen in several large retrospective analyses of tongue cancer patients of all ages.9,10 Finally, we also identified several clinical, pathologic, and treatment-related factors that significantly correlate with disease-specific survival. Although this study is clearly limited by its design as a retrospective review and by the small number of patients and variety of treatment methods, our findings are consistent with previous data from larger series of patients of all ages and from a prior surgical trial carried out at our center.
The presenting symptoms of dysphagia, odynophagia, trismus, weight loss, and neck mass all correlated significantly with decreased survival. These findings were not surprising because these factors are all generally associated with more advanced disease. Other information obtained from the patients’ histories, such as age, tobacco and alcohol use, and family history of cancer, did not appear to be predictive of survival. We had previously hypothesized that younger patients without histories of typical risk factors for SCCOT might not fare as well as older patients who smoke or drink. When patients were stratified on the basis of age less than or greater than 30 years, younger patients appeared to do better; however, the difference was not statistically significant. Similar results were seen with stratification by tobacco and alcohol use. That increased tumor size and nodal stage and the presence of distant metastases were all correlated with decreased survival came as no surprise and confirmed the results of previous series.11,12 The same can be said for the findings that pathologic criteria such as close margins, perineural invasion, lymphatic invasion, and vascular invasion were correlated with decreased survival.9 Finally, the improved survival rate that was seen in patients whose primary treatment included neck dissection supports our institutional policy that all patients with SCCOT who are treated surgically should undergo neck dissection for prognostic and therapeutic purposes. This policy was based on data from a previous study by Lydiatt et al.9 In that study, locoregional control and survival rates at 5 years were 50% and 33%, respectively, in patients with T1 or T2 N0 SCCOT treated with resection of the primary tumor alone, versus 91% and 55%, respectively, in patients treated with resection of the primary tumor and elective lymph node dissection. The data regarding neck dissection and the data on surgical margins indicate that the adequacy of resection of the primary tumor and the performance of an appropriate regional lymphadenectomy have a significant impact on the clinical outcome of young patients with SCCOT. Therefore we recommend aggressive primary treatment of young and older adult patients with SCCOT, including resection of the primary tumor with margins of 5 mm or greater and an appropriate neck dissection. REFERENCES 1. Friedlander PL, Schantz SP, Shaha AR, et al. Squamous cell carcinoma of the head and neck in young patients: a matched pair analysis. Head Neck 1997;20:363-8. 2. Siegelman-Danieli N, Hanlon A, Ridge J, et al. Oral tongue cancer in patients less than 45 years old: institutional experience and comparison with older patients. J Clin Oncol 1998;16:745-53.
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3. Martin-Granizo R, Rodriguez-Campo F, Naval L, et al. Squamous cell carcinoma of the oral cavity in patients younger than 40 years. Head Neck Surg 1997;117:268-75. 4. Atula S, Grenman R, Laippala P, et al. Cancer of the tongue in patients younger than 40 years. Arch Otolaryngol Head Neck Surg 1996;122:1313-9. 5. Sarkaria J, Harari PM. Oral tongue cancer in young adults less than 40 years of age: rationale for aggressive therapy. Head Neck 1994;16:107-11. 6. Byers R. Squamous cell carcinoma of the oral tongue in patients less than thirty years of age. Am J Surg 1975;130:475-8. 7. McGregor G, Davis N, Robins RE. Squamous cell carcinoma of the tongue and lower oral cavity in patients under 40 years of age. Am J Surg 1982;145:88-92.
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8. Kuriakose M, Sankaranarayanan M, Nair MK, et al. Comparison of oral squamous cell carcinoma in younger and older patients in India. Oral Oncol Eur J Cancer 1992;28B:113-20. 9. Lydiatt DD, Robbins KT, Byers RB, et al. Treatment of stage I and II oral tongue cancer. Head Neck 1993;15:308-12. 10. Franceschi D, Gupta R, Spiro RH, et al. Improved survival in the treatment of squamous cell carcinoma of the oral tongue. Am J Surg 1993;166:360-5. 11. Nyman J, Mercke C, Lindstrom J. Prognostic factors for local control and survival of cancer of the oral tongue. Acta Oncol 1993;32:667-73. 12. Reichard KW, Joseph KT, Cohen M, et al. Squamous cell carcinoma of the tongue: experience with 86 consecutive cases. J Surg Oncol 1993;54:239-42.
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OBJECTIVE: This study was designed to determine whether the incidence of squamous cell carcinoma of the oral tongue (SCCOT) in young adults has changed during the past 25 years and to determine prognostic factors for young adult patients (aged < 40 years) with SCCOT. METHODS AND PATIENTS: A retrospective review of young adults with SCCOT who sought treatment at the M. D. Anderson Cancer Center between 1973 and 1995 was undertaken. RESULTS: The percentage of young adult SCCOT patients at M. D. Anderson increased from 4% in 1971 to 18% in 1993. T stage, N stage, perineural invasion, and lymphatic invasion were all associated with decreased survival. Patients who received a neck dissection as part of their primary treatment had a better chance of survival than patients who did not. CONCLUSIONS: The incidence of SCCOT in the young adult population is increasing in the United States. Appropriate surgical management for young adults with SCCOT includes resection of the primary tumor along with a selective node dissection. (Otolaryngol Head Neck Surg 2000;122:44-51.)
T
he recent head and neck literature has given increasing attention to squamous cell cancer of the oral tongue (SCCOT) in young adults, which was not categorized as a distinct clinical entity until 1975.1-6 Authors have speculated that the incidence of SCCOT in young adults is increasing. Atula et al4 in Finland found that the percentage of SCCOT cases occurring in young adults in that nation increased from From the Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center. Presented at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, San Antonio, TX, September 13-16, 1998. Reprint requests: Jeffrey N. Myers, MD, PhD, Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 69, Houston, TX 77030. Copyright © 2000 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2000/$12.00 + 0 23/1/99076 44
3% per year for the decade 1953 to 1962 to 7% per year for the decade 1983 to 1992. Similarly, in our head and neck surgical practice at the University of Texas M. D. Anderson Cancer Center (UTMDACC), we have the general sense that we are seeing increasing numbers of young adults with SCCOT. However, the incidence of SCCOT in young adults at our institution and in the United States has not previously been evaluated. Authors have also suggested that younger patients with SCCOT have a worse prognosis than older patients.6 However, data regarding prognosis are conflicting. Byers6 reported a series of 11 patients aged 30 years or younger with SCCOT who were treated at UTMDACC between 1956 and 1973. Although 9 of these patients had smaller primary lesions (T1 or T2), a high percentage of patients (54%) had regionally metastatic disease at presentation. Overall, 6 of these 11 patients had locoregional control of their disease, and the 2-year survival rate was 45%, compared with a 65% 2-year survival rate in the 407 older patients with SCCOT treated at UTMDACC over the same period. McGregor et al7 reported on 27 patients 40 years or younger with SCCOT who received a variety of primary treatment modalities. The disease-free survival rate at 2 years was 78% (21 of 27 patients), which was actually better than that seen in patients older than 40 years. MartinGranizo et al3 from Spain reviewed their experience with 7 cases of SCCOT in patients younger than 40 years. These authors treated all of their patients with resection of the primary tumor and an elective or therapeutic neck dissection. This group of patients had a 70.8% survival rate at 18 months. Several authors have found similar survival rates for young adults and older patients with SCCOT.1-4 In the series by Atula et al,4 all but 1 of the 31 patients were treated initially with surgery, and 53% underwent neck dissection. These authors documented a 5-year survival rate of 70.6% and believed that there were no differences in clinical course or prognosis between young and older patients. A similar conclusion was drawn by Siegelmann-Danieli et al2 at the Fox Chase Cancer Center, who reviewed the records of 30 patients with SCCOT who were 45 years or younger and compared the results with the findings in 57 patients with SCCOT who were 46 years or older. Likewise, Freidlander et al1
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C
B
D
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Fig 1. Incidence of SCCOT at UTMDACC has increased steadily during the past 25 years (A). In addition, the percentage of patients with SCCOT at UTMDACC who are younger than 40 years at presentation has increased during the past 25 years (B). These increases reflect a national trend, as shown by review of the SEER database for patients of all ages with SCCOT (C) and for patients younger than 40 years with SCCOT (D).
found that younger patients with SCCOT had survival rates similar to those of older patients in their retrospective matched-pair analysis of patients treated at the Memorial Sloan-Kettering Cancer Center. Others have hypothesized that patients without typical risk factors for developing SCCOT do poorly compared with patients with the usual risk factors (ie, an extensive history of tobacco and alcohol use). An analysis of 25 patients younger than 35 years with SCCOT treated in India showed that the rate of tobacco use or betel quid chewing was low in these patients relative to the rate seen in older patients.8 These younger patients also had a much higher failure rate at 11 months compared with patients with SCCOT who were older than 60 years— 51.3% versus 37.8%. Similar results were published by Sarkaria and Harari5 in their review of 152 cases of SCCOT in young adult patients. These authors found that
although 64% of young adult patients had stage I and II disease at presentation, 57% had failures above the clavicle, and 47% ultimately died of their disease. It has been difficult to address questions concerning SCCOT in young adults: the incidence of SCCOT in this population is so low that it is hard to find a single institution with enough young adults with SCCOT to permit meaningful conclusions, even in a retrospective analysis. We decided to evaluate the combined clinical experience of practitioners treating young adults with SCCOT at UTMDACC during the past several decades. This study was conducted to determine whether the incidence of SCCOT in young adults has changed during the past 25 years and to determine treatment outcomes and clinicopathologic factors predictive of survival in a group of young adults (aged < 40 years) with SCCOT treated at UTMDACC.
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Table 1. Characteristics of young adults with SCCOT seen at UTMDACC between 1973 and 1995 Characteristic
Total No. of patients Age (y) Mean Median Range Race White African-American Hispanic Asian Other Follow-up (mo) Mean Median Range Risk factors Exposure to tobacco Exposure to alcohol Cancer in a 1st-degree relative Presenting symptoms Dysphagia Odynophagia Neck mass Weight loss Trismus Periodontal disease Otalgia TNM stage at presentation* T1 or T2 T3 or T4 N0 >N0
No. of patients (%)
64 31.3 32.5 19-39 56 (87.5) 0 (0) 6 (9.4) 0 (0) 2 (3.1) 36.0 27.0 0.1-169 26 (40.6) 35 (54.6) 6 (9.4) 17 (26.5) 8 (12.5) 18 (28.1) 17 (26.6) 5 (7.8) 11 (17.2) 24 (37.5) 35 (54.7) 14 (21.9) 36 (56.3) 18 (28.1)
*Tumor
stage was known for only 49 patients, and nodal stage was known for only 54 patients.
METHODS AND PATIENTS The medical records of all patients younger than 40 years who came to UTMDACC between 1973 and 1995 for evaluation of SCCOT were reviewed for clinicopathologic data and clinical outcomes. To determine whether presenting symptoms were associated with patient survival, data regarding dysphagia, odynophagia, neck mass, trismus, weight loss, history of periodontal disease, and otalgia were recorded and analyzed by univariate analysis. To test the hypothesis that the incidence of SCCOT is increasing, we examined our departmental and institutional databases for all patients evaluated for the diagnosis of SCCOT at UTMDACC between 1948 and 1997. To determine the incidence of SCCOT in the US population at large, we also examined the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. The number of patients younger than 40 years with
SCCOT was compared with the total number of cases of SCCOT for each year between 1973 and 1992. Two- and 5-year disease-specific survival rates were compared between patients with and without specific clinical and pathologic features to determine whether there were significant survival differences between groups. This was accomplished with χ2 analysis and, when the number of observations in a given group fell below 6, Fisher’s exact test, by use of SigmaStat statistical software (SPSS Inc, Chicago, IL). Kaplan-Meier disease-specific survival curves were generated, and log-rank test analysis of the statistical significance of variations between groups was carried out with Statistica for Windows software (StatSoft Inc, Tulsa, OK). RESULTS Incidence of SCCOT
Between 1948 and 1995, the number of patients with SCCOT seen at UTMDACC steadily increased from fewer than 10 patients per year to as many as 52 patients per year (Fig 1A). To determine whether the percentage of SCCOT cases occurring in young adults also increased, we compared the ratio of patients aged 40 years or younger with SCCOT to the total number of patients with SCCOT seen at UTMDACC for each year from 1963 to 1996. As seen in Fig 1B, the percentage of cases of SCCOT occurring in young adults increased dramatically during this period from less than 10% of all cases to 15% to 25% of all cases in the mid-1990s. Curious to know whether these increases were reflective of a shift in referral patterns or a true increase in the incidence of SCCOT in the general population, we examined the National Cancer Institute’s SEER database in a similar fashion. We found a steady increase in the total number of cases of SCCOT, from roughly 300 in 1973 to more than 500 in 1992 (Fig 1C). Also evident from this analysis was an increase in the percentage of cases of SCCOT that occurred in young adults, from 3% in 1973 to nearly 6% in 1993 (Fig 1D). Demographic Data
A total of 64 patients younger than 40 came to UTMDACC between 1973 and 1995 for evaluation of SCCOT. The clinicopathologic data and treatment outcomes for these patients are given in Table 1. Of the 64 patients whose charts were evaluated, 27 (42%) were initially treated elsewhere; 37 patients (58%) received their primary treatment at UTMDACC. Thirty-seven (58%) of the patients were men, and 27 (42%) were women. The patients ranged in age from 19 to 39 years. The mean age was 31.3 years, and the median age was 32.5 years. Follow-up for this group of patients ranged
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Fig 2. Disease-specific survival of all young adults treated for SCCOT at UTMDACC between 1973 and 1995.
Table 2. Effects of presenting symptoms on cumulative survival
Table 3. Effects of clinical stage on cumulative survival
Symptom
P value
Parameter
P value
Dysphagia Odynophagia Neck mass Trismus Weight loss Periodontal disease Otalgia
0.00060 0.00072 0.00232 0.01021 0.04649 0.58220 0.24238
T 1,2 vs 3,4 N>0 Distant metastases
0.09479 0.0035 0.00001
from less than 1 month to 169 months, with a mean follow-up time of 36 months. Fifty-nine percent of the patients were nonsmokers, and 45% used no alcohol. Presenting Symptoms and Clinical Outcomes
Patients treated at UTMDACC who had dysphagia, odynophagia, neck mass, trismus, or weight loss at presentation had significantly decreased survival compared with patients without these presenting symptoms (Table 2). Figure 2 shows the disease-specific survival of 37 patients initially treated for SCCOT at UTMDACC. The 5-year disease-specific survival rate was 77.7%. All patients without dysphagia at presentation for whom follow-up data were available were alive at 5 years, compared with a 5-year survival rate of less than 50% for patients with dysphagia at presentation (data not shown). Similar differences in outcomes were seen for patients with odynophagia or weight loss at presentation versus patients without these symptoms at presentation.
Other information obtained from the patients’ histories, such as age, tobacco and alcohol use, and family history of cancer, did not appear to be predictive of survival (data not shown). Clinical (TNM) Stage and Clinical Outcomes
Clinical stage at presentation and at the time of recurrence was clearly correlated with outcomes. In young adults with SCCOT initially treated at UTMDACC (n = 37), T2 and T3 tumors were the most common, occurring in 15 patients (40.5%) and 10 patients (27%), respectively. The 2-year survival rate was 93% for patients with early lesions (T1 and T2) versus 43% for patients with more advanced lesions (T3 and T4). Twenty-one of the young adults with SCCOT treated at UTMDACC (57%) had clinically negative necks, and 13 (35%) had palpable lymph nodes. In the remaining cases, the clinical nodal status was not specified. Of the patients with palpable nodes, 7 had N1 disease, 3 had N2a disease, 2 had N2b disease, and 1 had N3 disease. For patients with clinically negative necks, the 2- and 5year survival rates were 100% and 85%, respectively. In contrast, in patients with palpable lymph nodes, 2- and 5-year survival rates were only 40% and 14.3%, respectively (Fig 3).
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Fig 3. Disease-specific survival of young adults treated for SCCOT at UTMDACC according to the clinical nodal status (N stage) of their necks.
Fig 4. Effect of surgical margins on disease-specific survival of young adults treated for SCCOT at UTMDACC.
Distant metastases were seen in only 4 patients, and all of these patients died within 4 years. The effect of clinical stage on survival is summarized in Table 3. Pathologic Parameters and Clinical Outcomes
Review of pathologic features and analysis of their relationship to clinical outcomes yielded a number of significant findings. Seventeen (46%) of the 37 patients initially treated at UTMDACC had moderately differentiated squamous cell carcinoma, 12 patients (32%) had well-differentiated squamous cell carcinoma, and 2 patients (5%) had poorly differentiated tumors. Although the outcomes tended to be better in patients with well-differentiated tumors, this finding was not statistically significant because of the small number of patients with poorly differentiated tumors. Although
there is a great deal of literature to support the concept that depth of tumor invasion and tumor thickness correlate with regional metastases and decreased survival, these parameters were not documented well enough in our cohort to permit useful conclusions about the relationship between these features and survival. Clinical outcomes were also evaluated with respect to pathologic nodal stage. Twenty-four patients (65%) had no lymph nodes that were pathologically positive for metastatic tumor or had lymph node metastases in only 1 level of the neck. Level II of the neck was the most common site of nodal spread; level II metastases were seen in 7 patients. Only 4 patients had nodal metastases in more than 1 level of the neck, and there were no “skip” metastases (cases in which nodal spread bypassed upper neck nodes to present in lower neck
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A
B
Fig 5. Effects of regional (A) and local (B) recurrence on the disease-specific survival rate of young adults treated for SCCOT at UTMDACC.
nodes only). Only 4 patients (11%) had extracapsular extension of tumor, and these patients appeared to have shorter survival times, but differences in survival were not statistically significant. As seen for clinical staging of the neck, patients with positive nodes on pathologic review of the neck dissection specimen had decreased survival compared with patients without positive lymph nodes. Perineural invasion was seen in 10 (27%) of the specimens and was correlated with decreased survival: 2- and 5-year survival rates were 50% and 0%, respectively, in patients with perineural invasion, compared with 95% and 87.5%, respectively, in patients without this finding. Vascular and lymphatic invasion were also predictive of decreased survival. Of the 3 patients (8%) with lymphatic invasion, only 1 was alive at 2 years, whereas the 2-year survival rate in patients without this finding was 100%. Of the 3 patients whose specimens had vascular invasion, none was alive at 2 years. Close surgical margins (ie, margins < 5 mm) were also predictive of decreased survival (Fig 4). No
patients had positive margins on final pathologic review, although 2 patients initially had positive frozensection margins. It has been hypothesized that positive margins on frozen-section analysis, despite negative final margins, are associated with worse clinical outcomes because of possible retraction of the lingual muscle fibers with viable tumor cells to sites at a distance from the mucosal margin of resection. However, we did not have enough patients with positive frozen-section margins to evaluate this hypothesis in a statistically meaningful fashion. The data correlating pathologic criteria with diseasespecific survival of young adults with SCCOT are summarized in Table 4. In brief, close surgical margins, perineural invasion, lymphatic invasion, and positive lymph nodes all portended poorer outcomes. Treatment Received and Clinical Outcomes
Regardless of where patients were treated, those who had a neck dissection had a much better outcome.
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Table 4. Effects of pathologic criteria on cumulative survival Parameter
Margins ≤ vs > 5 mm Perineural invasion Lymphatic invasion Positive lymph nodes
P value
0.04706 0.02203 <0.00001 0.04817
Three- and 5-year survival rates were 81% and 72%, respectively, in patients who had neck dissections and 44% (P = 0.025) and 22% (P = 0.018), respectively, in patients whose necks were not dissected. Patients who had a local or regional recurrence had shorter survival times. As shown in Fig 5, patients with regional recurrence fared poorly, and those with local recurrence did even worse. Adjuvant radiotherapy was most often used in cases in which the primary tumor had close margins, when there was evidence of perineural invasion, when the multiple lymph nodes contained metastatic tumor, or when there was extracapsular extension of tumor outside the lymph node. Those patients who were treated with surgery and radiation had decreased survival rates relative to those treated with surgery alone at 3 (P = 0.09) and 5 (P = 0.015) years. Second Primary Tumors
Only 1 of the patients in this study was found to have a second primary tumor of the aerodigestive tract during the follow-up period. Bronchogenic squamous cell carcinoma developed in a 39-year-old patient a year after treatment for his tongue lesion, and he died of this second cancer within the next several months. DISCUSSION
We found that the incidence of SCCOT in young adults has increased not only at our institution but also in the US population at large. In addition, we found that the 77.7% 5-year overall survival rate of young adult patients treated at our hospital was comparable with the survival rates seen in several large retrospective analyses of tongue cancer patients of all ages.9,10 Finally, we also identified several clinical, pathologic, and treatment-related factors that significantly correlate with disease-specific survival. Although this study is clearly limited by its design as a retrospective review and by the small number of patients and variety of treatment methods, our findings are consistent with previous data from larger series of patients of all ages and from a prior surgical trial carried out at our center.
The presenting symptoms of dysphagia, odynophagia, trismus, weight loss, and neck mass all correlated significantly with decreased survival. These findings were not surprising because these factors are all generally associated with more advanced disease. Other information obtained from the patients’ histories, such as age, tobacco and alcohol use, and family history of cancer, did not appear to be predictive of survival. We had previously hypothesized that younger patients without histories of typical risk factors for SCCOT might not fare as well as older patients who smoke or drink. When patients were stratified on the basis of age less than or greater than 30 years, younger patients appeared to do better; however, the difference was not statistically significant. Similar results were seen with stratification by tobacco and alcohol use. That increased tumor size and nodal stage and the presence of distant metastases were all correlated with decreased survival came as no surprise and confirmed the results of previous series.11,12 The same can be said for the findings that pathologic criteria such as close margins, perineural invasion, lymphatic invasion, and vascular invasion were correlated with decreased survival.9 Finally, the improved survival rate that was seen in patients whose primary treatment included neck dissection supports our institutional policy that all patients with SCCOT who are treated surgically should undergo neck dissection for prognostic and therapeutic purposes. This policy was based on data from a previous study by Lydiatt et al.9 In that study, locoregional control and survival rates at 5 years were 50% and 33%, respectively, in patients with T1 or T2 N0 SCCOT treated with resection of the primary tumor alone, versus 91% and 55%, respectively, in patients treated with resection of the primary tumor and elective lymph node dissection. The data regarding neck dissection and the data on surgical margins indicate that the adequacy of resection of the primary tumor and the performance of an appropriate regional lymphadenectomy have a significant impact on the clinical outcome of young patients with SCCOT. Therefore we recommend aggressive primary treatment of young and older adult patients with SCCOT, including resection of the primary tumor with margins of 5 mm or greater and an appropriate neck dissection. REFERENCES 1. Friedlander PL, Schantz SP, Shaha AR, et al. Squamous cell carcinoma of the head and neck in young patients: a matched pair analysis. Head Neck 1997;20:363-8. 2. Siegelman-Danieli N, Hanlon A, Ridge J, et al. Oral tongue cancer in patients less than 45 years old: institutional experience and comparison with older patients. J Clin Oncol 1998;16:745-53.
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3. Martin-Granizo R, Rodriguez-Campo F, Naval L, et al. Squamous cell carcinoma of the oral cavity in patients younger than 40 years. Head Neck Surg 1997;117:268-75. 4. Atula S, Grenman R, Laippala P, et al. Cancer of the tongue in patients younger than 40 years. Arch Otolaryngol Head Neck Surg 1996;122:1313-9. 5. Sarkaria J, Harari PM. Oral tongue cancer in young adults less than 40 years of age: rationale for aggressive therapy. Head Neck 1994;16:107-11. 6. Byers R. Squamous cell carcinoma of the oral tongue in patients less than thirty years of age. Am J Surg 1975;130:475-8. 7. McGregor G, Davis N, Robins RE. Squamous cell carcinoma of the tongue and lower oral cavity in patients under 40 years of age. Am J Surg 1982;145:88-92.
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8. Kuriakose M, Sankaranarayanan M, Nair MK, et al. Comparison of oral squamous cell carcinoma in younger and older patients in India. Oral Oncol Eur J Cancer 1992;28B:113-20. 9. Lydiatt DD, Robbins KT, Byers RB, et al. Treatment of stage I and II oral tongue cancer. Head Neck 1993;15:308-12. 10. Franceschi D, Gupta R, Spiro RH, et al. Improved survival in the treatment of squamous cell carcinoma of the oral tongue. Am J Surg 1993;166:360-5. 11. Nyman J, Mercke C, Lindstrom J. Prognostic factors for local control and survival of cancer of the oral tongue. Acta Oncol 1993;32:667-73. 12. Reichard KW, Joseph KT, Cohen M, et al. Squamous cell carcinoma of the tongue: experience with 86 consecutive cases. J Surg Oncol 1993;54:239-42.
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