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Inicio Acta Otorrinolaringológica Española Discrepancy between clinical and pathological neck staging in oral cavity carcin...
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Vol. 69. Núm. 2.
Páginas 67-73 (Marzo - Abril 2018)
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Vol. 69. Núm. 2.
Páginas 67-73 (Marzo - Abril 2018)
Original article
DOI: 10.1016/j.otorri.2017.02.008
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Discrepancy between clinical and pathological neck staging in oral cavity carcinomas
Discrepancia entre el estadiaje clínico y patológico cervical en los carcinomas de cavidad oral
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Vânia Henriquesa,
Autor para correspondencia
vaniahenriques@gmail.com

Corresponding author.
, Eduardo Bredab, Eurico Monteirob
a Otolaryngology Department, Guimarães Hospital, Guimarães, Portugal
b Otolaryngology Department, Portuguese Institute of Oncology Dr. Francisco Gentil, Porto, Portugal
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Table 1. Correlation between clinical and pathological nodal staging.
Table 2. Prognostic factors in a Cox proportional hazard model (n=105).
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Abstract
Introduction

The presence of cervical lymph node metastases in patients with oral cavity squamous cell carcinoma reduces survival by up to 50%.

Objective

The aims of this study are to assess the accuracy of clinical N staging versus pathological N staging and its impact on survival in order to identify predictive factors associated with the presence of occult neck metastases.

Methods

Outcomes of 105 patients with oral cavity squamous cell carcinoma who underwent surgical treatment of the primary tumor and neck were retrospectively evaluated.

Results

For pN0 and pN+ patients 5-year overall survival was respectively 53% and 27%; disease specific survival was 66% for pN0 and 33% for pN+. Patients with clinical negative lymph nodes were pathologically upstaged in 62% of cases. Disease specific survival according to staging discrepancy had statistically significant impact on survival (p=0.009).

Conclusion

Clinical staging usually underestimates the presence of nodal disease. Neck dissection should be performed in cN0 oral cavity squamous cell carcinoma.

Keywords:
Oral cavity
Squamous cell carcinoma
Lymphatic metastases
Neck dissection
Survival
Tumor staging
Abbreviations:
OCSCC
OS
DSS
NRFR
ECS
FU
Resumen
Introducción

La presencia de metástasis ganglionares cervicales en los pacientes con carcinoma de la cavidad oral reduce la supervivencia hasta en un 50%.

Objetivos

Los objetivos de este estudio son evaluar la exactitud del estadiaje N clínico frente al estadiaje N patológico y su impacto en la supervivencia, de cara a identificar los factores predictivos asociados a la presencia de metástasis ocultas cervicales.

Métodos

Se han evaluado retrospectivamente los resultados de 105 pacientes con carcinoma epidermoide de la cavidad oral tras tratamiento quirúrgico del tumor primario y vaciamiento cervical.

Resultados

En los pacientes pN0 y pN+ la supervivencia global a los 5 años fue del 53 y del 27%, respectivamente, y la supervivencia específica libre de enfermedad fue del 66% para los pN0 y del 33% para los pN+. En los pacientes estadiados clínicamente como negativos se verificó un subestadiaje en el 62% de los casos. La supervivencia específica libre de enfermedad en función de la discrepancia del estadiaje tuvo un impacto estadísticamente significativo en la supervivencia (p=0,009).

Conclusión

El estadiaje clínico suele subestimar la presencia de enfermedad ganglionar. La disección cervical debe realizarse en los carcinomas de cavidad oral aunque se trate de uno cN0.

Palabras clave:
Cavidad oral
Carcinoma epidermoide
Metastasis ganglionares
Vaciamiento carvical
Supervivencia
Estadiaje tumoral
Texto completo
Introduction

Oral cancer is the sixth most common cancer worldwide with an estimated 300,000 new cases and 145,000 deaths in 2012.1,2 These tumors represents 30% of all head and neck solid tumors and histologically over 90% are squamous cell carcinomas. Oral cavity cancer biological behavior depends, among other factors, on the primary tumor location. Hard palate, superior alveolar ridge and buccal mucosa are known as having relatively indolent nature with a low risk of regional lymph node metastases, on the opposite oral tongue, floor of the mouth and inferior alveolar ridge have a high risk of apparent and occult cervical lymph node metastases.2,3

The presence of cervical lymph node metastases in patients with oral cavity squamous cell carcinomas (OCSCC) is an important adverse prognostic factor, decreasing the overall survival and disease-specific survival up to 50% and increasing neck recurrence and distant metastases rates.4,5

In fact, the seventh edition of the AJCC TNM Classification of Malignant Tumors for Head and Neck Cancers places the patients with a single regional metastatic node at an advanced stage regardless the T stage. Current lymph node staging guidelines for OCSCC are based on the clinical evaluation of lymph node size, the number of lymph nodes, and the presence of contralateral or bilateral regional disease.6 Still, this is a clinical staging system that does not incorporate pathologic data who could have the potential of altering the lymph node stage by revealing occult or additional positive lymph nodes not identified on routine physical examination or radiological evaluation. Indeed, discrepancy between clinical and pathological staging has been reported. However, the possible impact on survival, of the discrepancies between cN and pN evaluations, are still under debate. To accomplish these goals, a retrospective analysis was performed to assess the accuracy of the clinical N staging versus the pathological N staging and its impact on survival. Patients with distant metastases and patients classified as cN3 were censured due to the different prognostic survival outcome.7,8

Methods

All patients with a primary diagnosis of OCSCC proposed by the Head and Neck Interdisciplinary Tumor Board for surgical treatment with primary curative intention between the 1st of January of 2007 and the 31st of December of 2013, were enrolled in this study. The number of institutional affiliation, age, gender, histopathologic tumor classification according to the WHO International Classification of Diseases for Oncology (ICD-O-3), tumor localization, clinical TNM, cTNM, and histopathologic, pTNM, classification was registered. All patients performed neck dissection. Type and extent of neck dissection, histopathological variables were also considered points to be fulfilled in each patient. Bilateral elective neck dissection was performed for lesions located on the midline.

During the follow-up period (FU), patients were considered as being alive with and without oncologic disease, dead with local, regional or distant disease, dead without oncologic disease, and finally lost to FU. The cut-off point for statistical analysis was January 2016, encompassing a minimum FU of 24 months.

Clinical preoperative N classification was determined by neck palpation and by computed tomography and/or magnetic resonance imaging (MRI), supplemented by a positron emission tomography in advanced loco-regional disease. A clinical positive neck (cN+) notify the presence of metastatic nodal disease, and clinical negative neck (cN0) in the absence of any of this findings.

When postoperative histology proved nodal metastases the neck was classified as pathological positive neck (pN+) and the opposite were classified as pathological negative necks (pN0).

After histopathological analysis of the tumor specimen and the neck dissection, complementary treatment was done when adverse risk features as extracapsular nodal spread, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, perineural invasion or lymphovascular invasion were presented. The postoperative radiotherapy schedules were 60–66Gy in 2Gy fractions, five fractions per week over 6–6.6 weeks, and the postoperative radiochemotherapy was based on identical radiation treatment schedule plus concurrent cisplatin with 100mg per square meter of body-surface area intravenously on days 1, 22, and 43.

Statistical analysis was performed using SPSS 23.0 (SPSS Inc., Chicago, IL). Overall survival and disease-specific survival curves were calculated using the Kaplan–Meier method and statistical significance was determined by Log-Rank test. To evaluate the level of agreement of clinical and pathological classification the Kappa coefficient was executed. Statistical analysis was performed using Chi Square (χ2) and Fisher's exact test (if there were 10 or fewer patients in a group). Multivariate analysis was performed by Cox regression. Results were considered statistically significant when p<0.05.

Results

Analysis of the present study refers to the 105 patients with OCSCC. Eighty-five patients were male and 20 were female. Mean age at presentation was 55.3 years (range 38–90 years). Primary site location was as follows: oral tongue in 41.9%, floor of mouth in 35.2%, hard palate and superior and inferior alveolar ridge in 5.8%, buccal mucosa in 1.9% and a retromolar trigone in 15.2%.

Sixty-six patients presented a clinical local advanced disease (cT3T4) and 55 patients presented palpable nodal extension (cN+). Combining the cT and cN, 87 patients (82.8%) had a locoregional advanced disease.

Impact of the presence of pathological lymph node on survival outcome

The overall survival (OS) and disease-specific survival (DSS) rate is displayed in Fig. 1. The pN0 group presented a 5-year OS of 53% and DSS of 66%. The pN+ group presented 5-year OS of 20% and DSS of 33% (log-rank p=0.000 for OS and log-rank p=0.003 for DSS).

Figure 1.

Overall and disease-specific survival Kaplan–Meier curves for pN0 and pN+.

(0,17MB).

Further on, when separating the pN+ into pN1 and pN2, the results showed the same differences (log-rank p=0.000 for OS and log-rank p=0.000 for DSS) as seen in Fig. 2.

Figure 2.

Overall and disease-specific survival Kaplan–Meier curves depending on pN1 and pN2.

(0,19MB).
cN/pN assessment and accuracy

Fifty patients were staged as cN0 and 55 as cN+. Following surgery, 36 patients were staged as pN0, of these 19 were previously cN0. The discrepancy between clinical and pathological classification was 69.5%, with 48.6% of nodal disease being upstaged and 20.9% downstaged. The highest congruence between clinical and pathological N staging was seen for clinical N0 at 38% with pathological N0. The lowest correlation level was seen for cN1 (24% pN1) and cN2 (23% pN2). Concerning to cN0 patients, a 62% incidence of occult lymph node metastases was recorded, and a 55% (17 out of 31) of these had extracapsular spread.

For each patient with an assigned clinical stage, the corresponding pathological stage is summarized in Table 1, also as the rate of upstaging, downstaging or cases equally staged.

Table 1.

Correlation between clinical and pathological nodal staging.

              Stage discrepancy in N-stage (%)
  pN0  pN1  pN2a  pN2b  pN2c  Total  Upstaged  Unchanged  Downstaged 
cN0  19  10  12  50  31 (62%)  19 (38%)  – 
cN1  13  33  12 (36%)  8 (24%)  13 (40%) 
cN2a  22  8 (36%)  5 (23%)  9 (41%) 
Total  36  23  18  19  105  51(48.6%)  32(30.5%)  22(20.9%) 

As expected the level of agreement between clinical and pathological lymph node staging was poor, the Kappa coefficient was 0.07 (p>0.05). Contrary the level of agreement between cT and pT in this cohort was moderate with a Kappa coefficient of 0.58 (p=0.000).

Impact of staging discrepancy on survival

DSS function, regarding staging discrepancy, was done due to distinct nodal disease as a different treatment plan and prognosis. Four groups were established, Group 1: clinical negative neck patients with no pathological stage change; Group 2: clinical negative neck patients upstaged to positive nodal disease; Group 3: clinical positive neck patients with pathological positive neck and Group 4: clinical positive neck patients downstaged to negative nodal disease. Comparing the four groups, a statistically significant difference in survival (p=0.009) was present between these groups according to the Log-Rank test as seen in Fig. 3.

Figure 3.

Disease-specific survival according to stage discrepancy (blue line: group 1; green line: group 2; red line: group 3 and orange line: group 4). Group 1, 2, 3 and 4 had a 5-year DSS of 78%, 22%, 32% and 42% respectively.

(0,11MB).

The distribution of the pT in these four groups, is displayed in Fig. 4, the majority of the groups having an equally advanced pT stage. Relating to both pN0 groups, group 1 and 4, there is a significant difference respecting the percentage of patients with early local T stage, 47.4% and 23.5% respectively, and advanced T stage, 52.2% and 76.5%, respectively.

Figure 4.

Bar chart showing the distribution of pT between the four groups.

(0,06MB).
Prognostic factors influencing occult lymph node metastases and survival

Pathological T classification, tumor depth of invasion, tumor growth pattern, tumor differentiation pattern, vascular, perineural and bone invasion, tumor specimen margins, pathological N classification and ECS were all evaluated for prognostic purposes using Cox proportional hazards model for OS and for neck recurrence-free rate (NRFR), see Table 2. The only variable susceptible to alter overall survival on multivariable analysis was the presence of positive margins (p=0.031) and the only variable to alter regional recurrence free survival was extracapsular spread of disease (p=0.04).

Table 2.

Prognostic factors in a Cox proportional hazard model (n=105).

  Overall survival 5-yearNeck recurrence-free rate 5-year
  Risk  95% confidence interval  p value  Risk  95% confidence interval  p value 
Pathological T classification  1.1  0.9–2.1  0.103  0.8  0.3–2.5  0.180 
Tumor differentiation pattern  0.4  0.3–2.9  0.346  0.6  0.8–3.2  0.154 
Tumor growth pattern  0.9  0.7–1.9  0.464  0.8  0.3–2.3  0.754 
Depth of invasion  0.9  0.8–1.7  0.092  0.7  0.7–2.3  0.245 
Tumor specimen positive margins  1.4  1.2–1.5  0.031  0.8  0.4–1.5  0.684 
Vascular invasion  0.3  0.2–2.9  0.357  0.5  0.6–3.5  0.294 
Perineural invasion  0.5  0.7–2.8  0.193  0.9  0.9–2.4  0.121 
Pathological N classification  0.9  0.8–1.9  0.138  0.8  0.4–2.3  0.451 
ECS  0.7  0.5–2.4  0.244  1.2  1.1–1.9  0.040 

Depth of tumor invasion superior to 2mm and perineural invasion were the two prognostic factors influencing occult lymph node metastases on Chi-square test (p=0.037 and p=0.001 respectively).

Discussion

Analysis of clinical and demographic characteristics of the present study correlate with other series regarding the male predominance, age of presentation as well as primary site distribution.2,9 However, a more advanced local disease at diagnosis was presented in this cohort.

The prognostic impact of the nodal stage is well documented in the literature.3–5 Upstaging from cN0 to an pN+ has a negative impact on overall survival decreasing the 5-year survival rates to nearly one-half.10–12 In the present study, the presence of metastatic disease had a statistically significant impact on survival outcomes. A statistical significance on OS and DSS was found in the present sample, in accordance to the literature, proving that survival was reduced to a half in pN+ despite appropriate post-operative radiation or chemoradiation.

Staging concepts were created to group patients into similar categories of predictable survival and compare equivalent groups of patients in order to define the best treatment plan. Hence, patient counseling, treatment strategy, and prognosis are based on the accurate clinical staging at diagnosis, and discrepancy between clinical and pathological staging may have a negative impact on survival in clinically understaged patients, as may improve increased morbidity, due to treatment intensification in clinically overstaged patients.11,13 Clinical nodal staging is usually based on physical examination and imagiologic studies. Palpation alone has shown a limited sensitivity, specificity, and an overall accuracy of approximately, 64%, 85% and 75% respectively.13 Imaging studies increase sensitivity and specificity up to 81% and 96% and identify palpable occult nodal metastases in up to 27% of patients.13 However micrometastases, if present, are only detectable after neck dissection specimen histopathological analyze. Therefore, neck dissection combines two major advantages: accurate staging and treatment at the same time.

In 2004 Ross et al.12 published a prospective study with 61 patients with early T1–T2 OCSCC and oropharyngeal squamous cell carcinoma and found a 44% of upstaging from cN0 to pN+. Greenberg11 in 2005 reviewed 266 patients with OCSCC, 66% of the patients were T1–T2 and 24% were T3–T4, and reported an occult lymph node disease rate of 34%. A high level of overall stage discrepancy (69.5%) was found in this cohort as a high level of occult nodal disease, cN0/pN+, with a 62% incidence.

Regarding stage discrepancy, in our study, 48.6% patients were upstaged, 20.9% were downstaged and in 30.5% clinical staging was congruent with the pathological. This result is confirmed by the poor kappa agreement of 0.07 between clinical and pathological classification suggesting that in a larger number of patients the pathological classification is more advanced than the clinical one.

Biron et al.,9 in 2013 published a multi-institutional analysis of 379 patients with OCSCC, 65% of the patients in early stage and 24% in advanced stage, and achieved a higher clinical and pathological staging congruence of 68%, although their data demonstrated a staging discrepancy of 32%, there was no significantly altered survival. Previously, at this department, Ribeiro et al.14 retrospectively studied 144 patients with laryngeal and hypopharyngeal cancer and demonstrated a disparity of 60.5% of the cT3 restaged as pT4, also had a 40% of occult node metastasis, showing a tendency to understage tumors, both locally and regionally.

Gupta et al.,15 in 2015 reviewed 127 patients with OCSCC and reported a cN/pN congruence of 47%, a upstaging rate of 41% and a downstaging rate of 12%. Despite their data demonstrated a higher staging discrepancy, the survival rate was not significantly altered.

In contrast to previous studies, the presented staging discrepancy had a significant influence on survival. As seen in Fig. 3, the group of patients staged as cN0/pN0 had the best survival outcomes, as expected, with a 5-year 78% DSS. Surprisingly the group of patients staged as cN+/pN0 had a low survival (42% at 5-year). Although when analyzing the pT classification between group 1 and group 4 (see Fig. 4) a higher pT was observed in group 4. This might not be the only explanation possible, also an inaccurate radiological examination, incomplete nodal sampling during surgery or inaccurate pathological examination, may result in false pathological negative cases and can explain the treatment failure in these patients. This is, without any doubt, the group of patients that should be kept in a close FU. The poorest survival rate was observed in cN0/pN+ and cN+/pN+ patients with a 5-year survival of 22% and 32%, respectively. One of the most important findings in this study was the impact that occult regional metastasis had on survival.

In the presented group of 105 patients, 63% of the patients (n=66) were locally advanced, which creates a bias inducing a higher discrepancy. Also, this discrepancy, in addition to other possible reasons, may be due to delay between clinical diagnosis and pathologic analysis (mean delay of 2.5 months) and a low accuracy of the clinical staging tools, reflecting the subjective nature of physical examination and the inability to detect micrometastases by the imagiologic studies, resulting in upstaging. On the other hand, downstaging could result from incomplete nodal yield during neck dissection or from the sensitivity of pathologic methods used to detect occult metastases. The incidence of occult metastatic disease occurred in 62% and 55% of all occult lymph nodes had ECS leading to intensification of the treatment.

The association of ECS with poorer outcomes in OCSCC was first recognized in 70s and numerous subsequent studies13,15–20 further confirmed this association establishing the ECS presence as an adverse prognostic factor as in this study. With regard to occult lymph node metastases, depth of invasion and tumor perineural invasion are also well known histologic parameters that influence nodal disease spread21–24 therefore, selective neck dissection should be indicated in these cN0 patients with OCSCC.

This study has several limitations. This is a retrospective analysis of patients staged by four head and neck surgeons, with specimens interpreted by different pathologists. This heterogeneity however enables a more realistic representation of overall staging differences. In terms of survival analysis, one of the subgroups analyzed, namely the downstaged patients, was relatively small. This may therefore under represent a potentially significant difference in larger samples.

Conclusion

Discrepancy between clinical and pathological staging in OCSCC has significant prognostic impact on overall and disease specific survival. In the cN0 patients elective neck dissection adds low morbidity, allows to correctly stage patients and is an effective treatment modality for early metastatic disease. Depth of invasion (>2mm) and perineural invasion observed in the primary tumor can delineate a group of patients with a higher risk of harboring occult metastases. These patients should be treated electively with cervical neck dissection, nonadvocating a wait-and-see policy. Margin status and ECS, as expected, were the most important factors in OS and NRFR, respectively.

Funding

The authors have no funding, financial relationships.

Conflicts of interest

The authors have no conflicts of interest to disclose.

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