- Email: [email protected]
WITHDRAWN: Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study
YBJOM-4528; No. of Pages 5
ARTICLE IN PRESS Available online at www.sciencedirect.com
British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study M. Abu-Serriah a,∗ , K.A. Shah b,e , R. Rajamanohara a,f , A. Fasanmade c,g , J. Graystone c,g , S. Gerry d,h , S. Bond c,g a
Department of Oral & Maxillofacial Surgery, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK c Division of Oral & Maxillofacial Surgery, Head and Neck Surgery Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK d Centre for Statistics in Medicine, University of Oxford, Oxford, UK b
Accepted 14 May 2015
Abstract The depth of invasion is considered to be a predictor of occult metastases in the neck in patients with squamous cell carcinoma (SCC), but investigators do not agree about the depth at which the risk rises dramatically. As the association between depth of invasion of pT1 SCC of the oral tongue and occult metastases in the neck remains unknown, we collected data on patients with the disease and recorded the depth and pattern of invasion, neurovascular invasion, and presence of occult metastases. When all other factors were constant, the odds ratio for each millimetre increase in depth and risk of occult metastases was 1.09 (95% CI: 0.95 to 1.25, p = 0.23), which was not significant. Depth of invasion is not accurate and cannot be used as predictor of occult metastases in the neck in patients with pT1 SCC of the tongue. © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Oral tongue; Squamous cell carcinoma; Tumour thickness; Tumour depth of invasion; Neck metastasis
Introduction
∗ Corresponding author at: Department of Oral & Maxillofacial Surgery, Manchester Head and Neck Centre, Manchester Royal Infirmary, Central Manchester Foundation Trust, Manchester, M13 9WL, UK. Tel.: +44 (0)161 276 8639; fax: +44 (0)161 276 6090. E-mail address: [email protected] (M. Abu-Serriah). e Department of Cellular Pathology, John Radcliffe Hospital, Oxford, OX3 9DU, UK. f Department of Oral & Maxillofacial Surgery, John Radcliffe Hospital, Oxford, OX3 9DU, UK. g Division of Oral & Maxillofacial Surgery, The Head and Neck Surgery Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, UK. h Centre for Statistics in Medicine, University of Oxford, Oxford, OX3 7LD, UK.
Squamous cell carcinomas (SCC) of the oral cavity spread to the cervical lymph nodes in about 18% to 45% of cases.1 As occult metastases are not always identified by modern techniques of diagnostic imaging2 and their presence reduces overall survival by 30% to 50%,3 it is important to investigate the nodes in the neck. The oral tongue is the primary site most commonly affected, so we used it as the focus of our investigation.4 Management of the neck in T1 SCC of the oral tongue remains controversial, with some advocating elective neck dissection, and others, watchful waiting. Several authors5,6 have examined the value of different clinical, imaging, and histological investigations (including sentinel lymph node biopsy), and the use of biomarkers to guide decisions about elective neck dissection in patients with early disease, and
http://dx.doi.org/10.1016/j.bjoms.2015.05.013 0266-4356/© 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
YBJOM-4528; No. of Pages 5
2
ARTICLE IN PRESS M. Abu-Serriah et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
the thickness of the tumour and the depth of invasion have increasingly been used to indicate whether the operation is necessary. However, published work on depth of invasion as a predictor of nodal status is problematic. Although T1 SCC of the tongue is considered a different disease entity from T2, for analysis, most research groups around the world continue to pool data for both types, and occasionally for T3 and T4. Some studies have even combined tumours from different anatomical sites.5,7 There is no consensus about the depth of invasion (2–10 mm) beyond which the risk of occult metastases rises dramatically. In the UK, a depth of 4 mm has been recommended, but the rationale as to how it was identified is unclear.8 We therefore aimed to investigate the association between depth of invasion and presence of occult metastases in the neck in patients with pT1cN0 SCC of the oral tongue.
Material and methods We collected data from the Head and Neck Cancer Database at Oxford University Hospitals NHS Trust on patients who were seen between August 2000 and August 2013 and had been followed up for a minimum of one year. Patients with T2–4 SCC of the tongue, SCC of other anatomical sites, carcinoma in situ, or microinvasive SCC, and those with multiple carcinomas of the tongue, recurrent carcinoma, clinical or radiological nodal neck disease, or a previous history of radiotherapy to the head and neck, were excluded. Various pathological variables were gathered and depth of invasion was defined as the distance between the surrounding normal epithelial surface and the deepest invasive front. Statistical analysis Logistic regression models were used to investigate the association between occult metastases in the neck and potential prognostic factors. Results are presented as odds ratios with 95% confidence intervals and associated 2-sided p-values. To investigate the accuracy of depth of invasion as a diagnostic test for occult disease, the sensitivity and specificity at each millimetre were calculated. This was then displayed graphically using a receiver operating characteristic (ROC) curve. Statistical analysis was done with the help of Microsoft Excel 2011, and StataCorp 2013 (Stata: Release 13, Statistical Software, College Station, USA).
Results During the 13-year study period, 127 patients had primary pT1cN0 SCC of the oral tongue and of them, 108 had elective neck dissection (Table 1). There were more men (58%) than
Table 1 Results of the clinical and pathological variables assessed in patients with primary pT1cN0 squamous cell carcinoma of the oral tongue. Variable
No. (%)
Neck dissection Neurovascular invasion Non-cohesive front Grade: Well differentiated Moderately differentiated Poorly differentiated Anaplastic Pathologically detected metastases in the neck Extracapsular spread Recurrence at primary site Recurrence in neck Death
108 30/108 (28) 73/108 (68)
∗
16/108 (15) 78/108 (72) 14/108 (13) 0 39/108 (36) 17/39 (44) 14/108 (13) 4/108 (4)* 9/108 (8)
All recurrences appeared at the site of neck dissection.
women (42%), mean age was 61 years (range 23–87), and mean depth of invasion was 6 mm (range 0.5–16). The results (Table 2) show that for each millimetre increase in depth, the odds ratio for occult metastases being present increased by 16% (OR: 1.16; 95% CI: 1.04 to 1.30), which was significant (p = 0.008). The presence of neurovascular invasion meant that the odds ratio for occult metastases was 3.27 times higher than if it was absent (95% CI: 1.33 to 8.03, p = 0.01). However, after adjustment for neurovascular invasion, invasive front, and tumour grade, for each millimetre increase in depth it was 1.09 (95% CI: 0.95 to 1.25, p = 0.23) when all other factors were constant, which was not significant. There was no correlation between depth of invasion and risk of extracapsular spread in pT1 SCC of the oral tongue (OR: 1.05; 95% CI: 0.92 to 1.21, p = 0.46). To find out whether there was a specific cut-off value for depth of invasion, we graded the depth into a 1 mm continuous scale (Table 3) and calculated the sensitivity and specificity of the values (Table 4). Values between 6 and 9 mm had sensitivity and specificity of about 60%–77% and would predict the presence of occult metastases in the neck in roughly two-thirds of patients. To assess the overall accuracy of depth of invasion to predict occult metastases over the range of possible cut-off values shown in Table 4, we used a ROC curve (Fig. 1), which plots the sensitivity of a test, in this case, depth of invasion on the y-axis and false positives (1 − specificity) on the x-axis. Table 2 Association between pathologically detected metastases in the neck and microscopic variables. Variable
Odds ratio (95% CI)
p value
Depth of invasion (mm) Front: Cohesive Non-cohesive Neurovascular invasion Tumour grade
1.16 (1.04 to 1.30)
0.008
– 2.63 (0.98 to 7.03) 3.27 (1.33 to 8.03) 1.42 (0.66 to 3.06)
– 0.05 0.01 0.37
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
ARTICLE IN PRESS
YBJOM-4528; No. of Pages 5
M. Abu-Serriah et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx Table 3 Cut-off values for depth of invasion and pathologically detected metastases in the neck. Depth of invasion (mm)
<1 ≥1 and <2 ≥2 and <3 ≥3 and <4 ≥4 and <5 ≥5 and <6 ≥6 and <7 ≥7 and <8 ≥8 and <9 ≥9 and <10 ≥10 and <11 ≥11 and <12 ≥12 Total
Pathologically detected metastases in the neck No
Yes
2 7 13 3 6 12 6 4 0 1 5 0 10 69
0 2 1 3 2 4 4 0 2 2 16 1 2 39
Total
2 9 14 6 8 16 10 4 2 3 21 1 12 108
Fig. 1. Receiver operating characteristic (ROC) curve showing the accuracy of depth of invasion to predict pathologically detected metastases in the neck.
The area under the curve is calculated to indicate various degrees of accuracy: 0.9–1.0 excellent (90%–100%); 0.8–0.9 good (80%–90%); 0.7–0.8 fair (70%–80%); 0.6–0.7 poor (60%–70%); and 0.5–0.6 useless or worthless (50%–60%).9
3
If the curve lies exactly on the 45◦ line, then the test has only 50% accuracy, the same as tossing a coin. Based on the curve, the accuracy of depth of invasion to predict occult metastases in the neck in pT1 SCC of the oral tongue was poor (66%) (Fig. 1).
Discussion Controversy over management of the neck in patients with cT1cN0 SCC has stimulated the search for various predictors of occult metastases to identify those who might benefit most from elective neck dissection. Depth of invasion is one that is commonly investigated.10 To our knowledge, this is largest study to examine the nature of the association between invaded depth and occult metastases, and the usefulness of depth as a predictor of metastatic disease in the neck in patients with pT1cN0 SCC of the oral tongue. Other studies have pooled T1 and T2, and occasionally T3 and T4 lesions, so the fact that we know of no other published studies that have looked purely at the disease at this stage has made comparison difficult. In a retrospective study of 49 patients with T1 SCC of the oral tongue treated at 14 different hospitals in Sweden, Nathanson et al.4 concluded that a tumour thickness of more than 10 mm was associated with a significant risk of recurrence and poor survival. This was the only study we could find that looked at T1 SCC of the oral tongue in isolation. Unfortunately, it included cases from several hospitals that used different oncological practices, and it looked at recurrence and survival, rather than the risk of occult metastases. Whilst it is known that tumours that arise in different anatomical sites may have a different epidemiology, aetiology, behaviour, and prognosis, some authors have pooled them to study the importance of depth of invasion in the prediction of occult metastases, survival, and locoregional recurrence.5,7,11 To show the complexities associated with thickness, Woolgar and Scott suggested different cut-off values for tumours at different sites, even those in the same anatomical structure – for example, the lateral tongue
Table 4 Sensitivity and specificity of various cut-off values for depth of invasion in the prediction of pathologically detected metastases in the neck. Cut-off value for depth of invasion (mm)
Sensitivity (True positives)
Specificity (True negatives)
1 − Specificity (False positives)
≥1 ≥2 ≥3 ≥4 ≥5 ≥6 ≥7 ≥8 ≥9 ≥10 ≥11 ≥12
1.00 0.95 0.92 0.85 0.79 0.69 0.60 0.60 0.54 0.49 0.08 0.05
0.03 0.13 0.32 0.36 0.45 0.62 0.71 0.77 0.77 0.78 0.86 0.86
0.97 0.87 0.68 0.64 0.55 0.38 0.29 0.23 0.23 0.22 0.14 0.14
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
YBJOM-4528; No. of Pages 5
4
ARTICLE IN PRESS M. Abu-Serriah et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
(cut-off value 13.6 mm) compared with the ventral surface (cut-off value 9.1 mm).12 O’Brien et al., who found no differences among 145 cancers from different sites in the oral cavity, disagreed.11 Such heterogeneities have undermined the internal validity of these studies, prevented accurate comparison of data, and caused ongoing controversy. Failure of depth of invasion to consistently predict occult metastases in the neck raises questions about the accuracy of testing, and our study shows that the selection of one value or a predetermined cut-off value is not reliable. The reporting of only one value for sensitivity and specificity can provide a potentially misleading and serious oversimplification of a test’s accuracy.9 Our study shows that no specific value can consistently identify the patients who are at risk of occult metastases in the neck from the majority who are not, and the overall accuracy of using depth of invasion as a predictor in those with pT1 SCC of oral tongue is poor (66%). This is in agreement with other authors who have concluded that the use of any single predicting factor alone is neither sensitive nor specific enough to reliably select the patients who would benefit most from elective neck dissection.13,14 Although some authors think that depth of invasion is a reliable and superior prognostic marker for occult disease, local recurrence, and survival,2 our findings do not agree. The reason for this contradiction is unknown, but it is certainly feasible that a single morphological feature cannot accurately predict the biological behaviour of the tumour, which is decided by both morphological and cytogenetic factors. It is also possible that because the other studies had pooled data on tumours of various sizes or at different anatomical sites, it had skewed their findings and exaggerated the importance given to depth of invasion. The level of association between depth of invasion and occult disease may be more important with larger (T2–T4) tumours.15 Tumour thickness has not been uniformly measured to date. Depth of invasion and thickness are not the same, and a clear distinction should be made between them in published reports.16 We used depth of invasion because it reflects the aggressiveness of a tumour and its capacity to grow vertically,17 and we think that depth is more relevant to its behaviour than thickness. Geographical variations in the epidemiology of tumours and the patients studied may make it difficult to identify a consistent pattern of tumour behaviour among different head and neck oncological units across the world. Also, as there are difficulties associated with measuring the depth of invasion because specimens are processed in different ways, and because of shrinkage, variations in apparent thickness or depth because of different angles of sectioning, and because of differences in the experience of the reporting pathologist, varying degrees of measurement error can be introduced.18 This is most accentuated on diagnostic biopsies and meaningful measurement is best carried out on resected specimens. In our study, the incidence of occult disease in what is traditionally considered an early stage cancer was 36%, and in almost half of the cases (44%) there was extracapsular spread. Although the incidence of occult disease lies within
the reported range,15,19 the incidence of extracapsular spread is almost 3 times more than that reported by Nathanson et al. (15%).4 According to our findings, occult disease and the risk of extracapsular spread in patients with pT1 SCC of the oral tongue remain significant. Treatment of the neck must be considered carefully and based on the medical history, and on the clinical, imaging, and pathological assessment of individual patients. The study supports the current practice of many head and neck oncological surgeons, who consider patient-related (coexisting conditions) as well as tumour-specific (neurovascular invasion, grade, invasive front, mitotic figures, and biomarkers) factors in their decisions about the best way to manage the neck in tumours of this type. It is possible that a weighted scoring system20 that does not only consider thickness or depth, but other important patient-related and tumour-related factors, may be of more clinical importance. Advances in imaging technology, use of biomarkers, and the role of sentinel node biopsy require further research and validation. Therefore, the search to identify reliable and accurate predictor(s) of occult metastases, or approaches to the management of patients with pT1 SCC of the oral tongue, must continue. Our study has some limitations. It is retrospective and restricted to 108 patients. A larger sample size would enable better understanding of the association, but as pT1 SCC of the oral tongue comprises about 10% of all oropharyngeal SCC, an appropriately powered, prospective study in one centre may take several years to complete. Patients must continue to be managed by multidisciplinary teams until more suitable predictors or new approaches have been identified. Sentinel lymph node biopsy and advances in research into biomarkers may have an invaluable role in their future management.
Conflict of interest We have no conflicts of interest Ethics statement/confirmation of patient permission Not applicable. Financial disclosures None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. Part of this work was presented in the European Association of Cranio-Maxillofacial Surgeons, Dubrovnik, Croatia, 2012. Acknowledgments The authors would like to thank Kabir Ahluwalia, Felicity Smith and Felicity Brooks for helping with data collection.
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
YBJOM-4528; No. of Pages 5
ARTICLE IN PRESS M. Abu-Serriah et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
References 1. El-Naaj IA, Leiser Y, Shveis M, et al. Incidence of oral cancer occult metastasis and survival of T1-T2N0 oral cancer patients. J Oral Maxillofac Surg 2011;69:2674–9. 2. Po Wing Yuen A, Lam KY, Lam LK, et al. Prognostic factors of clinically stage I and II oral tongue carcinoma: a comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 2002;24:513–20. 3. Leemans CR, Tiwari R, Nauta JJ, et al. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer 1993;71:452–6. 4. Nathanson A, Agren K, Biörklund A, et al. Evaluation of some prognostic factors in small squamous cell carcinoma of the mobile tongue: a multicenter study in Sweden. Head Neck 1998;11: 387–92. 5. Spiro RH, Huvos AG, Wong GY, et al. Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg 1986;152:345–50. 6. Lim SC, Zhang S, Ishii G, et al. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 2004;10:166–72. 7. Brown B, Barnes L, Mazariegos J, et al. Prognostic factors in mobile tongue and floor of mouth carcinoma. Cancer 1989;64:1195– 202. 8. Roland NJ, Paleri V, editors. Head and neck cancer: multidisciplinary management guidelines. 4th ed. London: ENT; 2011. 9. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993;39:561–77.
5
10. O-charoenrat P, Pillai G, Patel S, et al. Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Oral Oncol 2003;39:386–90. 11. O’Brien CJ, Lauer CS, Fredricks S, et al. Tumor thickness influences prognosis of T1 and T2 oral cavity cancer—but what thickness? Head Neck 2003;25:937–45. 12. Woolgar JA, Scott J. Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 1995;17:463–72. 13. Sparano A, Weinstein G, Chalian A, et al. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 2004;131:472–6. 14. Johnson JT, Leipzig B, Cummings CW. Management of T1 carcinoma of the anterior aspect of the tongue. Arch Otolaryngol 1980;106:249–51. 15. Morton RP, Ferguson CM, Lambie NK, et al. Tumor thickness in early tongue cancer. Arch Otolaryngol Head Neck Surg 1994;120:717–20. 16. Gluckman JL, Pavelic ZP, Welkoborsky HJ, et al. Prognostic indicators for squamous cell carcinoma of the oral cavity: a clinicopathologic correlation. Laryngoscope 1997;107:1239–44. 17. Moore C, Kuhns JG, Greenberg RA. Thickness as prognostic aid in upper aerodigestive tract cancer. Arch Surg 1986;121:1410–4. 18. Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck 2005;27:1080–91. 19. Fakih AR, Rao RS, Borges AM, et al. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Am J Surg 1989;158:309–13. 20. Martinez-Gimeno C, Rodriguez EM, Vila CN, et al. Squamous cell carcinoma of the oral cavity: a clinicopathologic scoring system for evaluating risk of cervical lymph node metastasis. Laryngoscope 1995;105:728–33.
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
ARTICLE IN PRESS Available online at www.sciencedirect.com
British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study M. Abu-Serriah a,∗ , K.A. Shah b,e , R. Rajamanohara a,f , A. Fasanmade c,g , J. Graystone c,g , S. Gerry d,h , S. Bond c,g a
Department of Oral & Maxillofacial Surgery, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK c Division of Oral & Maxillofacial Surgery, Head and Neck Surgery Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK d Centre for Statistics in Medicine, University of Oxford, Oxford, UK b
Accepted 14 May 2015
Abstract The depth of invasion is considered to be a predictor of occult metastases in the neck in patients with squamous cell carcinoma (SCC), but investigators do not agree about the depth at which the risk rises dramatically. As the association between depth of invasion of pT1 SCC of the oral tongue and occult metastases in the neck remains unknown, we collected data on patients with the disease and recorded the depth and pattern of invasion, neurovascular invasion, and presence of occult metastases. When all other factors were constant, the odds ratio for each millimetre increase in depth and risk of occult metastases was 1.09 (95% CI: 0.95 to 1.25, p = 0.23), which was not significant. Depth of invasion is not accurate and cannot be used as predictor of occult metastases in the neck in patients with pT1 SCC of the tongue. © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Keywords: Oral tongue; Squamous cell carcinoma; Tumour thickness; Tumour depth of invasion; Neck metastasis
Introduction
∗ Corresponding author at: Department of Oral & Maxillofacial Surgery, Manchester Head and Neck Centre, Manchester Royal Infirmary, Central Manchester Foundation Trust, Manchester, M13 9WL, UK. Tel.: +44 (0)161 276 8639; fax: +44 (0)161 276 6090. E-mail address: [email protected] (M. Abu-Serriah). e Department of Cellular Pathology, John Radcliffe Hospital, Oxford, OX3 9DU, UK. f Department of Oral & Maxillofacial Surgery, John Radcliffe Hospital, Oxford, OX3 9DU, UK. g Division of Oral & Maxillofacial Surgery, The Head and Neck Surgery Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, OX3 7LE, UK. h Centre for Statistics in Medicine, University of Oxford, Oxford, OX3 7LD, UK.
Squamous cell carcinomas (SCC) of the oral cavity spread to the cervical lymph nodes in about 18% to 45% of cases.1 As occult metastases are not always identified by modern techniques of diagnostic imaging2 and their presence reduces overall survival by 30% to 50%,3 it is important to investigate the nodes in the neck. The oral tongue is the primary site most commonly affected, so we used it as the focus of our investigation.4 Management of the neck in T1 SCC of the oral tongue remains controversial, with some advocating elective neck dissection, and others, watchful waiting. Several authors5,6 have examined the value of different clinical, imaging, and histological investigations (including sentinel lymph node biopsy), and the use of biomarkers to guide decisions about elective neck dissection in patients with early disease, and
http://dx.doi.org/10.1016/j.bjoms.2015.05.013 0266-4356/© 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
YBJOM-4528; No. of Pages 5
2
ARTICLE IN PRESS M. Abu-Serriah et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
the thickness of the tumour and the depth of invasion have increasingly been used to indicate whether the operation is necessary. However, published work on depth of invasion as a predictor of nodal status is problematic. Although T1 SCC of the tongue is considered a different disease entity from T2, for analysis, most research groups around the world continue to pool data for both types, and occasionally for T3 and T4. Some studies have even combined tumours from different anatomical sites.5,7 There is no consensus about the depth of invasion (2–10 mm) beyond which the risk of occult metastases rises dramatically. In the UK, a depth of 4 mm has been recommended, but the rationale as to how it was identified is unclear.8 We therefore aimed to investigate the association between depth of invasion and presence of occult metastases in the neck in patients with pT1cN0 SCC of the oral tongue.
Material and methods We collected data from the Head and Neck Cancer Database at Oxford University Hospitals NHS Trust on patients who were seen between August 2000 and August 2013 and had been followed up for a minimum of one year. Patients with T2–4 SCC of the tongue, SCC of other anatomical sites, carcinoma in situ, or microinvasive SCC, and those with multiple carcinomas of the tongue, recurrent carcinoma, clinical or radiological nodal neck disease, or a previous history of radiotherapy to the head and neck, were excluded. Various pathological variables were gathered and depth of invasion was defined as the distance between the surrounding normal epithelial surface and the deepest invasive front. Statistical analysis Logistic regression models were used to investigate the association between occult metastases in the neck and potential prognostic factors. Results are presented as odds ratios with 95% confidence intervals and associated 2-sided p-values. To investigate the accuracy of depth of invasion as a diagnostic test for occult disease, the sensitivity and specificity at each millimetre were calculated. This was then displayed graphically using a receiver operating characteristic (ROC) curve. Statistical analysis was done with the help of Microsoft Excel 2011, and StataCorp 2013 (Stata: Release 13, Statistical Software, College Station, USA).
Results During the 13-year study period, 127 patients had primary pT1cN0 SCC of the oral tongue and of them, 108 had elective neck dissection (Table 1). There were more men (58%) than
Table 1 Results of the clinical and pathological variables assessed in patients with primary pT1cN0 squamous cell carcinoma of the oral tongue. Variable
No. (%)
Neck dissection Neurovascular invasion Non-cohesive front Grade: Well differentiated Moderately differentiated Poorly differentiated Anaplastic Pathologically detected metastases in the neck Extracapsular spread Recurrence at primary site Recurrence in neck Death
108 30/108 (28) 73/108 (68)
∗
16/108 (15) 78/108 (72) 14/108 (13) 0 39/108 (36) 17/39 (44) 14/108 (13) 4/108 (4)* 9/108 (8)
All recurrences appeared at the site of neck dissection.
women (42%), mean age was 61 years (range 23–87), and mean depth of invasion was 6 mm (range 0.5–16). The results (Table 2) show that for each millimetre increase in depth, the odds ratio for occult metastases being present increased by 16% (OR: 1.16; 95% CI: 1.04 to 1.30), which was significant (p = 0.008). The presence of neurovascular invasion meant that the odds ratio for occult metastases was 3.27 times higher than if it was absent (95% CI: 1.33 to 8.03, p = 0.01). However, after adjustment for neurovascular invasion, invasive front, and tumour grade, for each millimetre increase in depth it was 1.09 (95% CI: 0.95 to 1.25, p = 0.23) when all other factors were constant, which was not significant. There was no correlation between depth of invasion and risk of extracapsular spread in pT1 SCC of the oral tongue (OR: 1.05; 95% CI: 0.92 to 1.21, p = 0.46). To find out whether there was a specific cut-off value for depth of invasion, we graded the depth into a 1 mm continuous scale (Table 3) and calculated the sensitivity and specificity of the values (Table 4). Values between 6 and 9 mm had sensitivity and specificity of about 60%–77% and would predict the presence of occult metastases in the neck in roughly two-thirds of patients. To assess the overall accuracy of depth of invasion to predict occult metastases over the range of possible cut-off values shown in Table 4, we used a ROC curve (Fig. 1), which plots the sensitivity of a test, in this case, depth of invasion on the y-axis and false positives (1 − specificity) on the x-axis. Table 2 Association between pathologically detected metastases in the neck and microscopic variables. Variable
Odds ratio (95% CI)
p value
Depth of invasion (mm) Front: Cohesive Non-cohesive Neurovascular invasion Tumour grade
1.16 (1.04 to 1.30)
0.008
– 2.63 (0.98 to 7.03) 3.27 (1.33 to 8.03) 1.42 (0.66 to 3.06)
– 0.05 0.01 0.37
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
ARTICLE IN PRESS
YBJOM-4528; No. of Pages 5
M. Abu-Serriah et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx Table 3 Cut-off values for depth of invasion and pathologically detected metastases in the neck. Depth of invasion (mm)
<1 ≥1 and <2 ≥2 and <3 ≥3 and <4 ≥4 and <5 ≥5 and <6 ≥6 and <7 ≥7 and <8 ≥8 and <9 ≥9 and <10 ≥10 and <11 ≥11 and <12 ≥12 Total
Pathologically detected metastases in the neck No
Yes
2 7 13 3 6 12 6 4 0 1 5 0 10 69
0 2 1 3 2 4 4 0 2 2 16 1 2 39
Total
2 9 14 6 8 16 10 4 2 3 21 1 12 108
Fig. 1. Receiver operating characteristic (ROC) curve showing the accuracy of depth of invasion to predict pathologically detected metastases in the neck.
The area under the curve is calculated to indicate various degrees of accuracy: 0.9–1.0 excellent (90%–100%); 0.8–0.9 good (80%–90%); 0.7–0.8 fair (70%–80%); 0.6–0.7 poor (60%–70%); and 0.5–0.6 useless or worthless (50%–60%).9
3
If the curve lies exactly on the 45◦ line, then the test has only 50% accuracy, the same as tossing a coin. Based on the curve, the accuracy of depth of invasion to predict occult metastases in the neck in pT1 SCC of the oral tongue was poor (66%) (Fig. 1).
Discussion Controversy over management of the neck in patients with cT1cN0 SCC has stimulated the search for various predictors of occult metastases to identify those who might benefit most from elective neck dissection. Depth of invasion is one that is commonly investigated.10 To our knowledge, this is largest study to examine the nature of the association between invaded depth and occult metastases, and the usefulness of depth as a predictor of metastatic disease in the neck in patients with pT1cN0 SCC of the oral tongue. Other studies have pooled T1 and T2, and occasionally T3 and T4 lesions, so the fact that we know of no other published studies that have looked purely at the disease at this stage has made comparison difficult. In a retrospective study of 49 patients with T1 SCC of the oral tongue treated at 14 different hospitals in Sweden, Nathanson et al.4 concluded that a tumour thickness of more than 10 mm was associated with a significant risk of recurrence and poor survival. This was the only study we could find that looked at T1 SCC of the oral tongue in isolation. Unfortunately, it included cases from several hospitals that used different oncological practices, and it looked at recurrence and survival, rather than the risk of occult metastases. Whilst it is known that tumours that arise in different anatomical sites may have a different epidemiology, aetiology, behaviour, and prognosis, some authors have pooled them to study the importance of depth of invasion in the prediction of occult metastases, survival, and locoregional recurrence.5,7,11 To show the complexities associated with thickness, Woolgar and Scott suggested different cut-off values for tumours at different sites, even those in the same anatomical structure – for example, the lateral tongue
Table 4 Sensitivity and specificity of various cut-off values for depth of invasion in the prediction of pathologically detected metastases in the neck. Cut-off value for depth of invasion (mm)
Sensitivity (True positives)
Specificity (True negatives)
1 − Specificity (False positives)
≥1 ≥2 ≥3 ≥4 ≥5 ≥6 ≥7 ≥8 ≥9 ≥10 ≥11 ≥12
1.00 0.95 0.92 0.85 0.79 0.69 0.60 0.60 0.54 0.49 0.08 0.05
0.03 0.13 0.32 0.36 0.45 0.62 0.71 0.77 0.77 0.78 0.86 0.86
0.97 0.87 0.68 0.64 0.55 0.38 0.29 0.23 0.23 0.22 0.14 0.14
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
YBJOM-4528; No. of Pages 5
4
ARTICLE IN PRESS M. Abu-Serriah et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
(cut-off value 13.6 mm) compared with the ventral surface (cut-off value 9.1 mm).12 O’Brien et al., who found no differences among 145 cancers from different sites in the oral cavity, disagreed.11 Such heterogeneities have undermined the internal validity of these studies, prevented accurate comparison of data, and caused ongoing controversy. Failure of depth of invasion to consistently predict occult metastases in the neck raises questions about the accuracy of testing, and our study shows that the selection of one value or a predetermined cut-off value is not reliable. The reporting of only one value for sensitivity and specificity can provide a potentially misleading and serious oversimplification of a test’s accuracy.9 Our study shows that no specific value can consistently identify the patients who are at risk of occult metastases in the neck from the majority who are not, and the overall accuracy of using depth of invasion as a predictor in those with pT1 SCC of oral tongue is poor (66%). This is in agreement with other authors who have concluded that the use of any single predicting factor alone is neither sensitive nor specific enough to reliably select the patients who would benefit most from elective neck dissection.13,14 Although some authors think that depth of invasion is a reliable and superior prognostic marker for occult disease, local recurrence, and survival,2 our findings do not agree. The reason for this contradiction is unknown, but it is certainly feasible that a single morphological feature cannot accurately predict the biological behaviour of the tumour, which is decided by both morphological and cytogenetic factors. It is also possible that because the other studies had pooled data on tumours of various sizes or at different anatomical sites, it had skewed their findings and exaggerated the importance given to depth of invasion. The level of association between depth of invasion and occult disease may be more important with larger (T2–T4) tumours.15 Tumour thickness has not been uniformly measured to date. Depth of invasion and thickness are not the same, and a clear distinction should be made between them in published reports.16 We used depth of invasion because it reflects the aggressiveness of a tumour and its capacity to grow vertically,17 and we think that depth is more relevant to its behaviour than thickness. Geographical variations in the epidemiology of tumours and the patients studied may make it difficult to identify a consistent pattern of tumour behaviour among different head and neck oncological units across the world. Also, as there are difficulties associated with measuring the depth of invasion because specimens are processed in different ways, and because of shrinkage, variations in apparent thickness or depth because of different angles of sectioning, and because of differences in the experience of the reporting pathologist, varying degrees of measurement error can be introduced.18 This is most accentuated on diagnostic biopsies and meaningful measurement is best carried out on resected specimens. In our study, the incidence of occult disease in what is traditionally considered an early stage cancer was 36%, and in almost half of the cases (44%) there was extracapsular spread. Although the incidence of occult disease lies within
the reported range,15,19 the incidence of extracapsular spread is almost 3 times more than that reported by Nathanson et al. (15%).4 According to our findings, occult disease and the risk of extracapsular spread in patients with pT1 SCC of the oral tongue remain significant. Treatment of the neck must be considered carefully and based on the medical history, and on the clinical, imaging, and pathological assessment of individual patients. The study supports the current practice of many head and neck oncological surgeons, who consider patient-related (coexisting conditions) as well as tumour-specific (neurovascular invasion, grade, invasive front, mitotic figures, and biomarkers) factors in their decisions about the best way to manage the neck in tumours of this type. It is possible that a weighted scoring system20 that does not only consider thickness or depth, but other important patient-related and tumour-related factors, may be of more clinical importance. Advances in imaging technology, use of biomarkers, and the role of sentinel node biopsy require further research and validation. Therefore, the search to identify reliable and accurate predictor(s) of occult metastases, or approaches to the management of patients with pT1 SCC of the oral tongue, must continue. Our study has some limitations. It is retrospective and restricted to 108 patients. A larger sample size would enable better understanding of the association, but as pT1 SCC of the oral tongue comprises about 10% of all oropharyngeal SCC, an appropriately powered, prospective study in one centre may take several years to complete. Patients must continue to be managed by multidisciplinary teams until more suitable predictors or new approaches have been identified. Sentinel lymph node biopsy and advances in research into biomarkers may have an invaluable role in their future management.
Conflict of interest We have no conflicts of interest Ethics statement/confirmation of patient permission Not applicable. Financial disclosures None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. Part of this work was presented in the European Association of Cranio-Maxillofacial Surgeons, Dubrovnik, Croatia, 2012. Acknowledgments The authors would like to thank Kabir Ahluwalia, Felicity Smith and Felicity Brooks for helping with data collection.
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013
YBJOM-4528; No. of Pages 5
ARTICLE IN PRESS M. Abu-Serriah et al. / British Journal of Oral and Maxillofacial Surgery xxx (2015) xxx–xxx
References 1. El-Naaj IA, Leiser Y, Shveis M, et al. Incidence of oral cancer occult metastasis and survival of T1-T2N0 oral cancer patients. J Oral Maxillofac Surg 2011;69:2674–9. 2. Po Wing Yuen A, Lam KY, Lam LK, et al. Prognostic factors of clinically stage I and II oral tongue carcinoma: a comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 2002;24:513–20. 3. Leemans CR, Tiwari R, Nauta JJ, et al. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer 1993;71:452–6. 4. Nathanson A, Agren K, Biörklund A, et al. Evaluation of some prognostic factors in small squamous cell carcinoma of the mobile tongue: a multicenter study in Sweden. Head Neck 1998;11: 387–92. 5. Spiro RH, Huvos AG, Wong GY, et al. Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg 1986;152:345–50. 6. Lim SC, Zhang S, Ishii G, et al. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 2004;10:166–72. 7. Brown B, Barnes L, Mazariegos J, et al. Prognostic factors in mobile tongue and floor of mouth carcinoma. Cancer 1989;64:1195– 202. 8. Roland NJ, Paleri V, editors. Head and neck cancer: multidisciplinary management guidelines. 4th ed. London: ENT; 2011. 9. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993;39:561–77.
5
10. O-charoenrat P, Pillai G, Patel S, et al. Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Oral Oncol 2003;39:386–90. 11. O’Brien CJ, Lauer CS, Fredricks S, et al. Tumor thickness influences prognosis of T1 and T2 oral cavity cancer—but what thickness? Head Neck 2003;25:937–45. 12. Woolgar JA, Scott J. Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 1995;17:463–72. 13. Sparano A, Weinstein G, Chalian A, et al. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 2004;131:472–6. 14. Johnson JT, Leipzig B, Cummings CW. Management of T1 carcinoma of the anterior aspect of the tongue. Arch Otolaryngol 1980;106:249–51. 15. Morton RP, Ferguson CM, Lambie NK, et al. Tumor thickness in early tongue cancer. Arch Otolaryngol Head Neck Surg 1994;120:717–20. 16. Gluckman JL, Pavelic ZP, Welkoborsky HJ, et al. Prognostic indicators for squamous cell carcinoma of the oral cavity: a clinicopathologic correlation. Laryngoscope 1997;107:1239–44. 17. Moore C, Kuhns JG, Greenberg RA. Thickness as prognostic aid in upper aerodigestive tract cancer. Arch Surg 1986;121:1410–4. 18. Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck 2005;27:1080–91. 19. Fakih AR, Rao RS, Borges AM, et al. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Am J Surg 1989;158:309–13. 20. Martinez-Gimeno C, Rodriguez EM, Vila CN, et al. Squamous cell carcinoma of the oral cavity: a clinicopathologic scoring system for evaluating risk of cervical lymph node metastasis. Laryngoscope 1995;105:728–33.
Please cite this article in press as: Abu-Serriah M, et al. Can depth of invasion of pT1 carcinoma of the oral tongue predict occult metastases in the neck? A retrospective study. Br J Oral Maxillofac Surg (2015), http://dx.doi.org/10.1016/j.bjoms.2015.05.013