The importance of lymph node ratio for patients with mandibular infiltration of oral squamous cell carcinoma

Accepted Manuscript The importance of lymph node ratio for patients with mandibular infiltration of oral squamous cell carcinoma Ali-Farid Safi, MD, DMD, Martin Kauke, MD, Andrea Grandoch, MD, DMD, HansJoachim Nickenig, MD, DMD, Joachim Zöller, MD, DMD, Matthias Kreppel, MD, DMD PII:

S1010-5182(18)30097-0

DOI:

10.1016/j.jcms.2018.03.021

Reference:

YJCMS 2939

To appear in:

Journal of Cranio-Maxillo-Facial Surgery

Received Date: 4 December 2017 Revised Date:

5 March 2018

Accepted Date: 28 March 2018

Please cite this article as: Safi A-F, Kauke M, Grandoch A, Nickenig H-J, Zöller J, Kreppel M, The importance of lymph node ratio for patients with mandibular infiltration of oral squamous cell carcinoma, Journal of Cranio-Maxillofacial Surgery (2018), doi: 10.1016/j.jcms.2018.03.021. 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 patients with mandibular infiltration of oral squamous cell carcinoma

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Ali-Farid Safi (MD, DMD)1 , Martin Kauke (MD)1, Andrea Grandoch (MD, DMD)1, HansJoachim Nickenig (MD, DMD)1, Joachim Zöller (MD, DMD)1, Matthias Kreppel (MD,

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

Cologne, Germany

Corresponding author

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

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DMD)1

Department for Oral and Craniomaxillofacial Plastic Surgery University of Cologne

50931 Cologne

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Kerpener Straße 62

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Germany

e-mail: [email protected]

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

ACCEPTED MANUSCRIPT Summary

Purpose: Lymph node ratio (LNR) essentially improves assessment of prognosis and therapeutic decision making for patients with oral squamous cell carcinoma, as it considers

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both the number of positive lymph nodes and the number of dissected lymph nodes.

Mandibular infiltration by oral squamous cell carcinoma is a vital clinicopathological feature, significantly worsens prognosis. However, to the best of our knowledge, data on the influence

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of LNR on prognosis for patients with OSCC and mandibular infiltration are not available.

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Materials and Methods: A retrospective chart review of 89 patients with treatment-naive oral squamous cell carcinoma and histopathologically proven mandibular infiltration (pT4a) was performed. Exclusion criteria were primarily curative intended surgery (radical tumor resection, neck dissection and segmental mandibulectomy) with negative resection margins. Exclusion criteria were neoadjuvant chemoradiotherapy, erosive infiltration of the mandible, T4b classification, perioperative death, unresectable disease, synchronous malignancy,

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follow-up < 3 months, and inadequate information to correctly determine clinicopathological characteristics.

Results: We observed a significant correlation on univariate analysis between locoregional

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recurrence and pathologic N classification (p=0.004), perineural invasion (p=0.005) and lymph node ratio (p<0.001). On multivariate analysis, lymph node ratio (p=0.028) was shown

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to be an independent indicator for locoregional recurrence.

Conclusion: LNR predicted locoregional recurrence better than the conventional nodal staging system and therefore might serve as a more precise risk stratification tool. LNR > 7% led to a 11.419-fold higher risk for locoregional recurrence of patients with mandibular infiltration due to OSCC.

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ACCEPTED MANUSCRIPT INTRODUCTION Oral squamous cell carcinoma (OSCC) accounts for 5.6% of all malignant tumors worldwide, making it the sixth most common malignancy (Jemal et al. 2009). The annual incidence is approximately 263,000 worldwide and the mortality rate is approximately 128,000 per year

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(Jemal et al. 2009). However, in spite of significant diagnostic and therapeutic advances, survival rates could not be improved in the past three decades and remain below 50% (Vormittag et al. 2009). Once a locoregional relapse is diagnosed, the survival rate

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deteriorates from 90% to 30% (González García et al. 2009). However, prognosis and

therapeutic decision making significantly depend upon the localization of OSCC [2] [3].

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Mandibular infiltration by an oral squamous cell carcinoma is an essential clinicopathological feature of the tumor, which worsens prognosis to a 5-year survival rate of 29% and thus requires an aggressive therapeutic regimen (Jones et al. 1997). Oral cavity cancer adjacent to the mandible may invade the bone either through direct extension or perineural spread, and

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therefore surgical intervention requires besides tumor resection and neck dissection a segmental mandibulectomy (Mucke et al. 2011). Hence, the patient morbidity increases significantly, as the mandible plays a fundamental role in speech, mastication, airway

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maintenance and swallowing. Especially medullary bone invasion of the mandible is associated with a significantly higher risk of locoregional recurrence and therefore requires

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additional postoperative radiotherapy (Shaw et al. 2004). However, parameters allowing a more precise prognostic assessment are necessary to better stratify the risk of affected patients (Safi et al. 2017a). One of the most important clinicopathological parameters to predict prognosis is the evaluation of the cervical lymph node status based upon the N classification of the Union Internationale Contre le Cancer (UICC) / American Joint Committee on Cancer (AJCC) (Shah and Gil 2009) (Lee et al. 2017) (Yildiz et al. 2016). It regards the number, size, and localization of the neck lymph nodes and the prognosis generally worsens with advanced stage (Lee et al. 2017). However, in recent years it has been shown that consideration of the 2

ACCEPTED MANUSCRIPT ratio between the number of positive lymph nodes and the number of removed cervical lymph nodes (lymph node ratio [LNR]) may essentially improve assessment of prognosis and therapeutic decision making (Safi et al. 2017a) (Lemieux et al. 2016) (Patel et al. 2013) (Gonzalez-Garcia et al. 2009). Furthermore, it was demonstrated that LNR predicted

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locoregional recurrence better than the conventional N classification (Safi et al. 2017b) (Patel et al. 2013) (Gonzalez-Garcia et al. 2009). However, there is a paucity of data on how LNR affects prognosis depending on localization. In recent studies, we highlighted that for

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squamous cell carcinoma of the cheek and the tongue, that LNR is also a strong independent risk factor for locoregional recurrence in these tumor sites (Safi et al. 2017a) (Safi et al.

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2017b). Therefore, we suggested the implementation of LNR into the N classification (Safi et al. 2017c) (Safi et al. 2017d). As, to the best of our knowledge, there are no available data considering the importance of LNR for locoregional recurrence in patients with OSCC with mandibular infiltration, we aimed to investigate this issue in a retrospective chart review of 89

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patients treated in our department between 2002 and 2013.

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ACCEPTED MANUSCRIPT MATERIALS AND METHODS Patients and data collection Our retrospective study followed the guidelines of the Declaration of Helsinki. Inclusion criteria were patients with treatment-naive oral squamous cell carcinoma and

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histopathologically proven mandibular infiltration (pT4a), and primarily curative intended surgery (radical tumor resection, neck dissection and segmental mandibulectomy) with

negative resection margins. Exclusion criteria were neoadjuvant chemoradiotherapy, erosive

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infiltration of the mandible, T4b classification, perioperative death, unresectable disease, synchronous malignancy, follow-up < 3 months, and inadequate information to correctly

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determine clinicopathological characteristics. Our study consisted of 89 patients who were diagnosed and treated between 2002 and 2013 at our Department for Oral and Craniomaxillofacial Plastic Surgery. In accordance with existing literature, recurrence was defined as a tumor of similar histology appearing after 6 weeks of treatment and within the

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first 3 years after therapy of the primary tumor (González García et al. 2009). Regional recurrences were defined as recurrences within the lymph neck nodes and distant recurrences as metastasis outside the head and neck region. Due to the retrospective nature of this study, it

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was granted an exemption in writing by the University Hospital institutional review board. Clinicopathologic data were collected from medical records as well as pathology and surgery

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reports. Parameters were carefully reviewed and included gender, age, pathologic T classification, pathologic N classification, UICC stage, extracapsular spread, lymphovascular invasion, blood vessel invasion, perineural invasion, grading, and number of resected lymph nodes. We defined lymph node ratio as the ratio between positive lymph nodes and the total 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 edition. The staging was updated retrospectively to the 7th edition by using the histopathological reports. 4

ACCEPTED MANUSCRIPT Treatment strategies Treatment included radical surgery and neck dissection, depending on the tumor stage. Patients who were clinically classified as cN0 received selective neck dissection at least of the level I to III/IV. Patients with clinically positive cervical lymph node status (cN+) or

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histopathologically proven lymph node metastasis (pN+) were treated with a modified radical neck dissection of levels I to V. Whenever bilateral cervical lymph node metastasis was

present, we performed a bilateral neck dissection. Surgery in combination with postoperative

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radiotherapy was chosen for locally advanced disease. Radiotherapy included daily doses of

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1.8 to 2.0 Gy 5 days per week for a total dose of 60 to 65 Gy.

Tissue samples

Histopathological analysis of lymph nodes was performed at the Institute of Pathology, University of Cologne. After the lymph nodes were fixed in 5% formaldehyde, they were

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embedded in paraffin. Longitudinal bisection and further sectioning were obtained if the thickness was > 2 mm. From each paraffin block, two-step sections were cut at 50-µm levels. Afterwards, staining was performed with hematoxylin and eosin, as well as periodic

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acid−Schiff, to histologically examine the presence or absence of metastatic disease. All

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specimens were evaluated by two independent, experienced pathologists.

Statistical analysis

Contingency tables and the χ2 test were performed to analyze associations between clinicopathological features and recurrence. A p value < 0.05 was considered significant. The dependent variable was the presence of recurrence, and the independent variable the clinicopathological parameters. Kaplan-Meier analysis was performed to estimate the events of interest for locoregional recurrence, and the log-rank test was performed to determine differences. In multivariate analysis, the Cox proportional hazard model was performed to 5

ACCEPTED MANUSCRIPT estimate the impact of significant patient and tumor-related factors from univariate analysis on locoregional recurrence. Cutoff values for LNR and LODDS were obtained from receiver operating characteristic curves and the Youden index (Youden index = sensitivity + specificity − 1) (Fluss et al. 2005). For internal validation of our values, we performed B =

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150 bootstrap replications. All statistical analyses were performed using SPSS Statistics 24.0

RESULTS

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Patient characteristics and clinicopathologic data

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(IBM Corporation, Armonk, NY, USA).

At the time of diagnosis, patients had a mean age of 63.37 years and a median age of 64.0 years (range, 33 to 92 years) with a standard deviation of 11.91 years. The male to female ratio was 1.96 to 1, as there were 59 men and 30 women. In 14 (15.7%) patients, locoregional recurrence was diagnosed within 3 years after curative intended treatment. The median

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follow-up time was 34 months, with a range of 3 to 102 months.

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Functional results and complication rates in association to locoregional recurrence The results of our univariate analysis are listed in Table 1. We observed a significant

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correlation in univariate analysis between locoregional recurrence and pathologic N classification (p=0.004; Figure 1), perineural invasion (p=0.005), and lymph node ratio (p<0.001; Figure 2). The risk of locoregional recurrence was higher for patients with advanced N classification, perineural invasion, and a lymph node ratio above 7%. Patient characteristics depending upon the different nodal staging systems are listed in Table 2. The median value of the LNR for lymph node positive patients was 7% with a range between 1.3% to 29.4%. With the Youden index, the optimal cut-off point for LNR was calculated as 7%.

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ACCEPTED MANUSCRIPT In multivariate analysis (Table 3), the lymph node ratio (p=0.028) was shown as an independent indicator for locoregional recurrence. LNR > 7% led to an 11.419-fold higher

DISCUSSION

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risk for locoregional recurrence.

The specific subsites of the oral cavity significantly affect prognosis, as the biological

aggressiveness and the pathway of metastasizing clearly differ throughout the various regions

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of the oral cavity [2] [3]. Infiltration of the mandible plays a crucial role for prognosis, as it

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decreases the 5-year survival rate to 29% and at the same time requires an aggressive therapeutic strategy to minimize the risk of locoregional recurrence (Jones et al. 1997). Based on our statistical analysis, we found that the presence of cervical lymph node metastasis was significantly associated with locoregional recurrence (p = 0.004) for patients with OSCC and mandibular infiltration. Generally, the N classification is based upon localization, size, and

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number of pathologically altered cervical lymph nodes (Shah and Gil 2009). Numerous studies highlighted its paramount influence on prognosis and therapeutic decision making for

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patients with OSCC (Shah and Gil 2009) (Lee et al. 2017) (Patel et al. 2013) (Woolgar et al. 1995). Usually, an advanced N classification is associated with a higher risk of locoregional

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recurrence and therefore worsens the prognosis (Shah and Gil 2009) (Patel et al. 2013). We noticed in our study cohort, that only 2.3% of our patients with pN0 showed locoregional recurrence, whilereas 28.9% of patients with pN+ experienced locoregional relapse. This confirms the assumption that the exact assessment of cervical lymph node status plays a crucial role in the prognosis (Shah and Gil 2009) (Lee et al. 2017) (Safi et al. 2017d) (Safi et al. 2017e). However, in recent years, several studies have indicated certain shortcomings of the N classification, especially because it does not consider the extent of the dissected lymph nodes (Patel et al. 2013) (Gonzalez-Garcia et al. 2009). Therefore, the concept of lymph node

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ACCEPTED MANUSCRIPT ratio, based on the ratio between the number of positive lymph nodes and the number of dissected lymph nodes, has been increasingly explored (Vinh-Hung et al. 2004) (Patel et al. 2013). For different cancer sites, such as the breast, stomach, or colorectum, the prognostic superiority of the LNR over the conventional N classification was demonstrated (Woodward

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et al. 2006) (Vinh-Hung et al. 2004) (Patel et al. 2013). In 2013, Patel et al performed a

multicenter study in 4254 patients with oral squamous cell carcinoma and confirmed the

results from the above-mentioned cancer localizations (Patel et al. 2013). They pointed out

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that, in consideration of a growing trend towards more aggressive adjuvant treatment

strategies for oral squamous cell carcinoma, LNR might serve as a better risk stratification

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tool than the conventional N classification (Patel et al. 2013). To the best of our knowledge, our investigation is the first study confirming the importance of LNR for patients with OSCC leading to mandibular infiltration. Our multivariate analysis results show that LNR is a strong independent risk factor for locoregional recurrence, and patients who have an LNR > 7% are

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at an 11.419-fold greater risk. Interestingly, within our multivariate analysis, N classification was not determined as an independent risk factor for locoregional recurrence, probably due to the significant importance of LNR. Our cutoff value of 7% is in accordance with that of Patel

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et al. (LNR threshold, 7%), which represents the largest study on the importance of LNR for oral squamous cell carcinoma to date (Patel et al. 2013). In addition, we examined which of

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our LNR subgroups had the highest risk for locoregional recurrence. Similiar to published data, we found that those with an LNR between 16% and 20% most frequently experienced locoregional relapse (Lieng et al. 2016, Ong et al. 2016) (Prabhu et al. 2015). Shrime et al. and Urban et al. stated that, for patients with an LNR > 12.5%, adjuvant radiotherapy should be recommended, as in their study cohort it led to an improved 5-year survival rate (Shrime et al. 2009) (Urban et al. 2013). Both study groups emphasized that their findings indicated that an increased LNR correlates with an insufficient surgical resection of cervical lymph nodes and therefore necessitates adjuvant treatment strategies (Shrime et al. 2009) (Urban et al. 8

ACCEPTED MANUSCRIPT 2013). Prabhu et al. Recommended that, for patients with head and neck cancer, in addition to radiotherapy, chemotherapy should be urgently considered for patients with an LNR > 20% (Prabhu et al. 2015). They found that, even those patients in whom the resection margins were negative and no extracapsular growth was detectable, the risk for locoregional recurrence was

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significantly increased (Prabhu et al. 2015). However, several studies showed that the

prognostic superiority of LNR might be confounded by a limited nodal yield, as surgical technique, pathological analysis, and patient-related as well as tumor-related parameters

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significantly influence the number of dissected lymph nodes (Ebrahimi et al. 2014) (Chou et al. 2010). Furthermore, it was observed that the prognostic ability of LNR might be

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insufficient for patients with negative lymph node status, as it is equal to the conventional nodal staging system (pN0 and LNR, 0%) (Wang et al. 2008) (Vinh-Hung et al. 2004). However, we could delineate, in our multivariate analysis, the prognostic superiority of LNR towards N classification, and therefore we suggest consideration of LNR as a risk

OSCC.

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stratification tool for locoregional recurrence of patients with mandibular infiltration due to

Furthermore, we found, in our univariate analysis, a significant correlation between perineural

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invasion and locoregional recurrence (p=0.005). According to Liebig et al., perineural invasion is defined as a tumor in close proximity to a nerve involving at least 33% of its

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circumference or the existence of tumor cells in any of the 3 layers of the nerve sheath (Liebig et al. 2009). Numerous studies have indicated a significant association between perineural invasion and regional lymph node metastasis, poor locoregional control, and worse overall survival (Liebig et al. 2009) (Brandwein-Gensler et al. 2005). Similar to our study, Shaw et al. were able to demonstrate that perineural invasion was highly predictive for locoregional recurrence within their cohort of patients with OSCC invading the mandible (Shaw et al. 2004). However, in our multivariate analysis, perineural invasion could not be demonstrated as an independent risk factor for locoregional recurrence. 9

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CONCLUSION For patients with mandibular infiltration of oral squamous cell carcinoma (OSCC), a lymph node ratio (LNR) > 7% is associated with a significantly higher risk for locoregional relapse.

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LNR predicts locoregional recurrence better than the conventional nodal staging system, and therefore might serve as a more precise risk stratification tool for locoregional recurrence. However, further studies, especially those conducted in larger cohorts, are necessary to

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evaluate our findings and to improve understanding of the influence of the lymph node ratio

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on OSCC with mandibular infiltration.

Conflict of interest

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None

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breast cancer. J Clin Oncol 24:18: 2910-2916, 2006. Woolgar, J. A., J. Scott, E. D. Vaughan, J. S. Brown, C. R. West and S. Rogers. Survival, metastasis and recurrence of oral cancer in relation to pathological features. Ann R Coll Surg Engl 77:5: 325-331, 1995. Yildiz, M. M., I. Petersen, E. Eigendorff, P. Schlattmann and O. Guntinas-Lichius. Which is the most suitable lymph node predictor for overall survival after primary surgery of head and neck cancer: pN, the number or the ratio of positive lymph nodes, or log odds? J Cancer Res Clin Oncol 142:4: 885-893, 2016. 14

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Figure 1. Kaplan-Meier curve of the influence of pN classification on locoregional recurrence.

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Figure 2. Kaplan-Meier curve of the influence of lymph node ratio on locoregional

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recurrence.

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ACCEPTED MANUSCRIPT Table 1. Patient characteristics and univariate analysis Number of patients

p Value 0.290

59 30

11 3

44 45

7 7

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0.963

44 15 30

1 5 8

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0.004

0.573

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80 9

0.261

73 16

10 4

0.694

79 10 74 15

5 72 12

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Gender Male Female Age < Median > Median Pathologic N classification N0 N1 N2 Extracapsular spread No Yes Lymphovascular invasion No Yes Blood vessel invasion No Yes Perineural Invasion No Yes Grading Well Moderate Poor Number of resected lymph nodes 0-10 11-15 16-20 21-25 26-30 >31 Lymph node ratio <0.07 >0.07 Treatment Surgery Surgery + radiotherapy Surgery +

Number of recurrences

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Variable

4 20 11 12 4 38

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0.005 8 6 0.141 0 10 4 0.399 0 4 2 3 1 6 <0.001

61 28

2 12 0.079

6 54 29

0 6 8

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radiochemotherapy

ACCEPTED MANUSCRIPT Table 2. Patient characteristics depending upon the different nodal staging systems Variable

pN0

pN +

LNR <0.07

LNR >0.0 7

23 21

36 9

38 23

21 7

24 20

20 25

31 30

13 15

39 5

41 4

55 6

25 3

37 7

36 9

52 9

39 5

40 5

54 7

2 12 6 2 4 18

SC

M AN U 21 7

25 3

TE D

3 38 3

AC C

Well Moderate Poor Number of resected lymph nodes 0-10 11-15 16-20 21-25 26-30 >31

43 1

31 14

56 5

18 10

2 34 9

4 50 7

1 22 5

2 8 5 10 0 20

2 12 8 7 4 28

2 8 3 5 0 10

EP

Male Female Age < Median > Median Extracapsular spread No Yes Lymphovascular invasion No Yes Blood vessel invasion No Yes Perineural Invasion No Yes Grading

RI PT

Gender

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Table 3. Multivariate analysis of significant parameters Standard error

p Value

95% Confidence interval

2.157

1.469

0.601

0.121-38.391

2.243

0.743

0.277

0.523-9.628

11.419

1.106

0.028

1.307-99.798

AC C

EP

TE D

M AN U

SC

N classification (N0 vs N+) Perineural invasion (yes vs. no) Lymph node ratio (<0.07 vs. >0.07)

Hazard ratio

RI PT

Variable

AC C

EP

TE D

M AN U

SC

RI PT

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ACCEPTED MANUSCRIPT Figure 1

AC C

EP

TE D

M AN U

SC

RI PT

Kaplan-Meier curve on the influence of pN classification on locoregional recurrence

ACCEPTED MANUSCRIPT Figure 2

AC C

EP

TE D

M AN U

SC

RI PT

Kaplan-Meier curve on the influence of lymph node ratio on locoregional recurrence