Journal of Surgical Oncology 2014;109:639–644
Predictors of Prognosis for Squamous Cell Carcinoma of Oral Tongue SHIVAKUMAR THIAGARAJAN, MS, DNB,1 SUDHIR NAIR, MS, MCh,1* DEEPA NAIR, MS, DNB,1 PANKAJ CHATURVEDI, MS,1 SHUBHADRA V. KANE, MD,2 JAI PRAKASH AGARWAL, MD, DMRT,3 AND ANIL K. D’CRUZ, MS, DNB1 1
Head and Neck Services, Tata Memorial Hospital, Mumbai, India Department of Pathology, Tata Memorial Hospital, Mumbai, India Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India 2
3
Background and Objectives: Certain tumor‐related factors like thickness increases the risk of nodal metastasis and may affect survival in patients with oral tongue cancers. The objective of this study is to identify those tumor‐related prognostic predictors that can potentially influence decision for adjuvant radiotherapy. Methods: A retrospective review of all patients with oral tongue cancers treated primarily by surgery at Tata Memorial Hospital between January 2007 and June 2010. The demographic and commonly reported histopathological features were analyzed for their influence on disease free and overall survival. Results: Five hundred eighty‐six patients were eligible for the study, of which 416 were males and 117 were females. Follow‐up details were available for 498 (85%) patients with a median follow‐up of 18 months and mean follow‐up of 22 months. There were 302 patients who were alive and disease free at the last follow‐up. This group had a mean follow‐up of 27 months and median follow‐up of 27.5 months. Disease recurrences during follow‐up were observed in 184 (31%) patients. Sixty‐one patients died subsequently. Perineural invasion significantly affected disease free survival (DFS). A tumor thickness of more than 11 mm significantly affected the overall survival (OS). Conclusion: Other than nodal metastasis, tumor‐related factors like thickness and perineural invasion are adverse prognostic factors and can influence survival. These patients, especially in case of early stage cancers, may potentially benefit from postoperative adjuvant radiotherapy. Level of Evidence: 2b.
J. Surg. Oncol. 2014;109:639–644. 2014 Wiley Periodicals, Inc.
KEY WORDS: tongue squamous cell carcinoma; tumor thickness, survival, nodal metastasis
INTRODUCTION Several factors affect survival in squamous cell carcinoma of the oral tongue. The nodal metastasis represents the single most important prognostic factor [1] and survival falls below 40% [2] in its presence. Nodal metastasis is higher in patients with larger (higher T stage) and thicker tumors as well as those with adverse histological features like perineural invasion and poor differentiation [3]. Tumors thicker than 4 mm have a significantly higher risk of nodal metastasis compared to thinner ones [4]. The clinical significance of tumor‐related factors like thickness and perineural invasion have not been defined properly. Even though a few studies have also shown that tumor thickness affects survival in oral tongue cancers, a lot of them are small case series spanning over more than 10 years [5]. While the surgery for the primary and the neck nodes has remained the same throughout the last decade, there has been a considerable change in the indication and type of postoperative adjuvant treatment. Postoperative adjuvant radiotherapy is offered for patients with nodal metastasis or with large tumors. With the evidence emerging from the randomized control trials on the use of postoperative chemo‐ radiotherapy in head and neck cancers [6,7], most centers administer postoperative concurrent chemo‐radiotherapy for head and neck cancers patients with adverse factors like extra capsular spead (ECS) and microscopically positive margins. Bernier et al. [7] also included the perineural invasion (PNI) and lymphovascular emboli (LVE) as adverse histological factors and showed benefit from postoperative adjuvant chemo‐radiotherapy. Hence, an analysis of factors influencing survival in patients receiving current evidence based management may identify those adverse prognostic factors that need further attention. The present study had a larger cohort of patients with squamous cancers limited to a
2014 Wiley Periodicals, Inc.
single subsite (oral tongue) of the oral cavity and treated in a single institution over a shorter span of time.
Patients and Methods The electronic medical records of patients with pathologically proved squamous cell carcinoma of the tongue operated at Tata Memorial Hospital, a tertiary cancer center, between January 2007 and June 2010 were screened for the study. Cases were selected based on the following eligibility criteria: treatment na€|ve, surgery as the first‐line treatment and carcinoma of the oral tongue being the index lesion. We excluded those patients who had epicenter of disease in the base of tongue, those who were treated initially outside TMH, those who received chemotherapy as
Abbreviations: ECS, extra capsular spread; LVE, lymphovascular emboli; DFS, disease free survival; OS, overall survival; PMMC, pectoralis major myocutaneous flap; MND, modified neck dissection; PORT, postoperative radiotherapy; CCRT, concurrent chemo radiotherapy; SEER, surveillance, epidemiology and end results; HR, hazard ratio; HNSCC, head and neck squamous cell carcinoma. All authors are full time employees of Tata Memorial Hospital and received no special financial support for this study. *Correspondence to: Sudhir Nair, MS, MCh, Head and Neck Services, Tata Memorial Hospital, Parel, Mumbai, India 400012. Fax: þ91‐22‐24146937. E‐mail: [email protected] Received 24 August 2013; Accepted 12 January 2014 DOI 10.1002/jso.23583 Published online 12 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
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Thiagarajan et al.
initial modality of treatment (NACT) as well as those presented as recurrent or second primary disease at oral tongue. Of the total 877 patients screened, 586 patients were eligible for the study. The clinical and demographic details as well as the histopathological data (Table I) of these patients were obtained from the medical records. Information regarding patient survival and disease status was also retrieved from medical records and by telephonic interviews. Follow‐up details were available for 498 (85%) patients with a median follow‐up of 18 months. The primary endpoint of this study was loco‐regional recurrence and or distant metastasis. Death was considered as a secondary end point. TABLE I. Patient’s Demographic, Clinical, Pathological and Follow‐Up Details No of patients Demographic details Factors Age 40 years >40 years Mean Median Sex Male Female Habits Tobacco chewing Smoking Alcohol consumption Unknown Histopathological details Tumor type Ulceroinfiltrative Ulceroproliferative Lymphovascular emboli Yes No Perineural invasion Yes No Pathological node status N0 Nþ Extracapsular spread Yes No Grade Well differentiated Moderately differentiated Poorly differentiated Margins Free of tumor Close/Positive Pattern of disease failure Type of recurrence Local Regional Distant Second primaries Total Status of patients at last follow‐up Alive and disease free Alive with disease Died of cancer Died of other causes Not available
Journal of Surgical Oncology
190 (32.4%) 396 (67.6%) 47 years 48 years 416 (70.9%) 170 (29.1%) 364/541 130/541 107/541 45/586
(67.2%) (25.5%) (19.7%) (7.6%)
390 (66.6%) 196 (33.4%) 12 (2%) 574 (98%) 152 (25.9%) 434 (74.1%) 275 (47%) 311 (53%) 205/311 (66%) 96/311 (34%) 39 (6.6%) 402 (68.6%) 145 (24.8%) 523 (89.2%) 63 (10.8%)
34 (7%) 86 (17%) 38 (8%) 26 (5%) 184 (37%)
302 (51.5%) 135 (23%) 60 (10.8%) 1 (0.2%) 88 (15%)
Statistical analysis was done using the software SPSS20.0 (IBM, Armonk, NY). Disease free (DFS) and overall survival (OS) was calculated by Kaplan Meier method. We defined DFS as the period from date of diagnosis until date of first recurrence: loco‐regional or systemic. The OS (overall survival) is defined as the period from date of diagnosis until death from any cause. The date of diagnosis was taken as the date of registration at Tata Memorial Hospital as this being a referral hospital for all cancers. Dates of disease recurrences were collected from the medical records when they were diagnosed histologically or radiologically. The variables for univariate analysis were selected based on their clinical relevance as well as those previously described in the literature and done using log‐rank test (Table III). All significant (P < 0.05) variables were subsequently tested (multivariate) with cox‐regression analysis using forward stepwise selection. ROC curves were utilized to identify the ideal cutoff of tumor thickness, having the best sensitivity and specificity.
RESULTS Demographic Details The demographic details of the study population are summarized in Table I. The AJCC (6th edition) clinical and pathological T and N classification for them is presented in Table II.
Treatment details All patients underwent surgery as the primary modality of treatment (Fig. 1). We did selective neck dissection I–III in 250 cases, Modified radical neck dissection (MND) in 321 cases and radical neck dissection in nine patients. Four patients had neck dissection level I–IV. MND were done in patients with clinically positive neck nodes and those who required pectoralis major myocutaneous flap (PMMC) for reconstruction. As per the institutional practice, in patients who did not have palpable neck nodes (Clinically N0), under went selective neck dissection (levels I–III). These samples were immediately examined by the pathologist within the OT complex and doubtful nodes were subjected for frozen section. If reported positive, the remaining levels (IV and V) were cleared in the same sitting [8]. Postoperative adjuvant treatment in the form of radiotherapy (PORT) or concurrent chemo‐radiotherapy (CCRT) was given as per the institutional guidelines [9]. Patients with single node less than three centimeter (N1) without out extracapsular extension (ECS) or those with close margins (microscopically free margin less than 5 cm from the tumor) received PORT. Patients with multiple nodes, extra capsular spread (ECS) and those with microscopically positive resection margins received postoperative concurrent chemo radiotherapy (CCRT). The adjuvant treatment details are summarized in Figure 2. The PORT is given using conventional beam, standard fractionation: 200 cGy once daily for 5 days covering both neck and primary. The entire operative bed is treated to a dose of 46 Gy in 23 fractions with photons. The areas of high risk are then boosted to a dose equivalent of 56–60 Gy with shrinking field technique. If concurrent chemotherapy is needed in addition to radiotherapy, we use weekly cisplatin at 40 mg/m2 [10].
Pathological Features The maximum surface dimension of the primary lesions ranged from 4 to 85 mm (mean, 30 mm; median, 28 mm) and thickness from 2 to 44 mm (mean, 13 mm; median, 12 mm). Majority had an ulcero‐ infiltrative type of lesion and most had moderately differentiated tumors (Table I). Perineural invasion was seen in 105 (25.9%) cases and lymphovascular embolization in 12 (2.0%) cases. Taking a cuff of 0.5 cm of normal tissue around the surgical specimen as a tumor free margin, the margins were free in 523 patients (89.2%) and close or
Squamous Cell Carcinoma of Oral Tongue
641
TABLE II. Clinical and Pathological T and N Cross Tabulation (n ¼ 586) T classification Clinical T Classification T1 T2 T3 T4 Total no. of patients Path T classification T1 T2 T3 T4 Total no. of patients
No. of patients by clinical (c) and pathologic (p) nodal classification cN0 54 204 60 34 352 pN0 93 151 30 1 275
cN1 11 64 37 34 146 pN1 29 64 27 0 120
cN2a 3 6 9 6 24 pN2a 2 0 1 0 3
cN2b 0 9 15 20 44 pN2b 26 89 17 1 133
cN2c 1 1 5 11 18 pN2c 1 24 29 0 54
Total no. of patients cN3 0 2 0 0 2 pN3 0 1 0 0 1
69 286 126 105 586 151 329 104 2 586
positive (
Predictors of Prognosis for Squamous Cell Carcinoma of Oral Tongue SHIVAKUMAR THIAGARAJAN, MS, DNB,1 SUDHIR NAIR, MS, MCh,1* DEEPA NAIR, MS, DNB,1 PANKAJ CHATURVEDI, MS,1 SHUBHADRA V. KANE, MD,2 JAI PRAKASH AGARWAL, MD, DMRT,3 AND ANIL K. D’CRUZ, MS, DNB1 1
Head and Neck Services, Tata Memorial Hospital, Mumbai, India Department of Pathology, Tata Memorial Hospital, Mumbai, India Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India 2
3
Background and Objectives: Certain tumor‐related factors like thickness increases the risk of nodal metastasis and may affect survival in patients with oral tongue cancers. The objective of this study is to identify those tumor‐related prognostic predictors that can potentially influence decision for adjuvant radiotherapy. Methods: A retrospective review of all patients with oral tongue cancers treated primarily by surgery at Tata Memorial Hospital between January 2007 and June 2010. The demographic and commonly reported histopathological features were analyzed for their influence on disease free and overall survival. Results: Five hundred eighty‐six patients were eligible for the study, of which 416 were males and 117 were females. Follow‐up details were available for 498 (85%) patients with a median follow‐up of 18 months and mean follow‐up of 22 months. There were 302 patients who were alive and disease free at the last follow‐up. This group had a mean follow‐up of 27 months and median follow‐up of 27.5 months. Disease recurrences during follow‐up were observed in 184 (31%) patients. Sixty‐one patients died subsequently. Perineural invasion significantly affected disease free survival (DFS). A tumor thickness of more than 11 mm significantly affected the overall survival (OS). Conclusion: Other than nodal metastasis, tumor‐related factors like thickness and perineural invasion are adverse prognostic factors and can influence survival. These patients, especially in case of early stage cancers, may potentially benefit from postoperative adjuvant radiotherapy. Level of Evidence: 2b.
J. Surg. Oncol. 2014;109:639–644. 2014 Wiley Periodicals, Inc.
KEY WORDS: tongue squamous cell carcinoma; tumor thickness, survival, nodal metastasis
INTRODUCTION Several factors affect survival in squamous cell carcinoma of the oral tongue. The nodal metastasis represents the single most important prognostic factor [1] and survival falls below 40% [2] in its presence. Nodal metastasis is higher in patients with larger (higher T stage) and thicker tumors as well as those with adverse histological features like perineural invasion and poor differentiation [3]. Tumors thicker than 4 mm have a significantly higher risk of nodal metastasis compared to thinner ones [4]. The clinical significance of tumor‐related factors like thickness and perineural invasion have not been defined properly. Even though a few studies have also shown that tumor thickness affects survival in oral tongue cancers, a lot of them are small case series spanning over more than 10 years [5]. While the surgery for the primary and the neck nodes has remained the same throughout the last decade, there has been a considerable change in the indication and type of postoperative adjuvant treatment. Postoperative adjuvant radiotherapy is offered for patients with nodal metastasis or with large tumors. With the evidence emerging from the randomized control trials on the use of postoperative chemo‐ radiotherapy in head and neck cancers [6,7], most centers administer postoperative concurrent chemo‐radiotherapy for head and neck cancers patients with adverse factors like extra capsular spead (ECS) and microscopically positive margins. Bernier et al. [7] also included the perineural invasion (PNI) and lymphovascular emboli (LVE) as adverse histological factors and showed benefit from postoperative adjuvant chemo‐radiotherapy. Hence, an analysis of factors influencing survival in patients receiving current evidence based management may identify those adverse prognostic factors that need further attention. The present study had a larger cohort of patients with squamous cancers limited to a
2014 Wiley Periodicals, Inc.
single subsite (oral tongue) of the oral cavity and treated in a single institution over a shorter span of time.
Patients and Methods The electronic medical records of patients with pathologically proved squamous cell carcinoma of the tongue operated at Tata Memorial Hospital, a tertiary cancer center, between January 2007 and June 2010 were screened for the study. Cases were selected based on the following eligibility criteria: treatment na€|ve, surgery as the first‐line treatment and carcinoma of the oral tongue being the index lesion. We excluded those patients who had epicenter of disease in the base of tongue, those who were treated initially outside TMH, those who received chemotherapy as
Abbreviations: ECS, extra capsular spread; LVE, lymphovascular emboli; DFS, disease free survival; OS, overall survival; PMMC, pectoralis major myocutaneous flap; MND, modified neck dissection; PORT, postoperative radiotherapy; CCRT, concurrent chemo radiotherapy; SEER, surveillance, epidemiology and end results; HR, hazard ratio; HNSCC, head and neck squamous cell carcinoma. All authors are full time employees of Tata Memorial Hospital and received no special financial support for this study. *Correspondence to: Sudhir Nair, MS, MCh, Head and Neck Services, Tata Memorial Hospital, Parel, Mumbai, India 400012. Fax: þ91‐22‐24146937. E‐mail: [email protected] Received 24 August 2013; Accepted 12 January 2014 DOI 10.1002/jso.23583 Published online 12 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
640
Thiagarajan et al.
initial modality of treatment (NACT) as well as those presented as recurrent or second primary disease at oral tongue. Of the total 877 patients screened, 586 patients were eligible for the study. The clinical and demographic details as well as the histopathological data (Table I) of these patients were obtained from the medical records. Information regarding patient survival and disease status was also retrieved from medical records and by telephonic interviews. Follow‐up details were available for 498 (85%) patients with a median follow‐up of 18 months. The primary endpoint of this study was loco‐regional recurrence and or distant metastasis. Death was considered as a secondary end point. TABLE I. Patient’s Demographic, Clinical, Pathological and Follow‐Up Details No of patients Demographic details Factors Age 40 years >40 years Mean Median Sex Male Female Habits Tobacco chewing Smoking Alcohol consumption Unknown Histopathological details Tumor type Ulceroinfiltrative Ulceroproliferative Lymphovascular emboli Yes No Perineural invasion Yes No Pathological node status N0 Nþ Extracapsular spread Yes No Grade Well differentiated Moderately differentiated Poorly differentiated Margins Free of tumor Close/Positive Pattern of disease failure Type of recurrence Local Regional Distant Second primaries Total Status of patients at last follow‐up Alive and disease free Alive with disease Died of cancer Died of other causes Not available
Journal of Surgical Oncology
190 (32.4%) 396 (67.6%) 47 years 48 years 416 (70.9%) 170 (29.1%) 364/541 130/541 107/541 45/586
(67.2%) (25.5%) (19.7%) (7.6%)
390 (66.6%) 196 (33.4%) 12 (2%) 574 (98%) 152 (25.9%) 434 (74.1%) 275 (47%) 311 (53%) 205/311 (66%) 96/311 (34%) 39 (6.6%) 402 (68.6%) 145 (24.8%) 523 (89.2%) 63 (10.8%)
34 (7%) 86 (17%) 38 (8%) 26 (5%) 184 (37%)
302 (51.5%) 135 (23%) 60 (10.8%) 1 (0.2%) 88 (15%)
Statistical analysis was done using the software SPSS20.0 (IBM, Armonk, NY). Disease free (DFS) and overall survival (OS) was calculated by Kaplan Meier method. We defined DFS as the period from date of diagnosis until date of first recurrence: loco‐regional or systemic. The OS (overall survival) is defined as the period from date of diagnosis until death from any cause. The date of diagnosis was taken as the date of registration at Tata Memorial Hospital as this being a referral hospital for all cancers. Dates of disease recurrences were collected from the medical records when they were diagnosed histologically or radiologically. The variables for univariate analysis were selected based on their clinical relevance as well as those previously described in the literature and done using log‐rank test (Table III). All significant (P < 0.05) variables were subsequently tested (multivariate) with cox‐regression analysis using forward stepwise selection. ROC curves were utilized to identify the ideal cutoff of tumor thickness, having the best sensitivity and specificity.
RESULTS Demographic Details The demographic details of the study population are summarized in Table I. The AJCC (6th edition) clinical and pathological T and N classification for them is presented in Table II.
Treatment details All patients underwent surgery as the primary modality of treatment (Fig. 1). We did selective neck dissection I–III in 250 cases, Modified radical neck dissection (MND) in 321 cases and radical neck dissection in nine patients. Four patients had neck dissection level I–IV. MND were done in patients with clinically positive neck nodes and those who required pectoralis major myocutaneous flap (PMMC) for reconstruction. As per the institutional practice, in patients who did not have palpable neck nodes (Clinically N0), under went selective neck dissection (levels I–III). These samples were immediately examined by the pathologist within the OT complex and doubtful nodes were subjected for frozen section. If reported positive, the remaining levels (IV and V) were cleared in the same sitting [8]. Postoperative adjuvant treatment in the form of radiotherapy (PORT) or concurrent chemo‐radiotherapy (CCRT) was given as per the institutional guidelines [9]. Patients with single node less than three centimeter (N1) without out extracapsular extension (ECS) or those with close margins (microscopically free margin less than 5 cm from the tumor) received PORT. Patients with multiple nodes, extra capsular spread (ECS) and those with microscopically positive resection margins received postoperative concurrent chemo radiotherapy (CCRT). The adjuvant treatment details are summarized in Figure 2. The PORT is given using conventional beam, standard fractionation: 200 cGy once daily for 5 days covering both neck and primary. The entire operative bed is treated to a dose of 46 Gy in 23 fractions with photons. The areas of high risk are then boosted to a dose equivalent of 56–60 Gy with shrinking field technique. If concurrent chemotherapy is needed in addition to radiotherapy, we use weekly cisplatin at 40 mg/m2 [10].
Pathological Features The maximum surface dimension of the primary lesions ranged from 4 to 85 mm (mean, 30 mm; median, 28 mm) and thickness from 2 to 44 mm (mean, 13 mm; median, 12 mm). Majority had an ulcero‐ infiltrative type of lesion and most had moderately differentiated tumors (Table I). Perineural invasion was seen in 105 (25.9%) cases and lymphovascular embolization in 12 (2.0%) cases. Taking a cuff of 0.5 cm of normal tissue around the surgical specimen as a tumor free margin, the margins were free in 523 patients (89.2%) and close or
Squamous Cell Carcinoma of Oral Tongue
641
TABLE II. Clinical and Pathological T and N Cross Tabulation (n ¼ 586) T classification Clinical T Classification T1 T2 T3 T4 Total no. of patients Path T classification T1 T2 T3 T4 Total no. of patients
No. of patients by clinical (c) and pathologic (p) nodal classification cN0 54 204 60 34 352 pN0 93 151 30 1 275
cN1 11 64 37 34 146 pN1 29 64 27 0 120
cN2a 3 6 9 6 24 pN2a 2 0 1 0 3
cN2b 0 9 15 20 44 pN2b 26 89 17 1 133
cN2c 1 1 5 11 18 pN2c 1 24 29 0 54
Total no. of patients cN3 0 2 0 0 2 pN3 0 1 0 0 1
69 286 126 105 586 151 329 104 2 586
positive (
