The importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the tongue

Accepted Manuscript The importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the tongue Ali-Farid Safi, MD, DMD, Andrea Grandoch, MD, DMD, Hans-Joachim Nickenig, MD, DMD, Joachim E. Zöller, MD, DMD, Matthias Kreppel, MD, DMD PII:

S1010-5182(17)30140-3

DOI:

10.1016/j.jcms.2017.04.008

Reference:

YJCMS 2658

To appear in:

Journal of Cranio-Maxillo-Facial Surgery

Received Date: 17 January 2017 Revised Date:

20 March 2017

Accepted Date: 18 April 2017

Please cite this article as: Safi A-F, Grandoch A, Nickenig H-J, Zöller JE, Kreppel M, The importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the tongue, Journal of Cranio-Maxillofacial Surgery (2017), doi: 10.1016/j.jcms.2017.04.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

The importance of lymph node ratio for locoregional recurrence of squamous cell carcinoma of the tongue

Ali-Farid Safi (MD, DMD)1,2, Andrea Grandoch (MD, DMD)

1,2

, Hans-Joachim Nickenig

1

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(MD, DMD) 1,2, Joachim E. Zöller (MD, DMD)1,2, Matthias Kreppel (MD, DMD)1,2

Department for Oral and Craniomaxillofacial Plastic Surgery, University of Cologne,

Centre of Integrated Oncology (CIO) Cologne-Bonn, Germany

Corresponding author Dr. med. Dr. med. dent. Ali-Farid Safi

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Cologne, Germany

University of Cologne Kerpener Straße 62

Germany

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50931 Cologne

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Department for Oral and Craniomaxillofacial Plastic Surgery

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e-mail: [email protected]

Phone: +49 221 478 96594 Fax: +49 221 478 7360

Funding disclosures: There are no funding disclosures from any authors

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Introduction Oral squamous cell carcinoma (OSCC) represents one of the most common malignancies worldwide (Shah and Gil, 2009). 263,000 newly diagnosed cases and 128,000 deaths are registered per year (Shah and Gil, 2009).

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Although remarkable changes in diagnostic and therapeutic techniques have occurred, survival rates have not improved over the last three decades, and still remain below 50% (Feller and Lemmer, 2012). Locoregional recurrence plays a major role for the poor prognosis

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of these patients (Patel et al., 2013). Mortality rate in these patients is approximately 90%, while the 5-year overall survival rate decreases from 90% to 30% when recurrence is

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diagnosed (Gonzalez-Garcia et al., 2009). Therefore, identification of risk factors for locoregional recurrences is of utmost importance in optimizing diagnosis and therapy of affected patients. Traditional pathological markers used in clinical routines derive from the TNM staging system. Furthermore, perineural invasion, lymphovascular invasion,

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extracapsular spread, and close or positive resection margins help to assess risk of relapse of OSCC (Ong et al., 2016). Several studies have indicated lymph node density or lymph node ratio (LNR), defined as the ratio between amount of pathological cervical lymph nodes and

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total amount of resected cervical lymph nodes, as a promising additional prognostic parameter

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for OSCC (Patel et al., 2013; Ong etal., 2016). The majority of studies have demonstrated lymph node ratio as superior to conventional nodal staging system in the prognosis of locoregional recurrences (Patel et al., 2013). However, there is a lack of data concerning the different anatomical subtypes of OSCC. Considering the different anatomical regions leads to a reduction of the number of confounding variables and thus may help to find more valuable data. In 2016 Ong et al. and Lieng et al. concluded from their study on the influence of lymph node ratio on the prognosis of SCC of the tongue that LNR is a reliable and applicable prognostic parameter (Ong et al., 2016; Lieng et al., 2016). Nevertheless, their inclusion criteria differed from each other and, furthermore, they were conducted on a relatively small 1

ACCEPTED MANUSCRIPT group of patients. To the best of our knowledge, further studies on the influence of LNR on locoregional recurrence of SCC of the tongue, besides those from Lieng et al. and Ong et al., do not exist (Lieng et al., 2016; Ong et al., 2016). Therefore, we evaluated in our retrospective chart review whether lymph node ratio could be validated as an independent risk factor for

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locoregional recurrences of tongue SCC.

Materials and methods

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Patients and data collection

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Our retrospective study followed the guidelines of the Helsinki declaration. Inclusion criteria were patients with treatment-naive squamous cell carcinoma of the tongue and primarily curative-intended surgery with negative resection margins. Exclusion criteria were neoadjuvant chemoradiotherapy, perioperative death, N3 disease, unresectable disease, synchronous malignancy, and follow-up of less than 3 months.

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Consequently our study consisted of 130 patients, who were diagnosed and treated between 2003 and 2013. Patients with second primary tumors were excluded from our study. In

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accordance with existing literature, recurrence was defined as a tumor of similar histology appearing after 6 weeks of treatment and within the first 3 years after therapy of the primary

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tumor (Gonzalez-Garcia et al., 2009). Regional recurrences were defined as recurrences within the lymph neck nodes and distant recurrences as metastases outside the head and neck region.

Clinicopathological data were collected from medical records as well as pathology and surgery reports. Parameters were carefully reviewed and included gender, age, pathological Tclassification,

pathological

N-classification,

UICC

stage,

extracapsular

spread,

lymphovascular invasion, blood vessel invasion, perineural invasion, grading, and number of resected lymph nodes. All cases were staged histopathologically according to the Union Internationale Contre le Cancer (UICC) tumor, node, metastasis (TNM) classification, 7th 2

ACCEPTED MANUSCRIPT edition. Staging was updated retrospectively to the 7th edition by using the histopathological reports. The clinicopathological characteristics and results of our univariate analysis are listed in Table 1.

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Treatment strategies

Treatment included radical surgery and neck dissection. In cases with limited disease only surgery was performed. Surgery in combination with postoperative radiotherapy was chosen

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for locally advanced disease. Radiotherapy included daily doses of 1.8–2.0 grays, 5 days per

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week, for a total dose of 60–65 Gy.

Statistical analysis

Contingency tables and χ2-tests were performed to analyze associations between clinicopathological features and recurrence. All statistics were two-sided and a p-value of

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<0.05 was considered as significant. Multivariate analysis was performed using binary logistic regression analysis. The dependent variable was presence of recurrence and the independent variable comprised the clinicopathological parameters. All statistical analyses

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were performed using SPSS Statistics 22.0 (IBM Corporation, Armonk, NY).

Results

Patient characteristics and clinicopathological data At the time of diagnosis patients had a mean age of 60.68 years and a median age of 61.5 years (with a range from 25 to 92 years), with a standard deviation of 14.35 years. The maleto-female ratio was 1.3:1, as there were 72 men and 57 women. In 23 patients (17.7%) locoregional recurrence was diagnosed within 3 years after curative-intended treatment. The mean follow-up time was 41.51 months, with a standard deviation of 35.13 months (range 3

ACCEPTED MANUSCRIPT from 3 to 92 months).

Functional results and complication rates in association with locoregional recurrence of OSCC

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We found a significant correlation in univariate analysis between locoregional recurrence and pathologic N-classification (p < 0.001), UICC stage (p < 0.0001), perineural invasion (p = 0.025), grading (p = 0.001), number of resected lymph nodes (p = 0.007) and lymph node

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ratio (p < 0.001). Risk of locoregional recurrence was higher for patients with advanced Nclassification, UICC stage, and histopathological grading.

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The median value of the LNR for lymph node patients was 6%, with a maximum of 45%. This cut-off point is in line with previous studies. We categorized the patients into a group with an LNR under the cut-off value of 6% and another group with an LNR above the cut-off value.

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Seven cases of patients with a cN0-classified lymph node status showed pathological cervical lymph nodes after elective neck dissection. Their mean lymph node ratio was 0.055. Patients preoperatively classified as cN1 had a mean LNR of 0.071 and cN2 patients a mean LNR of

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10.92%. Univariate analysis revealed a significant difference between the different cN groups (p = 0.002). In multivariate analysis (Table 2) LNR was shown as an independent risk factor

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for locoregional recurrence (p = 0.003). Patients with an LNR above 6% had a 4.81-fold higher risk of recurrence than patients with an LNR under the cut-off value.

Discussion Tumor recurrence is a major problem in treatment of patients with OSCC (Patel et al., 2013). The mortality rate of patients with recurrences is approximately 90%, despite noticeable advancements in diagnostic and therapeutic methods in recent decades (Patel et al., 2013). Recurrence rates are reported for 6.9–37.4% of patients with OSCC (Ermer et al., 2015; 4

ACCEPTED MANUSCRIPT Camisasca et al, 2011; Seoane et al., 2010.). This is in line with our findings, as locoregional relapse occurred in 17.7% of our study group. A major challenge in treatment of patients with OSCC remains in finding parameters that predict prognosis and help to identify patients at higher risk for locoregional recurrences. Usually TNM-based staging, in combination with

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pathological markers such as perineural invasion, lymphovascular invasion, extracapsular spread, and resection margins, are applied to stratify risk of recurrence for patients with OSCC (Patel et al., 2013). Within these parameters, the nodal staging system and the amount

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of resected and pathological cervical lymph nodes led to the establishment of the lymph node ratio. Multiple studies indicated this as a strong independent prognostic parameter not only for

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OSCC but also for breast, esophageal, or vulvar cancer (Patel et al., 2013; Ong et al., 2016). The largest study on the influence of LNR on OSCC was performed through a multiinstitutional study by Patel et al. in a cohort of 4254 patients (Patel et al., 2013). They validated LNR as a strong independent prognostic parameter of outcomes in OSCC and

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suggested LNR as an adjunct to the conventional TNM staging system. In contrast to their study, we did not consider the complete oral cavity but solely the tongue. Thus we aimed to reduce the amount of confounding variables, for example biological behavior or clinical

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possibility of inspection and detection, which depend on the anatomical region. To the best of our knowledge only Ong et al. in 2015 and Lieng et al. in 2016 have, to date, reported on the

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influence of LNR on SCC of the tongue (Ong et al., 2016; Lieng et al., 2016). Compared with our study their cohorts were smaller and the time period in which their patients were included was longer. Thus a potential bias based on the change of surgical technique and consequently the nodal yield may have had an influence on their results. Our univariate and multivariate analysis revealed a strong impact of LNR on locoregional recurrences of SCC of the tongue. In line with existing literature we analyzed a cut-off point of 6% (Patel et al.: LNR = 7%; Gil et al.: 6%; Sayed et al.: 8.8%) (Patel et al., 2013; Sayed et al., 2013; Gil et al., 2009). Patients with a higher LNR than 6% had a 4.81-fold higher risk of 5

ACCEPTED MANUSCRIPT locoregional recurrences than patients with lower LNR. Ong et al. reported a cut-off point the same as ours, and Lieng et al. a value of 14.3% (Ong et al., 2016; Lieng et al., 2016). However, Lieng et al. only considered patients with positive cervical lymph node status, whereas we also included patients with negative cervical lymph nodes in accordance with

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Ong et al (Lieng et al., 2016; Ong et al., 2016). The majority of existing literature showed that the highest-risk group comprised those with lymph node ratios between 13% and 20% (Prabhu et al., 2015). Our finding is similar – the group with the highest risk for locoregional

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recurrence in our study was those with a lymph node ratio of 16–20%.

Compared with the conventional nodal staging system our data suggest that LNR is a more

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superior risk factor than N-classification and number of resected lymph nodes both in univariate and multivariate analysis. The majority of published studies presented similar findings and therefore concluded that LNR is a very useful tool to apply in clinical routines to identify patients at higher risk of recurrence of OSCC (Patel et al., 2013). Nevertheless, LNR

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presents a potential bias, as it depends on surgical technique and processing of the pathological specimens. This may result in errors in the evaluation of the nodal yield (Patel et al., 2013). However, multiple studies could demonstrate, in multivariate analysis, the

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importance of LNR not only in the prognosis of OSCC, but also for other cancer sites (Patel et al., 2013; Ong et al., 2016; Prabhu et al., 2015).

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Our study demonstrates the importance of further pathological markers in evaluating the risk of locoregional recurrences of OSCC. We found a strong, significant correlation of grading with locoregional recurrence of SCC of the tongue (p < 0.001). A large number of publications outlined the significant role of histological grading in metastasis, resection margins, and survival rates, with grading being an independent prognostic factor for survival (Ermer et al., 2015; Yanamoto et al., 2012). Although multivariate analysis could not confirm the significant importance of grading, we could show a borderline statistically significant difference, with p = 0.07. Although grading is potentially subjective, and the inter- and intra6

ACCEPTED MANUSCRIPT observer validation debatable, our data suggest the importance of grading for patients with SCC of the tongue. From our univariate analysis we also detected a significant correlation between perineural invasion and locoregional recurrence. Perineural invasion occurs in up to 52% of head and neck squamous cell carcinomas (Fagan et al., 1998). According to Liebig et

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al. it is defined as a tumor in close proximity to a nerve involving at least 33% of its circumference, or existence of tumor cells within any of the three layers of the nerve sheath (Liebig et al., 2009). Various studies have demonstrated a significant association between

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perineural invasion and cervical lymph node metastasis, poor locoregional control, and poor overall survival (Liebig et al., 2009; Brandwein-Gensler et al., 2005). However, we could not

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confirm these findings through our multivariate analysis.

Conclusions

We conclude that lymph node ratio (LNR) may be a useful parameter in stratifying risk of

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locoregional recurrence in patients with squamous cell carcinoma of the tongue. Thus, LNR might help to improve diagnosis and therapy of affected patients. Nonetheless, further studies,

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especially those conducted on larger cohorts, are needed to evaluate our findings and to improve understanding of the influence of LNR in management of patients with SCC of the

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tongue.

Acknowledgements and conflict of interest The authors report no financial disclosure and no conflicts of interest.

List of references Brandwein-Gensler M, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, Hille JJ, Genden E, Urken ML and Wang BY. Oral squamous cell carcinoma: histologic risk assessment, but not 7

ACCEPTED MANUSCRIPT margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol 292: 167-178, 2005. Camisasca DR, Silami MA, Honorato J, Dias FL, de Faria PA and Lourenco Sde Q. Oral squamous cell carcinoma: clinicopathological features in patients with and without

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recurrence. ORL J Otorhinolaryngol Relat Spec 733: 170-176, 2011.

Ermer MA, Kirsch K, Bittermann G, Fretwurst T, Vach K and Metzger MC. Recurrence rate and shift in histopathological differentiation of oral squamous cell carcinoma – a long-term

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retrospective study over a period of 13.5 years. J Craniomaxillofac Surg 437: 1309-1313, 2015.

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Fagan JJ, Collins B, Barnes L, D'Amico F, Myers EN and Johnson JT. Perineural invasion in squamous cell carcinoma of the head and neck. Archives of Otolaryngology – Head & Neck Surgery 1246: 637-640, 1998.

Feller L and Lemmer J. New 'second primary' cancers. SADJ 674: 175-178, 2012.

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Gil Z, Carlson DL, Boyle JO, Kraus DH, Shah JP, Shaha AR, Singh B, Wong RJ and Patel SG. Lymph node density is a significant predictor of outcome in patients with oral cancer. Cancer 11524: 5700-5710, 2009.

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Gonzalez-Garcia R, Naval-Gias L, Roman-Romero L, Sastre-Perez J and Rodriguez-Campo FJ. Local recurrences and second primary tumors from squamous cell carcinoma of the oral

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cavity: a retrospective analytic study of 500 patients. Head Neck 319: 1168-1180, 2009. Liebig C, Ayala G, Wilks J, Verstovsek G, Liu H, Agarwal N, Berger DH and Albo D. Perineural invasion is an independent predictor of outcome in colorectal cancer. J Clin Oncol 2731: 5131-5137, 2009. Lieng H, Gebski VJ, Morgan GJ and Veness MJ. Important prognostic significance of lymph node density in patients with node positive oral tongue cancer. ANZ J Surg 869: 681-686, 2016.

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ACCEPTED MANUSCRIPT Ong W, Zhao R, Lui B, Tan W, Ebrahimi A, Clark JR, Soo KC, Tan NC, Tan HK and Iyer NG. Prognostic significance of lymph node density in squamous cell carcinoma of the tongue. Head Neck 38 Suppl 1: E859-866, 2016. Patel SG, Amit M, Yen TC, Liao CT, Chaturvedi P, Agarwal JP, Kowalski LP, Ebrahimi A,

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Clark JR, Cernea CR, Brandao SJ, Kreppel M, Zoller J, Fliss D, Fridman E, Bachar G, Shpitzer T, Bolzoni VA, Patel PR, Jonnalagadda S, Robbins KT, Shah JP and Gil Z. Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes

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Research. Br J Cancer 1098: 2087-2095, 2013.

Prabhu RS, Hanasoge S, Magliocca KR, Hall WA, Chen SA, Higgins KA, Saba NF, El-Deiry

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M, Grist W, Wadsworth JT, Chen AY and Beitler JJ. Lymph node ratio influence on risk of head and neck cancer locoregional recurrence after initial surgical resection: implications for adjuvant therapy. Head Neck 376: 777-782, 2015.

Sayed SI, Sharma S, Rane P, Vaishampayan S, Talole S, Chaturvedi P, Chaukar D,

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Deshmukh A, Agarwal JP and D'Cruz A K. Can metastatic lymph node ratio (LNR) predict survival in oral cavity cancer patients? J Surg Oncol 1084: 256-263, 2013. Seoane J, Varela-Centelles P, Lopez-Nino J, Vazquez I, Abdulkader I and Garcia-Caballero

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T. Gingival mucinous adenocarcinoma of a minor salivary gland. J Periodontol 814: 626-631, 2010.

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Shah JP and Gil Z. Current concepts in management of oral cancer surgery. Oral Oncol 4545: 394-401, 2009.

Yanamoto S, Yamada S, Takahashi H, Yoshitomi I, Kawasaki G, Ikeda H, Minamizato T, Shiraishi T, Fujita S, Ikeda T, Asahina I and Umeda M. Clinicopathological risk factors for local recurrence in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 4110: 11951200, 2012.

Table legends 9

ACCEPTED MANUSCRIPT Table 1: Analysis of locoregional recurrence factors in 130 patients with squamous cell carcinoma of the tongue

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Table 2: Multivariate analysis of significant parameters

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ACCEPTED MANUSCRIPT Table 1: Analysis of locoregional recurrence factors in 130 patients with squamous cell carcinoma of the tongue Variable

N (%)

N (%) recurrences

0.153

Gender Male

73 (56.2)

16

Female

57 (43.8)

7

< median

65 (50%)

12

> median

65 (50%)

11

57 (43.8)

9

T2

50 (38.5)

9

T3

11 (8.5)

3

T4

12 (9.3)

2

Pathological Nclassification N0

<0.001

19 (14.6)

N2

30 (23.1)

UICC Stage

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81 (62.3)

N1

2

14

<0.001

41 (31.5)

II

32 (24.6)

III

23 (17.7)

IV

34 (26.2)

Extracapsular spread No Yes Lymphovascular invasion

4

4

2

13

0.099

122 (93.8)

20

8 (6.2)

3 0.062

115 (88.5)

18

15 (11.5)

5

116 (89.2)

20

14 (10.8)

3

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No

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I

0.601

Blood vessel invasion

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Yes

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0.609

Pathological Tclassification T1

No

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0.795

Age

Yes

p

Perineural invasion

0.025

No

112 (86.2)

16

Yes

18 (13.8)

7

Grading

0.001

Well

12 (9.2)

0

Moderate

105 (80.8)

16

Poor

13 (10)

7

Number of resected lymph nodes 0–10

0.007 24 (18.5)

4

11–15

18 (13.8)

3

16–20

16 (12.3)

5

21–25

16 (12.3)

4

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12 (9.2)

0

>31

44 (33.8)

7

Lymph node ratio

<0.001 65

8

>0.06

65

15

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<0.06

ACCEPTED MANUSCRIPT Table 2: Multivariate analysis of significant parameters EXP (B)

Standard error

p

95% CI for EXP (B)

Lymph node density

4.81

1.134

0.003

3.032–7.821

Grading

4.691

0.852

0.07

0.883–24.915

UICC

1.236

0.175

0.857

0.124–12.357

Perineural invasion 2.447 Number of resected lymph 0.998 nodes N-classification 1.201

0.759

0.238

0.553–10.835

0.014

0.913

0.52

0.725

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Variable

0–1.441

0.343–11.567