Significance of radiologically determined prognostic factors for head and neck cancer Lodder, W.L.

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1 UvA-DARE (Digital Academic Repository) Significance of radiologically determined prognostic factors for head and neck cancer Lodder, W.L. Link to publication Citation for published version (APA): Lodder, W. L. (2013). Significance of radiologically determined prognostic factors for head and neck cancer General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 18 Nov 2018

2 C h a p t e r2 Tumor thickness in oral cancer using an intra-oral ultrasound probe. Wouter L. Lodder Hendrik J. Teertstra I. Bing Tan Frank A. Pameijer Ludi E. Smeele Marie-Louise F. van Velthuysen Michiel W. M. van den Brekel Eur Radiology 2011;21(1):

3 Chapter 2 ABSTRACT Objective To investigate tumor thickness measurement with an intra-operative ultrasound (US) probe. Methods A retrospective data analysis was undertaken for a total of 65 patients with a T1-2 oral cavity cancer, who were seen at a tertiary referral centre between 2004 and The correspondence between tumor thickness measured by ultrasonography and histopathology was assessed by Pearson s correlation coefficient, and also between tumor thickness and the development of neck metastasis. Results In 11 cases, intra-oral measurement was not optimal due to limited mouth opening (n=2) or impossibility to depict the lesion (n=9). Tumor thickness measured by US correlated well with histopathology (n=23, R 2 =0.93). Tumor thickness of 7mm carries a risk of lymph node metastasis of 12%, whereas in tumors exceeding 7mm this risk is 57% (p=0.001). Twenty-five percent developed neck metastasis and 19% had local recurrence. Conclusion Tumor thickness is an important predictive marker for lymph node metastases. As such, it can help in decision-making with regard to management of the primary tumor and neck. Based upon our findings, a wait-and-see policy is only warranted for superficial lesions with tumor thickness of less than 7mm, but only if regular follow-up using US-guided aspiration of the neck is ensured. 30

4 TUMOR THICKNESS MEASURED BY ULTRASOUND INTRODUCTION Predicting the risk of lymph node metastases in clinically N0 patients with oral cancer is very important in treatment planning of the neck. Tumor thickness has been shown to be one of the most important features in predicting lymph node metastases in oral cancer. Since 1986 several studies have focused on tumor thickness. 1-3 In 2005 Pentenero et al. 4 showed in a large review cut-off points as prognostic factors ranging from 2 mm to 10 mm. Table 1 shows cutoff values for all studies used in this article and studies performed after the review of Pentenero et al. Not only tumor thickness is an important predictive factor, other characteristics of the tumor are: epidemiologic parameters such as age, sex, race, alcohol, and/ or tobacco intake clinical parameters (TNM stage, site) and histopathological parameters such as the tumor border, being either infiltrative or more pushing, perineural invasion and vascular invasion. 4-6 Recently, it has also been shown that gene expression of the primary tumor correlates with the risk of cervical metastases. 7 Separate from predicting the development of lymph node metastases, the measurement of tumor thickness may have implications for the treatment of the primary tumor as well. Limited oral cancer in general is treated surgically, using postoperative radiotherapy or chemoradiation in the case of unfavourable histopathological features. In superficial oral cancer, apart from local excision, CO 2 laser resections as well as photodynamic therapy (PDT) have been shown to yield excellent results as well. 8 Chapter 2 However, the results of these alternative treatments are very much dependent on the amount of tumor infiltration (i.e. tumor thickness). Although depth of infiltration is predictive for the chance of local recurrence as well 6, it is not routinely used as an indication for postoperative radiotherapy in most clinics. A recent study showed that tumor thickness is also predictive for the risk of contralateral cervical metastasis in tongue carcinoma. 9 To measure tumor thickness, different techniques are available. Several studies compared intra-oral ultrasound with magnetic resonance imaging (MRI) or computed tomography (CT). 10,11 In 1989, Iro and Nitsche 12 showed that using a miniaturised transducer enables the depiction of tumors of the anterior tongue and the floor of the mouth without artifacts. They found this method to be superior to conventional ultrasound for this region. 31

5 Chapter 2 Since June 2007 we have been using a new intra-operative transducer (Philips IU-22 L 15-7; 7-15 MHz). In this study, we present our results with respect to the feasibility of ultrasound measurement of intraoral tumor thickness, correlation with the presence of lymph node metastases as well as correlation with MRI, with histopathology as the golden standard. Reviewed articles Year Number patients TNM Site N+ (mm) Survival (mm) Spiro et al Any TN Oral cavity 2 2 Mohit et al T1-2N0 FOM Rasgon et al Any TN Oral cavity 5 - Woolgar et al T2 Tongue 8 8 Martinez et al Any TN Oral cavity 7 - Fukano et al Any TN Tongue 5 - Shintani et al Any TN Oral cavity 8 - Byers et al Any TN Tongue 4 - Scheer et al Any TN Oral cavity Veness et al Any TN Tongue 5 5 Jing et al Any TN Oral cavity Clark et al Any TN Oral cavity 5 - Wallwork et al Any TN FOM Suzuki et al T1-2N0 FOM 5 - Okura et al Any TN Tongue Kim et al Any TN Oral cavity 8 8 El-Okeily et al T1-3N0 Oral cavity Natori et al Any TN Tongue 8 8 Huang et al Any TN Oral cavity 4 - Table 1. Reviewed articles from 1986 till 2009, displayed with number of patients, TNM stage, studied site, and cut-off values found by ultrasonography for N0 versus pathological N+. Abbreviations: FOM = floor of mouth; N+: depth invasion significant for nodal involvement. METHODS AND MATERIALS Selection criteria All patients with stage T1-T2 oral cancer planned for transoral excision or photodynamic therapy (PDT) in our department were included (n=65). All patients were seen between 2004 and Participants Ages ranged from 42 to 89 years (mean 65 years) and the sex ratio was 34 men 32

6 TUMOR THICKNESS MEASURED BY ULTRASOUND to 31 women. The cancers were localised in the tongue (n=38), the floor of the mouth (n=22) and elsewhere in the mouth (n=5). Clinical T-stages of the 65 patients were as follows: T1 (n=50), T2 (n=15), N-stages were: N0 (n=59), N1 (n=4) and N2 (n=2). Intraoral US was used in all 65 patients, and MRI was performed in 36 cases. MRI was only performed as part of the preoperative treatment planning, in patients possibly applicable for transoral excision. In 13 cases the lesion was not found on MRI, because of superficial growth. These lesions were interpreted as minimal lesions of less than 1 mm thick. Patients underwent transoral excision (n=30), CO 2 laser excision (n=3) or photodynamic therapy (PDT) (n=29), or a combination of surgery with postoperative radiotherapy (n=3). Within the group of patients treated with PDT (n = 29) the localisations were as follows: 13 tumors of the tongue, 13 in the floor of the mouth and 3 elsewhere in the mouth. Twelve patients underwent a primary neck dissection. Histopathological data on thickness were available in all 33 surgically treated patients. Chapter 2 Current treatment protocol Ultrasound measurement of tumor thickness is currently used to select patients treatable with PDT. In tumors of less than 5 mm thick PDT treatment can be used as light penetration up to 1 cm. Especially in cases where surgery carried a risk of Warthin s duct obstruction or a marginal mandibulectomy we choose PDT. For thicker tumors we always perform a local excision. The neck is staged using ultrasound-guided aspiration cytology (USgFNAC) and a sentinel node procedure in the case of a negative USgFNAC and treatment of the primary with transoral excision. For negative sentinel nodes a wait-and-see policy is the standard. In the case of positive sentinel nodes or a positive USgFNAC a neck dissection is carried out. Measurement of tumor thickness For ultrasound measurement of tumor thickness an intra-operative transducer (Philips IU-22, L15-7; 7-15 MHz) was used (N = 44). Before June 2007, a small parts transducer probe (5-7 MHz) was used in 21 patients. Tumor thickness was measured by placing the probe directly on the lesion. The same radiologist (H.J.T.) performed all intra-oral measurements on the outpatient clinic, one or 2 weeks before surgery without anaesthesia. 33

7 Chapter 2 Using an ultrasound probe or MRI, in fact the thickness of the tumor is measured and not the depth of infiltration from an imaginary line at the level of the mucosal surface. So in this study we measured maximal tumor thickness, also histopathological, and not the depth of infiltration. On histological sections, the tumor thickness was measured using the ocular micrometer. The MRI examinations were performed on a 3.0 T scanner (Philips Achieva release 3.2.1, Philips Medical Systems, Best, the Netherlands) using a dedicated 16-channel SENSE neurovascular coil. The following series were acquired: STIR TSE COR, TR (Repetition time), IR (inversion time), TE (echo time) 3880/180/20 ms, ETL:12, FOV 300/228/40mm, matrix:320/320, 2nex, slice thickness 4mm;STIR TSE TRA,TR/ IR/TE 4228/180/20, ETL:12, FOV : 180/200/80 mm, matrix 300/312, 2 nex, SW 3,5 mm, T1 TSE TRA, TR/TE: 780/10, ETL:5, FOV 180/180/80, matrix 384/384, 2 nex, slice thickness: 3,5mm ; T1 3D Thrive (performed after intravenous injection of 15 cc gadoterate meglumine (Dotarem), TR/TE: 5/2,22, ETL:90,TA:10, FOV230/272/220, matrix 288/288, 2 nex Slice thickness: 0,8 mm; T1 TSE COR ( post contrast): TR/ TE:812/10, ETL:6, FOV: 180/150/96mm, matrix: 320/320,3 nex,slice thickness 3,5 mm. The ultrasound findings of the patients treated with PDT and CO 2 laser could not be correlated with histopathological measurements, for obvious reasons. Figure 1 shows the measurement of a tumor using the 3 techniques. Statistical analysis The correlation between tumor thickness as measured by ultrasound, MRI and in the histopathological sections was evaluated. Pearson s product correlation analysis was performed on all data in order to determine the overall correlation between them. The correlation between tumor thickness and the presence of lymph node metastases was analysed using the Chi-squared test. 34

8 TUMOR THICKNESS MEASURED BY ULTRASOUND a b A c Chapter 2 Figure 1. Tumor thickness measured on histology, US and MRI. a Histological section showing a tumor of the tongue. Tumor thickness is 8 mm (A indicates diameter). b US picture of the same tumor of the tongue. c Tumor thickness measured on MRI. RESULTS Tumor thickness In all 65 patients US measurement of the oral lesion was obtained. For 11 cases intraoral measurement was not optimal due to limited mouth opening (n=2) or the impossibility of depicting the lesion (n=9). There was no difference between the old and the new transducer probe (4 versus 7 cases). Tumor thickness ranged from 1 mm to 35 mm, with an average of 8 mm. Magnetic resonance imaging was performed in 36 patients. Tumor thickness ranged from 1 mm to 24 mm, with an average of 5 mm. On histopathology (n=33), tumor thickness ranged from 1 mm to 35 mm with an average of 8 mm. 35

9 Chapter 2 Correlation with histopathology Correlation between ultrasound and histopathology could be made in 31 cases. In two surgically treated patients ultrasound could not be performed. Correlation between MRI and histopathology could be made in 22 cases. Pearson s product correlation (Figs. 2 and 3) between US and MRI imaging was significantly different. With a correlation product of R 2 =0.87, US correlated better with histopathology than MRI (R 2 =0.54). Comparing the old transducer used before 2007 and the new intraoral probe, the Pearson s product was respectively 0.05 versus 0.93 (Fig. 4) ,00 20,00 Histopathological tumor thickness 30,00 20,00 10,00 Histopathological tumor thickness 15,00 10,00 5,00 R Sq Linear = 0,865 R Sq Linear = 0,536 0,00 0,00 0,00 5,00 10,00 15,00 Ultrasound tumor thickness 20,00 25, MRI tumor thickness Figure 2. Pearson s correlation between tumor thickness measured on histological section and by ultrasound (n=32). The Pearson s correlation product was R 2 =0,87. Figure 3. Correlation between tumor thickness on histological section and by MRI (n=22). The Pearson s correlation product is R 2 =0,54. 12,00 40,00 10,00 Histological tumor thickness 8,00 6,00 Histological tumor thickness 30,00 20,00 10,00 4,00 R Sq Linear = 0,048 R Sq Linear = 0,927 2,00 0,00 3,00 4,00 5,00 6,00 Ultrasound tumor thickness 7,00 8,00 0,00 5,00 10,00 15,00 Ultrasound tumor thickness 20,00 25,00 Figure 4. Correlation between tumor thickness on histological section and by ultrasound. Sub-selection between a Philips small parts transducer probe (5-7MHz), n=9 (left) and the intraoperative transducer probe, Philips IU-22 (right), n=23. 36

10 TUMOR THICKNESS MEASURED BY ULTRASOUND Neck node metastases In total, 12 patients (N0 =6, N1 =4, N2 =2) initially underwent 12 neck dissections, 6 therapeutic and 6 elective. Of these 12 neck dissections, 9 were pathological N+ (pn+). In total, 53 clinically N0 patients did not undergo a neck dissection initially. During follow-up, 7 patients in this wait and see group developed a neck node metastasis. Of these 7 patients 3 also had local recurrence. Thus, a total of 16 of the 65 (25%) patients were pn+. Of these 16 patients in 13 cases ultrasound could be performed. Chapter 2 Correlation of tumor thickness and lymph node involvement In the patients with available histopathology measurement histopathological measured tumor thickness was used to correlate with lymph node metastasis. For the 32 cases in which histopathology was not possible the ultrasoundmeasured thickness was used (only measured with the new intraoral transducer probe). Therefore in total correlation was possible in 56 patients (Fig. 5). One metastasis (1/20=5%) was found in patients with a histological tumor thickness of 3 mm or less. Four patients had cervical metastasis with tumor thickness between 4 and 7 mm (4/22 = 18%). When the tumor thickness exceeded 7 mm the cervical metastases rate increased to 57% (8/14). The difference in metastasis for 7 mm tumor thickness is significant at p = Table 2 shows sensitivity and specificity by cut-off value. 20 pn-stadium positive (pn+) negative (pn0) 15 Count mm 4-7 mm 7-10 mm >9 mm Tumor thickness by ultrasonography Figure 5. Relationship between tumor thickness and cervical metastases. Tumor thickness measured by intra-oral ultrasound probe, if not available measured by histopathology (n =56). Grey represents the patients with no neck metastasis within the 2-year follow up period. Dark grey represents the patients with positive neck nodes during the follow up period. 37

11 Chapter 2 Correlation of tumor thickness and lymph node involvement by site Within the group of tongue carcinomas (n=36) none of the patients had cervical metastasis with histological tumor thickness of 3 mm or less (Fig. 6) Three patients had cervical metastasis with tumor thickness between 4 and 7 mm (3/18 = 17%). When the tumor thickness exceeded 7 mm the cervical metastasis rate increased to 44% (4/9). The difference in metastasis for 7 mm tumor thickness is significant with p = Within the group of floor of mouth carcinomas (n=15) none of the patients had cervical metastasis with histological tumor thickness of 7 mm or less. When the tumor thickness exceeded 7 mm the cervical metastasis rate increased to 80% (4/5). The difference in metastasis for 7-mm tumor thickness is significant at p = Cut-off point Sensitivity Specificity P-value Total group (n=56) 3 mm/ < 3 mm 90% 26% mm/ < 4 mm 95% 33% mm/ < 5 mm 88% 39% mm/ < 6 mm 90% 53% mm/ < 7 mm 88% 57% mm/ < 8 mm 87% 64% <0.001 Tongue carcinomas (n=36) 3 mm/ < 3 mm 100% 21% mm/ < 4 mm 100% 26% mm/ < 5 mm 89% 29% mm/ < 6 mm 92% 42% mm/ < 7 mm 89% 44% mm/ < 8 mm 86% 43% Floor of mouth carcinomas (n=15) 3 mm/ < 3 mm 100% 40% mm/ < 4 mm 100% 50% mm/ < 5 mm 100% 67% mm/ < 6 mm 100% 80% mm/ < 7 mm 100% 80% mm/ < 8 mm 100% 100% < mm/ < 8 mm 100% 100% <0.001 Table 2. Sensitivity, specificity and significance level versus cut-off points for tumor thickness. 38

12 TUMOR THICKNESS MEASURED BY ULTRASOUND Local recurrence versus tumor thickness Tumor thickness measured by histopathology was used for correlation with local recurrences. In our series, 12 patients (12/65 = 19%) had a local recurrence within the follow-up period. In 5 cases, recurrences occurred at a thickness of 0-4 mm (5/20=25%), none in the 4-7-mm group, 2 in the 7-10-mm group (2/7= 22%) and no local recurrence occurred in the group with tumor thickness of >9 mm. There was no significant correlation between chance of local recurrence and tumor thickness. Chapter 2 15 pn-stadium positive (pn+) negative (pn0) pn-stadium positive (pn+) negative (pn0) 6 10 Count Count mm 7-10 mm >9 Tumor thickness by ultrasonography mm 7-10 mm >9 Tumor thickness by ultrasonography Figure 6. Relationship between tumor thickness and cervical metastases divided by site. Tumor thickness measured by intra-oral ultrasound probe, if not available measured by histopathology. Grey represents the patients with no neck metastasis within the 2-year follow up period. Dark grey represents the patients with positive neck nodes during the follow up period. Left represents the group with tongue carcinoma s (n=36), Right represents the group with floor of mouth carcinoma s (n=15). DISCUSSION Synopsis of key/new findings Although this is a retrospective study, although all measurements were performed only once and by the same observer and although histology was not available in all patients this study demonstrates that the measurement of tumor thickness with the new generation of intraoral US transducers correlates well with histopathological thickness in oral cavity cancer (R 2 =0.93). Between 2004 and 2007, we used a non-dedicated small parts transducer for measurement and this yielded inferior results (R 2 =0.05). This clearly shows that it is necessary to use a dedicated small parts transducer to obtain reliable measurements. 39

13 Chapter 2 In our study, MRI correlated less well with histopathology than US (R 2 =0.54). Worldwide MRI measurements are regularly performed in patients with oral cancer. In our series, 13 of the 36 patients had lesions that could not be measured by MRI because of superficial growth and these were treated with PDT. Therefore histopathological measurement could not be performed. We were able to perform correlation in 26 cases, in these cases both MRI and histopathological measurements were available, in those few cases the correlation was only R 2 =0.54. In this study, the risk of metastasis in the neck with tumor thickness of 6 mm or less was 12% (5 out of 42) whereas when tumor thickness was 7 mm or more this risk was 57% (8 out of 14). For tongue carcinoma, the risk of metastasis in the neck with tumor thickness of 6 mm or less was 11% (3 out of 27) whereas when tumor thickness was 7 mm or more this risk was 44% (4 out of 9). For floor of mouth carcinoma, the risk of metastasis in the neck with tumor thickness of 6 mm or less was 0% (0 out of 10) whereas when tumor thickness was 7 mm or more this risk was 80% (4 out of 5). From these data we conclude that within the overall group 7 mm tumor thickness is the cut-off value that optimally stratifies patients at a low versus high risk of development of neck node metastases (p=0.001). However, as shown in Table 2, it is a matter of compromise between the sensitivity and specificity of a given cut-off value to make a choice for the optimal value. With a cut-off point of 7 mm, the sensitivity in our study was 85% and the specificity 57% (Table 2). By dividing the group by site, the optimal cutoff value would be 7 mm for both groups, although this was determined within small groups (n=36 vs. n=15). Comparisons with other studies Our findings, using the dedicated intra-oral/intra-operative probe confirm those published by Iro and Nitsche. 12 Rasgon et al. 3 showed that the percentage of cervical lymph node metastases in lesions less than 5 mm thick was significantly lower compared with those with lesions with a thickness more than 5 mm. Also Shintani et al. 10, who studied 24 patients, found a strong correlation between tumor thickness measured with US and histology (Pearson s product R 2 = 0.98). They found that tumors thicker than 20 mm showed discordant results, possibly caused by tissue constriction during fixation with formalin. Lesions smaller than 10 mm showed a significantly better correlation. 40

14 TUMOR THICKNESS MEASURED BY ULTRASOUND Shintani et al. 10, also compared the accuracy of US and MRI in assessing tumor thickness. They found that ultrasound and MRI correlated well with histopathology. However, MRI could not identify most of the tumors less than 5.0 mm thick. Preda et al. 11 showed a significant direct correlation between the measured histological and measured MRI tumor thickness (correlation coefficient=0.80, p<0.0001). In the literature, discussion remains as to which cut-off point is optimal 1-4,10-30 and in the more recent literature, cut-off points range between 3 and 8 mm. 2,13 In a large clinical review by Pentenero et al. 4, tumor thickness was shown to be an important parameter for predicting nodal metastases and for survival. They showed that in the literature the cut-off thickness predicting neck metastasis and survival varied from 1.5 mm to 10 mm. Thus, it remains difficult to choose a reliable cut-off point for elective neck treatment and/or adjuvant radiotherapy. The indication for elective neck treatment is mainly based on the expected risk of occult metastases. With respect to this risk assessment, Spiro et al. 1 retrospectively analysed tumor thickness in 92 patients treated with surgery for tongue and floor of mouth carcinomas. They concluded that for clinically N0 oral cancer, elective neck dissection was indicated in patients with depth invasion of more than 2 mm because in these tumors the risk of metastases reached 40%. Fukano et al. 13 on the other hand showed that tongue tumors exceeding 5 mm carried a risk of 65% for neck metastases whereas those infiltrating 5 mm or less had a risk of only 6% (significant difference, p= ). Chapter 2 A meta-analysis by Huang et al. 2 showed an association between tumor thickness and cervical lymph-node involvement and they stated that the optimal cut-off point for tumor thickness is 4 mm. For oral cavity tumors thicker than 4 mm, prophylactic neck management should generally be recommended according to this study. At present, little is known about the correlation between tumor thickness and local recurrences of oral cavity carcinomas. In our study, there was no significant difference in local recurrences using the cut-off point for tumor thickness of more or less than 7 mm. Yuen et al. 6 showed in 2002 that tumor thickness is prognostic for both nodal and local recurrence in oral carcinomas. With a tumor thickness less than 3 mm 0% had local recurrences, and 8% had nodal 41

15 Chapter 2 metastases; tumor thickness of more than 3 mm and up to 9 mm had 44% subclinical nodal metastasis and 7% local recurrence; tumor thickness of more than 9 mm had 53% subclinical nodal metastasis and 24% local recurrence. In our series, not enough patients with tumor thickness of 10 mm or more were included to compare these results. Extracting the results from Spiro et al. 1 local recurrence occurred in 5% of the group of tumors with thickness < 2mm (2/40), 9% (3/35) within the group 3-8 mm thick and 25% (4/17) for the group with thickness > 9 mm. Local recurrence occurred significantly more in the group with tumor thickness of more than 8 mm, at p= 0,035. Yet more factors like perineural invasion, radical operation, postoperative treatment and N-staging should also be considered in relation to local recurrence. 6 Clinical applicability of the study From this and other studies it is clear that state-of-the-art ultrasound has a high correlation with histopathological thickness. 10,12 Ultrasound thus seems to be the optimal technique in patients with no limited mouth opening or base of tongue involvement. Ultrasound measurement is more reliable than MRI for the measurement of tumor thickness, especially in superficial lesions. All currently available literature shows depth of invasion or tumor thickness measurements of the primary tumor, most often only in small groups. The identification of a cut-off with adequate utility for clinical decision-making requires large studies and independent validation. Tumor thickness is an important predictive marker for lymph node metastases. As such it can help in decision-making with regard to management of the primary tumor and neck. Based upon our findings a wait-and-see policy is only warranted in superficial lesions with tumor thickness less than 7 mm, but only if regular follow-up using US-guided aspiration of the neck is ensured. 31,32 42

16 TUMOR THICKNESS MEASURED BY ULTRASOUND References 1. Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. (1986) Predictive value of tumor thickness in squamous carcinomas confined to the tongue and floor of the mouth. Am J Surg 152: Huang SH, Hwang D, Lockwood G, Goldstein DP, O Sullivan B. (2009) Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity. Cancer 115(7): Rasgon BM, Cruz RM, Hilsinger RL, Sawicki, (1988) Relation of lymph-node metastasis to histopathologic appearance in oral cavity and oropharyngeal carcinoma: a case series and literature review. Laryngoscope; 99: Pentenero M, Gandolfo S, Carrozzo M. (2005) 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; 27: Brandwein-Gensler M, Teixeira MS, Lewis CM et al. (2005);Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival.am J Surg Pathol. 29(2): Po Wing Yuen A, Lam KY, Lam LK et al. (2002) 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 24(6): Roepman P, de Jager A, Groot Koerkamp MJ, Kummer A, Slootweg PJ, Holstege FC. (2006) Maintenance of head and neck tumor gene expression profiles upon lymph node metastasis. Cancer Res.; 66(23): Biel MA, (2007) Photodynamic Therapy Treatment of Early Oral and Laryngeal Cancers. Photochem Photobiol.; 83(5): Bier-Laning CM, Durazo-Arvizu R, Muzaffar K et al. (2009) Primary tumor thickness as a risk factor for contralateral cervical metastases in T1/T2 oral tongue squamous cell carcinoma. Laryngoscope 119(5): Shintani S, Yoshihama Y, Ueyama Y et al, (2001) The usefulness of intraoral ultrasonography in the evaluation of oral cancer. Int J Oral Maxillofac Surg; 30: Preda L, Chiesa F, Calabrese L et al., (2006) Relationship between histologic thickness of tongue carcinoma and thickness estimated from preoperative MRI. Eur Radiol; 16: Iro H, Nitsche N. (1989) Intra-oral sonography in neoplasms of the mouth and base of the tongue. HNO; 37(8): Fukano H, Matsuura H, Hasegawa Y, Nakamura S. (1997) Depth of invasion as a predictive factor for cervical lymph node metastasis in tongue carcinoma. Head Neck: 19(3): Mohit-Tabatabai MA, Sobel H, Rush BF, Mashberg A. (1986) Relation of thickness of floor of mouth stage I and II cancers to regional metastasis. Am J Surg; 152(4): Woolgar JA, Scott J, (1995) Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck; 17(6): Martínez-Gimeno C, Rodriguez E, Vila CN, Varela CL, (1995) Squamous cell carcinoma of the oral cavity: a clinicopathologic scoring system for evaluating risk of cervical lymph node metastasis. Laryngoscope; 105(7): Byers RM, El Naggar A, Lee YY et al. (1998) Can we detect or predict the presence of occult nodal metastases in patients with squamous carcinoma of the oral tongue? Head Neck; 20(2): Scheer M, Kubler A, Manawi NN, Reuther T, Zöller JE. (2005) Endosonographic imaging of tumor thickness in oral squamous cell cancer and its effect on the incidence of lymph node metastases. Mund Kiefer Gesichtschir; 9(5): Veness MJ, Morgan G, Sathiyaseelan Y, Gebski V. (2005) Anterior tongue cancer and the incidence of cervical lymph node metastases with increasing tumour thickness: should elective treatment to the neck be standard practice in all patients? ANZ J Surg; 75(3): Jing J, Li L, He W, Sun G. (2006) Prognostic predictors of squamous cell carcinoma of the buccal mucosa with negative surgical margins. J Oral Maxillofac Surg; 64(6): Chapter 2 43

17 Chapter Clark JR, Naranjo N, Franklin JH, de Almeida J, Gullane PJ. (2006) Prognostic variables in N0 oral carcinoma. Otolaryngol Head Neck Surg; 135(5): Wallwork BD, Anderson S, Coman WB. (2007) Squamous cell carcinoma of the floor of the mouth: tumour thickness and the rate of cervical metastasis. ANZ J Surg; 77(9): Suzuki M, Suzuki T, Asai M et al. (2007) Clinicopathological factors related to cervical lymph node metastasis in a patient with carcinoma of the oral floor. Acta Otolaryngol Suppl; 559: Okura M, Iida S, Aikawa T et al. (2008) Tumor thickness and paralingual distance of coronal MR imaging predicts cervical node metastases in oral tongue carcinoma. AJNR Am J Neuroradiol 29(1): Kim SY, Roh J, Kim JS et al. (2008) Utility of FDG PET in patients with squamous cell carcinomas of the oral cavity. Eur J Surg Oncol; 34: El-Okeily M, El-Bouihi M, Ricard AS et al. (2008) Mouth floor and mobile tongue epidermoid carcinomas thickness: prognostic value. Rev Stomatol Chir Maxillofac; 109(2): Natori T, Koga M, Anegawa E et al. (2008) Usefulness of intra-oral ultrasonography to predict neck metastasis in patients with tongue carcinoma. Oral Dis; 14(7): Jones KR, Lodge-Rigal R, Reddick RL et al., (1992) Prognostic factors in the recurrence of stage I and II squamous cell cancer of the oral cavity. Arch Otolaryngol Head Neck Surg; 118: Hosal AS, Unal O, Ayhan A, (1998) Possible prognostic value of histopathologic parameters in patients with carcinoma of the oral tongue. Eur Arch Otorhinolaryngol; 255: Nathanson A, Agren K, Biorklund A et al., (1989) Evaluation of some prognostic factors in small squamous cell carcinoma of the mobile tongue: a multicentre study in Sweden. Head Neck; 11: Van den Brekel MW, Stel HV, Castelijns JA, Croll GJ, Snow GB.(1991) Lymph node staging in patients with clinically negative neck examinations by ufltrasound and ultrasound-guided aspiration cytology. Am J Surg. 162(4): Van den Brekel MW. (1996) US-guided fine-needle aspiration cytology of neck nodes in patients with N0 disease. Radiology. 201(2):

18 TUMOR THICKNESS MEASURED BY ULTRASOUND Letter to the Editor European Radiology 2011; 2011 Jun;21(6): Sir, It emerges from the interesting recent article by Lodder WL et al. 1 on tumor thickness in oral cancer using an intraoral ultrasound probe, that tumor thickness is indeed one of the important predictive markers for lymph node metastasis and can definitely help in decision making regarding management of the primary tumors and neck. We consider that this type of investigation will be helpful in preoperative treatment planning in primary centres or in developing countries where the organizational structure and economical factors limit the use of CT and MRI. In the present study, the authors have appropriately compared the tumor thickness obtained by ultrasound with that obtained by histopathology. It is a known fact that histopathological prognosticators, especially those associated with invasive tumor margins, are potent determinants of lymph node metastasis, prognosis and thus survival rate. These routinely possible (by H & E staining) and significant histopathological prognosticators are: histopathological grades (especially multifactorial and invasive tumor margin grading system), lymphovascular invasion, perineural invasion, bone involvement (in case of floor of the mouth in the present study) and sialoadenotropism/ ductal invasion. Furthermore, histological subtyping/ categorization is also of import as adenosquamous, undifferentiated, spindle cell and basaloid variants of oral squamous cell carcinoma have poor prognosis due to extensive and early local spread and regional and distant metastasis. However verrucous carcinoma and carcinoma cuniculatum are very well differentiated and have a good prognosis. But unfortunately it has been observed in many recent articles related to determination of lymph node metastasis and prognosis that these vital histopathological prognosticators are not compared and co-related with the investigating parameter (example: USG for tumor thickness in the present study). In routine practice, for any individual patient all these parameters are always considered together. Such comprehensive analysis has paramount importance and should have been done and mentioned in the study for better understanding of the investigating parameter and its together consideration. In our opinion the efficacy of consideration of all parameters together for lymph node metastasis, prognosis and survival will be better than taking into account Chapter 2 45

19 Chapter 2 only a single parameter. In the histopathological analysis of lymph nodes, apart from the positive and negative status, the laterality of positive nodes, number of positive nodes, size of the metastatic deposit, anatomical level of involvement, extracapsular spread and extent and embolisation/permeation of perinodal lymphatics plays substantial role in validating prognosis and survival. However these easily interpretable but equally important parameters are unfortunately not regarded in the present study and many other studies published in the literature. Inclusion of such touchstones and its co-relation with the investigating parameter will help in better evaluation of this aspect of oral cancer. In the present study, the tumor thickness in T1 and T2 stages of oral cancer and N1 and N2 stages of nodal metastasis is not revealed. However, the article mentions tumor thickness being predictive for the risk of contralateral cervical metastasis in tongue carcinoma. But the authors have failed to discuss this point fully in the study. We believe that the inclusion of these points would have strengthened the study. The given retrospective study mentions only a single radiologist being involved. Although the chances of objective variation are very less, the values in this study were in millimetres which are likely to differ among different radiologists. Hence use of multiple radiologists and their degree of agreement using Kappa test should be done in future similar studies. Sachin C. Sarode & Swarada Karmarkar & Gargi S. Sarode Department of Oral Pathology and Microbiology, Dr. D.Y. Patil Dental College and Hospital, Maheshnagar, Pimpri, Pune 18 Maharashtra, India Reference 1. Lodder WL, Teertstra HJ, Tan IB, Pameijer FA, Smeele LE, van Velthuysen MLF, van den Brekel MWM (2010) Tumour thickness in oral cancer using an intra-oral ultrasound probe. Eur Radiol Jan;21(1):

20 TUMOR THICKNESS MEASURED BY ULTRASOUND Author Reply European Radiology 2011;21(6): Dear Editor, We appreciate the comments made by the authors with regards to our paper Tumor thickness in oral cancer using an intraoral ultrasound probe. It emerges that intra-oral ultrasound is helpful in decision-making regarding management of the primary tumor and neck. We do agree with the authors that tumor thickness is not the only important predictive factor for lymph node metastasis, as we describe in the introduction section of our article, other important characteristics of the tumor are: epidemiologic parameters such as age, sex, race, alcohol, and/or tobacco intake, clinical parameters (TNM stage, site) and histopathological parameters such as the tumor border, being either infiltrative or more pushing, perineural invasion and vascular invasion. 1 In the opinion of the authors all parameters for lymph node metastasis should be studied together. In 2002 Yuen et al. 2 studied the prognostic significance of multiple factors for subclinical nodal metastasis in 72 patients with multivariate analysis. In the multivariate analysis, tumor thickness was the only significant independent prognostic factor for subclinical nodal metastasis (p=0.031). T stage, vascular invasion, lymphatic vessel invasion, perineural invasion and shape were not significant prognostic for nodal metastasis. Most of the described factors are not routinely determined, or only significant in univariate analysis (for example: basaloid variants 3, sialoadenotropism/ductal invasion 4 ) and therefore will be more difficult to use as prognosticator. In 2005 Woolgar 5 reviewed histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. The influence of sialoadenotropism (extension of dysplasia down the orifices of minor salivary glands) and ductal invasion on survival is uncertain but both features are associated with increased local recurrence and second primary tumors. This conclusion is formulated based on the study by Daley et al. 4 In 2.14% (26/1216) salivary ductal invasion was present, based upon those 26 cases they concluded: routine measured depth of ductal invasion appears to have no significance with respect to prognosis. Furthermore the authors state bone involvement is significant histopathological prognostic, however in our study we only included T1 or Chapter 2 47

21 Chapter 2 T2 squamous cell carcinomas of the tongue or floor of mouth. Hence bone involvement was not present in our population. With this study we tried to present our results with respect to the feasibility of ultrasound measurements of intra-oral tumor thickness, for that reason we published this article in a radiologically orientated journal. No statement was made to evaluate the significance of tumor thickness on prognosis and survival rate. Since June 2007 we have been using a new intra-operative transducer. In our current treatment protocol, in tumors of less than 5-mm thick, PDT treatment can be used as light penetration up to 1 cm. With this first analysis we showed that ultrasound with our new probe gave a Pearson s correlation up to R 2 =0.93. To have a similar test result in every patient, one radiologist performed all measurements. It requires large studies and independent validation to evaluate interand intraobserver variability and the identification of a cut-off value with adequate utility for clinical decision-making. To conclude, we agree with the authors tumor thickness is an important, but not the only, predictive marker for lymph node metastasis, as such, it can help in decision-making with regard to management of the primary tumor and neck. Our purpose of this study was to evaluate only the feasibility of intra-oral measurements with our new probe. Wouter L. Lodder, Department of Head and Neck surgery and Oncology, Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. 48

22 TUMOR THICKNESS MEASURED BY ULTRASOUND References 1. Lodder WL, Teertstra HJ, Tan IB, Pameijer FA, Smeele LE, van Velthuysen MLF, van den Brekel MWM (2010) Tumour thickness in oral cancer using an intra-oral ultrasound probe. Eur Radiol Jan;21(1): Po Wing Yuen A, Lam KY, Lam LK, Ho CM, Wong A, Chow TL, Yuen WF, Wei WI (2002) 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 24: Witzenburg SM, Niehans GA, George E, Daly K, Adams GL (1998) Basaloid squamous carcinoma: a clinical comparison of two histologic types with poorly differentiated squamous cell carcinoma. Otolaryngol Head Neck Surg 119: Daly TD, Lovas JG, Peters E, Wysocki GP, McGaw TW (1996) Salivary gland duct involvement in oral epithelial dysplasia and squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81: Woolgar JA (2006) Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol 42: Chapter 2 49

23 Chapter 2 Letter to the editor: Is preoperative ultrasonography accurate in measuring tumor thickness and predicting the incidence of cervical metastasis in oral cancer? Oral Oncology 2010;46(8):627; To the editor: We would like to take the opportunity to comment on the recently published article by Taylor et al. 1 Is preoperative ultrasonography accurate in measuring tumor thickness and predicting the incidence of cervical metastasis in oral cancer?. As the authors mention, tumor thickness in oral cancer is an important predictive marker for lymph node metastases and can be useful for the management of primary tumor and neck. Since 1986, several studies 2 have focused on the prognostic importance of tumor thickness of primary oral cancer. Natori et al. 3 correlated tumor thickness as measured by both histopathology and ultrasound to the risk of lymph node metastasis. In multivariate analyses, tumor thickness on ultrasound was a significant predictor of neck metastases. (Cut-off point 8 mm, expected risk of 67.4% on metastatic disease, p=0.04.) Given the available evidence in the literature, we disagree with Taylor et al. 1 asserting they are the first to correlate tumor thickness measured by ultrasonography with the risk of cervical lymph node metastases. We further wondered why the authors proposed a cut-off of 5 mm for elective treatment of the neck based upon a relatively limited series of 21 cases, with an expected risk of 65% on metastatic disease. Although they do not explicitly recommend foregoing neck dissection for patients with smaller tumor thickness, they do also not caution the reader to draw this conclusion when this would be highly warranted. According to the upper limit of a 95% confidence interval around the observed proportion of zero nodal metastases among four patients with a tumor thickness below 5 mm, their data are consistent with up to 55% of all such patients having nodal metastases. In 2005 Pentenero et al. 4 showed in a large systematic review cut-off points as prognostic factors ranging from 2 to 10 mm. In a recently published meta-analysis based on 16 studies Huang et al. 5 found an optimal cut-off point of 4 mm. With a cut-off point of 4 mm the false negative percentage was 4.5 (95% CI ) against 16.6% (95% CI ) for cut-off point of 5 mm. The identification of a cut-off with adequate utility for clinical decision-making 50

24 TUMOR THICKNESS MEASURED BY ULTRASOUND requires large studies and independent validation. To conclude, the report by Taylor et al. 1 provides an impressive confirmation of the accuracy of tumor thickness measurements by ultrasound compared with histology. However, their study is not the first to relate tumor thickness measured by ultrasound with nodal metastasis, nor is it large enough to provide meaningful information on a thickness cut-off for the identification of patients unlikely to benefit from a neck dissection. As a consequence, recommendations have to be made with caution, taking into account statistical uncertainty. Irrespective of tumor thickness, a wait and see policy has been shown to be warranted only in case of regular follow-up, using ultrasound guided fine needle aspiration of the neck. 6,7 Chapter 2 Wouter L. Lodder, Michael Hauptmann, Hendrik J. Teertstra, Michiel W.M. van den Brekel, and Alfons J. Balm, Department of Head and Neck surgery and Oncology, Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. References 1. Taylor SM, Drover C, MacEachern R, et al. Is preoperative ultrasonography accurate in measuring tumor thickness and predicting the incidence of cervical metastasis in oral cancer? Oral Oncol 2010;46: Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. Predictive value of tumor thickness in squamous carcinomas confined to the tongue and floor of the mouth. Am J Surg 1986;152: Natori T, Koga M, Anegawa E, et al. Usefulness of intra-oral ultrasonography to predict neck metastasis in patients with tongue carcinoma. Oral Dis 2008;14: 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: Huang SH, Hwang D, Lockwood G, Goldstein DP, O Sullivan B. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity. Cancer 2009;115(7): van den Brekel MW, Stel HV, Castelijns JA, Croll GJ, Snow GB. Lymph node staging in patients with clinically negative neck examinations by ultrasound and ultrasound-guided aspiration cytology. Am J Surg 1991;162(4): van den Brekel MW. US-guided fine-needle aspiration cytology of neck nodes in patients with N0 disease. Radiology 1996;201(2):

25 Chapter 2 Author Reply Oral Oncology 2010;46(8):628; To the editor: I appreciate the comments made by Dr. Lodder and colleagues with regards to our paper Is preoperative ultrasonography accurate in measuring tumor thickness and predicting the incidence of cervical metastasis in oral cancer. There appears to be no debate that preoperative ultrasound is helpful in measuring tumor depth and therefore can be used for planning the subsequent treatment of the clinically negative neck. I thank him for stressing to the readership of Oral Oncology that there remains considerable debate as to the appropriate cut-off depth for performing an elective neck dissection in early oral cancer. I do agree with Dr. Lodder that given our sample size of 21 patients it is difficult to draw any conclusions with regards to this specific cut-off point. In our cohort of patients, however, none had cervical metastasis if their tumor thickness was less than 5 mm and this was found to be statistically significant with a p-value of His group does refer to a recently published metanalysis published by Huang et al. out of the University of Toronto where the optimal cut-off point was determined to be 4 mm. The review included 1136 patients and there was a statistically significant difference between the 4 mm and 5 mm tumor thickness cut-off points. Our conclusion that an elective neck dissection should be strongly considered if the tumor thickness is 5 mm or above remains true in our study group, however, there is mounting evidence that a significant number of patients (16.6% according to the review by Huang et al.) with 4 mm thick tumors would also benefit from an elective neck dissection. I think most of us would agree that ongoing research in this area is required before any conclusive statements are made with regards to this. Our Head and Neck Oncology group at Dalhousie University in Halifax, Nova Scotia, Canada initiated this study in 2001 and the study was closed in We first presented our preliminary data locally in Atlantic Canada in 2002 and the completed results published in Oral Oncology were presented at our Canadian Otolaryngology- Head and Neck Surgery Annual Meeting in May of The manuscript was prepared in the summer of 2004 and was not submitted for publication in Oral Oncology until after the International Oral Oncology Meeting in Toronto, Canada in July of This delay in 52

26 TUMOR THICKNESS MEASURED BY ULTRASOUND publication is regrettable and the responsibility is mine. At the time of the manuscript preparation in 2004, to my knowledge, our group was the first to correlate preoperative tumor thickness, as measured by ultrasonography, to the risk of nodal metastasis. I once again thank Dr. Lodder and his colleagues for their comments and for citing some recently published papers that I have overlooked given the delay in publication. S. Mark Taylor Section of Head and Neck Surgery/Reconstructive Surgery, Division of Otolaryngology-Head and Neck Surgery, Dalhousie University, Halifax, Nova Scotia, Canada. Chapter 2 53