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The effects of tumor size, degree of differentiation, and depth of invasion on the risk of neck node metastasis in squamous cell carcinoma of the oral cavity.

Abstract

Cervical lymph node metastasis is the most important prognostic factor in patients with head and neck carcinoma. We retrospectively analyzed the effects of three different variables--tumor size, degree of differentiation, and depth of invasion--on the risk of neck node metastasis in 50 adults who had been treated with surgery for primary squamous cell carcinoma of the oral cavity. Primary tumor depth and other pathologic features were determined by reviewing the pathology specimens. Preoperatively, 36 of the 50 patients were clinically NO; however, occult lymph node metastasis was found in 13 of these patients (36.1%). The prevalence of neck node metastasis in patients with T1/T2 and T3/T4 category tumors was 51.5 and 58.8%, respectively. The associations between the prevalence of neck node metastasis and both the degree of differentiation and the depth of invasion were statistically significant, but there was no significant association between neck node metastasis and tumor size. We conclude that the prevalence of neck lymph node metastasis in patients with squamous cell carcinoma of the oral cavity increases as the tumor depth increases and as the degree of tumor differentiation decreases from well to poor, as has been shown in previous studies. It is interesting that tumor size, which is the most important component of the TNM system, was not significantly associated with neck node involvement.

Introduction

Squamous cell carcinomas of the oral cavity are relatively common among the head and neck cancers. As they grow, they invade the surrounding tissue and metastasize to cervical lymph nodes. This is believed to occur as a result of the filtering effect of the rich lymphatic system on the tumor cells' route of drainage. The lymphatic system captures the cancer cells and prevents them from spreading to the other organs. Cervical lymph node metastasis is the single most important prognostic factor for patients with head and neck carcinoma. (1-4) Therefore, appropriate management of the neck is important.

During the evaluation of cancer patients, the TNM classification has traditionally been used as an objective, internationally accepted system. However, several studies have shown that many factors other than size, node involvement, and metastasis have varying degrees of influence on a particular patient's prognosis. These factors include histologic grade, degree of differentiation, depth of invasion, tumor thickness, perineural perivascular invasion, growth pattern, and epidemiologic factors such as age, sex, race, and alcohol and tobacco use. (5,6) Since there are associations between these factors and prognosis, it is logical to think that there might also be an association between these factors and cervical lymph node involvement.

The prefixes c and p are used to designate clinical (preoperative) and pathologic (postoperative) tumor status, respectively. There is a consensus that large (cT3 or cT4) head and neck tumors and cN+ neck disease necessitate treatment of the cervical lymph nodes. However, in patients with early-stage disease, there are many doubts as to which approach to the neck is best? It is generally known that overall survival for patients with clinically negative lymph nodes is high. The main problem in the management of early-stage cancers is node involvement as a result of undetectable subclinical node metastasis. (6) Despite advances in imaging techniques for the detection of lymph node spread, occult metastases are unidentified in 20 to 50% of lymph node-negative patients. (7,8) These patients eventually develop a clinically evident cervical metastasis, usually within 2 years. (9,10) While Kamer et al showed that local failure was the most important factor affecting the final outcome, survival among patients with neck node involvement is usually poor. (11)

In this article, we describe our study to determine whether the prevalence of cervical lymph node involvement is influenced by tumor size, degree of differentiation, and depth of invasion.

Patients and methods

Eligibility criteria. We retrospectively identified a group of patients who had been admitted to the Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital. Inclusion criteria for this study included T1 to T4 oral cavity cancer that was primarily treated with wide excision of the tumor and simultaneous bilateral or unilateral neck dissection, depending on the tumor location and the status of the neck. Surgery was followed by radiotherapy and/or chemotherapy if necessary. Patients who had been previously treated with radiotherapy or chemotherapy were excluded.

Preoperative assessments of neck lymph node metastasis were based on physical examination. Some patients' charts also included ultrasonography, computed tomography, and/or magnetic resonance imaging scans. Evaluations of distant metastases were based on chest x-ray findings and further imaging if needed. When a proven or suspected distant metastasis was detected, the patient was excluded from the study.

Our study population was made up of 50 patients who met our eligibility criteria. This group included 36 men and 14 women, aged 27 to 77 years (mean: 55); they had been seen between April 3, 2006, and Sept. 5, 2008. Of the 50 tumors, 24 were located in the tongue, 12 in the oral floor, 7 in the gingiva, 4 in the retromolar trigone, 2 in the buccal mucosa, and 1 in the hard palate (table 1). We found no incidence of lip cancer.

Histopathologic examination. Surgical specimens were oriented and labeled by surgeons and fixed in 10% buffered formalin by pathologists. The specimens were then processed and examined under microscopic vision. Paraffin was applied 1 day after fixation. Information on the presence or absence of cervical lymph node metastasis, tumor size, degree of differentiation, and depth of invasion was obtained from the pathology reports. The depth of invasion was calculated as the distance between the basal membrane and the deepest point of the invaded stromal tissue.

Statistical analysis. The significance of lymph node metastasis with different variables was investigated by means of the Fisher exact test. A p value of [less than or equal to] 0.05 was considered to be statistically significant.

Results

Tumor size. Evaluation of preoperative tumor size revealed that 15 patients were classified as cT1, 18 as cT2, 10 as cT3, and 7 as cT4 (table 2). For purposes of statistical analysis, we subclassified early- and late-stage tumors into two groups: T1/T2 (n = 33) and T3/T4 (n = 17).

Degree of differentiation. Tumors were well differentiated in 21 cases, moderately differentiated in 14, and poorly differentiated in 5. The degree of differentiation in 10 cases was undetermined, and these 10 cases were not included in the statistical assessments of differentiation (table 2).

Depth of invasion. Depth of invasion was 5 mm or less in 10 patients, 5.1 to 10 mm in 15 patients, and more than 10 mm in 25 (table 2).

Neck node involvement. On preoperative examination, 14 patients were node-positive (cN+) and 36 were node-negative (cN0). On postoperative pathology, however, 27 patients were found to be pN+, including 13 of the 36 patients who had been classified as cN0. Therefore, the prevalence of occult neck metastasis was 36.1% (table 2 and table 3).

Associations. The data were analyzed for associations between the presence of neck no de metastasis and tumor size, differentiation, and depth of invasion.

Tumor size. Neck metastases (pN+) were found in 17 of the 33 T1/T2 patients (51.5%) and in 10 of the 17 T3/ T4 patients (58.8%). The difference was not statistically significant (table 4 and table 5).

Degree of differentiation. Neck node metastasis was present in 8 of 21 cases of well-differentiated squamous cell carcinoma (38.1%), in 6 of 14 moderately differentiated tumors (42.9%), and in 4 of 5 poorly differentiated tumors (80.0%). The association between increasing node involvement and the decreasing degree of differentiation from well to poor was statistically significant (p = 0.027) (table 4).

We also evaluated the prevalence of node metastasis according to differentiation among the 28 cN0 patients in whom differentiation was known. We found node involvement in 3 of 14 patients with well-differentiated carcinoma (21.4%), in 4 of 10 with moderately differentiated disease (40.0%), and in 3 of 4 cases with poorly differentiated cancer (75.0%). The association between node metastasis and the degree of differentiation in the cN0 group was statistically significant (p = 0.023.)

Depth of invasion. Node metastases were present in 4 of 10 patients with a depth of invasion of 5 mm or less (40.0%), in 6 of 15 patients whose depth of invasion was between 5.1 and 10 mm (40.0%), and in 17 of 25 patients with invasion more than 10 mm (68.0%). There was a statistically significant association between a higher prevalence of lymph node metastasis and a greater depth of tumor (p = 0.011) (table 4).

When we evaluated depth of invasion in the 36 cN0 cases, the corresponding rates of neck node metastasis were 22.2, 35.7, and 46.1%. The association of node metastasis with the depth of invasion in the cN0 group was statistically significant (p = 0.05).

Discussion

Treatment of the neck should always be performed when there are obvious clinically detectable lymph nodes in a patient with squamous cell carcinoma of the oral cavity. But in patients with a clinically negative neck or with early-stage oral cavity carcinoma (T1/T2, N0), treatment of the neck remains controversial. The two options for managing the neck in these cases are elective neck dissection and a wait-and-see approach.

The advantages of elective neck dissection are that it can (1) provide accurate neck staging, (2) allow for the removal of any neck metastasis that might be present, and (3) help determine the need for radiotherapy. In addition to the obvious disadvantage of the morbidity of a second surgery, neck dissection might destroy the natural tumor barrier. (12)

Considering the high rates of occult metastasis that have been reported by various authors, elective neck dissection has many proponents. (9,13) In our study, the rate of occult metastasis was 36.1%, which is about average for cases of upper aerodigestive tract squamous cell carcinoma. The implication of this finding is that a wait-and-see policy could miss a metastasis in about 1 of every 3 patients. On the other hand, one can find in the literature that some wait-and-see groups had better survival rates than did groups of patients who had undergone elective neck dissection. (14,15) Yet despite the disadvantages of dissection and the advantages of watchful waiting, the preference in most cancer centers, and in our institution, is for elective treatment of the neck, especially in patients whose primary tumor is located on the tongue or oral floor.

Others have found that the surface size of a tumor does not correlate with the incidence of metastasis in oral squamous cell carcinoma. (9,16,17) Therefore, consideration of a patient's T category might not be sufficient for making optimal treatment decisions. Of the different variables that are related to neck metastasis, two of the most important are depth of invasion and tumor thickness. (3) These two terms are sometimes used interchangeably, but their meanings are not the same. Depth of invasion is used to define the extension of tumor beneath the epithelial surface, where epithelium is destroyed. Tumor thickness is used to define the measurement of a tumor's vertical bulk; it encompasses both the exophytic and endophytic portions of the tumor. (6)

Many studies have demonstrated that depth of invasion is an appropriate factor on which to base predictions of cervical metastasis in oral squamous cell carcinoma. (6,13,18,19) Other studies have shown that there is a statistically significant association between depth of invasion and neck node metastasis in all patient groups, including clinically NO groups. We believe that this association is most important in cN0 patients because of the controversy surrounding the need for neck dissection.

Hosal et al reported that patients with a tumor depth of less than 9 mm fared significantly better than those whose depth was greater than 9 mm (p < 0.05). (20) Therefore, tumor depth should be taken into consideration when deciding on neck treatment. Hosal et al recommended that elective node dissection be performed only in those patients with a tumor depth greater than 9 mm to optimize cure rates and avoid surgical morbidity in those patients who are unlikely to develop a neck metastasis. (20)

Likewise, Ambrosch et al reported that tumor depth was strongly correlated with node disease, but they found no such association with pathologic tumor size (pT) or histologic grade. (16) Their study showed that a depth of 2 mm was a valuable threshold for determining the risk of lymph node metastasis. Shaha et al reported that tumor thickness between 2 and 9 mm is associated with a 50% rate of node metastasis. (21) Fukano et al (23) and Yuen et al (22) recommended elective neck treatment for patients with a tumor depth of 5 and 3 mm, respectively. Although there is no doubt about the importance of tumor depth, no consensus has yet been reached on a valid cutoff point. (23) The fact that different authors report different thresholds might be attributable to factors such as individual definitions of tumor depth and differences in oblique sectioning during the processing of surgical specimens.

Yuen et al also reported that of all the tumor parameters and predictive models that they evaluated, tumor thickness was the only one that had a statistically significant predictive value for subclinical node metastasis, local recurrence, and survival. (22)

We hope that future multicenter studies will include a large number of cases and standardized measurements of depth of invasion, which might lead to identification of an ideal cutoff value. But some important issues must be addressed. One is that the depth of invasion is usually measured postoperatively in a pathologic specimen. Most operations begin with neck dissection followed by tumor excision and, if possible, en bloc resection of the tumor and neck specimen together. So most of the time we do not know what the depth of invasion is preoperatively, so we obviously cannot use it as a basis for deciding whether or not to operate. We hope that in the future, with the use of radiologic techniques such as magnetic resonance imaging, preoperative tumor depth will be determined accurately and with a high degree of association with pathologic findings so that we can evaluate the neck before surgery, especially in N0 cases.

Another possible way of determining depth of invasion might be to study frozen sections of the primary tumor intraoperatively before deciding on neck treatment, but again, the problem here is that neck dissection is performed prior to tumor excision in most cases.

Another parameter that we used in our study was the histologic differentiation of tumor. We found that well-differentiated tumors were significantly associated with the lowest prevalence of neck metastasis and that poorly differentiated tumors were significantly associated with the highest prevalence. This finding was consistent with those of some other basic studies on oral cavity squamous cell carcinoma. For example, Chen et al studied 94 patients with tongue cancer and found that those with poor and moderately differentiated tumors had a higher rate of neck node involvement than did patients with well-differentiated tumors. (18) Likewise, An et al showed that tumor differentiation was correlated not only with neck node involvement but with regional recurrence, as well. (24) On the other hand, the study by Fukano et al found no significant association between the degree of tumor differentiation and pN0 and pN+ status. (13)

Many authors who have studied differentiation have also evaluated other histopathologic factors, such as perineural invasion, lymphovascular permeation, and muscle invasion. (13,18) These studies have also shown a significant association between node neck involvement and histopathologic factors.

In our study, we subclassified patients according to tumor size into two groups: T1/T2 and T3/T4. The prevalence of neck node metastasis in the two groups was 51.5 and 58.8%, respectively. Since this difference was not statistically significant, we conclude that as tumor size increases, the rate of node metastasis does not significantly increase. A similar result was reported by Chen et al.18 On the other hand, it has been shown that T category tends to be more advanced in N+ groups.19 These conflicting findings might be attributable to several histopathologic factors, such as depth of invasion, degree of differentiation, and type of growth pattern (i.e., exophytic or endophytic).

In conclusion, we found that two of the three variables we analyzed--degree of differentiation and depth of invasion--were significantly correlated with neck node metastasis. We find it relevant that tumor size was not correlated with metastasis, which is significant because the TNM system is so widely used to evaluate patients preoperatively. The drawback of such a great reliance on the TNM system is that other important variables-especially depth of invasion--might not be considered. Obviously, the reason for a failure to consider depth of invasion is that it is difficult to evaluate preoperatively. In the future, we hope that depth of invasion can be determined preoperatively by the use of imaging techniques or intraoperatively by the use of frozen-section analysis so that we can achieve more accurate staging.

References

(1.) Sessions DG, Spector GJ, Lenox I, et al. Analysis of treatment results for oral tongue cancer. Laryngoscope 2002;112(4):616-25.

(2.) Le Tourneau C, Velten M, Jung GM, et al. Prognostic indicators for survival in head and neck squamous cell carcinomas: Analysis of a series of 621 cases. Head Neck 2005;27(9):801-8.

(3.) De Zinis LO, Bolzoni A, Piazza C, Nicolai P. Prevalence and localization of nodal metastases in squamous cell carcinoma of the oral cavity: Role and extension of neck dissection. Eur Arch Otorhinolaryngol 2006;263(12):1131-5.

(4.) Ferlito A, Rinaldo A, Devaney KO, et al. Detection of lymph node micrometastases in patients with squamous carcinoma of the head and neck. Eur Arch Otorhinolaryngol 2008;265(10):1147-53.

(5.) 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(12):1080-91.

(6.) Kane SV, Gupta M, Kakade AC, D'Cruz A. Depth of invasion is the most significant histological predictor of subclinical cervical-lymph node metastasis in early squamous carcinomas of the oral cavity. Eur J Surg Oncol 2006;32(7):795-803.

(7.) Aksoy F, Veyseller B, Binay O, et al. Patterns of cervical metastasis from squamous cell carcinoma of the head and neck [in Turkish]. Kulak Burun Bogaz Ihtis Derg 2010;20(5):249-54.

(8.) Shah JP, Candela FC, Poddar AK. The patterns of cervical lymph node metastases from squamous carcinoma of the oral cavity. Cancer 1990;66(1):109-13.

(9.) Hiratsuka H, Miyakawa A, Nakamori K, et al. Multivariate analysis of occult lymph node metastasis as a prognostic indicator for patients with squamous cell carcinoma of the oral cavity. Cancer 1997;80(3):351-6.

(10.) Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oralsquamous cell carcinoma: Histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol 2005;29(2): 167-78.

(11.) Kamer S, Esassolak M, Demirci S, et al. Relapse patterns and related prognostic factors in patients with mobile tongue cancer treated with postoperative radiotherapy. J BUON 2009;14(1):51-6.

(12.) Onerci M, Yilmaz T, Gedikoglu G. Tumor thickness as a predictor of cervical lymph node metastasis in squamous cell carcinoma of the lower lip. Otolaryngol Head Neck Surg 2000;122(1):139-42.

(13.) Fukano H, Matsuura H, Hasegawa Y, Nakamura S. Depth of invasion as a predictive factor for cervical lymph node metastasis in tongue carcinoma. Head Neck 1997;19(3):205-10.

(14.) Vandenbrouck C, Sancho-Garnier H, Chassagne D, et al. Elective versus therapeutic radical neck dissection in epidermoid carcinoma of the oral cavity: Results of a randomized clinical trial. Cancer 1980;46(2):386-90.

(15.) Nieuwenhuis EJ, Castelijns JA, Pijpers R, et al. Wait-and-see policy for the NO neck in early- stage oral and oropharyngeal squamous cell carcinoma using ultrasonography-guided cytology: Is there a role for identification of the sentinel node? Head Neck 2002;24(3):282-9.

(16.) Ambrosch P, Kron M, Fischer G, Brinck U. Micrometastases in carcinoma of the upper aerodigestive tract: Detection, risk of metastasizing, and prognostic value of depth of invasion. Head Neck 1995;17(6):473-9.

(17.) Moore C, Kuhns JG, Greenberg RA. Thickness as prognostic aid in upper aerodigestive tract cancer. Arch Surg 1986;121(12):1410-14.

(18.) Chen YW, Yu EH, Wu TH, et al. Histopathological factors affecting nodal metastasis in tongue cancer: Analysis of 94 patients in Taiwan. Int J Oral Maxillofac Surg 2008;37(10):912-16.

(19.) Lim SC, Zhang S, Ishii G, et al. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 2004;10(1 Pt 1):166-72.

(20.) Hosal AS, Unal OF, Ayhan A. Possible prognostic value of histopathologic parameters in patients with carcinoma of the oral tongue. Eur Arch Otorhinolaryngol 1998;255(4):216-19.

(21.) Shaha AR, Spiro RH, Shah JP, Strong EW. Squamous carcinoma of the floor of the mouth. Am J Surg 1984;148(4):455-9.

(22.) Yuen AP, Lam KY, Wei WI, et al. A comparison of the prognostic significance of tumor diameter, length, width, thickness, area, volume, and clinicopathological features of oral tongue carcinoma. Am J Surg 2000;180(2):139-43.

(23.) Po Wing Yuen A, Lam KY, Lam LK, et al. Prognostic factors of clinically stage I and II oral tongue carcinoma--a comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 2002;24(6):513-20.

(24.) An SY, Jung EJ, Lee M, et al. Factors related to regional recurrence in early stage squamous cell carcinoma of the oral tongue. Clin Exp Otorhinolaryngol 2008;1(3):166-70.

Mehmet Haksever, MD; Hasan Mete Inancli, MD; Umit Tuncel, MD; Sefik Sinan Kurcuoglu, MD; Melek Uyar, MD; Omer Genc, MD; Cigdem Irkkan, MD

From the Department of Otorhinolaryngology (Dr. Haksever, Prof. Tuncel, Dr. Kurkcuoglu, Dr. Uyar, and Dr. Genc) and the Department of Pathology (Dr. Irkkan), Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara, Turkey; and the Department of Otorhinolaryngology-Head and Neck Surgery, Near East University Faculty of Medicine, Nicosia, Cyprus (Dr. Inancli).

Corresponding author: Hasan Mete Inancli, MD, Semih Sancar Caddesi, Haldo Boratas Sokak, M. Kemal Saym Apt. Daire No: 3, Girne, Mersin 10, Turkey. Email: hminancli@yahoo.com
Table 1. Demographic data and tumor site

Variable n (%)

Sex

 Male 36 (72)
 Female 14 (28)

Age, yr

 [less than or equal to] 30 4 (8)
 31 to 40 5 (10)
 41 to 50 10 (20)
 51 to 60 11 (22)
 61 to 70 16 (32)
 [greater than or equal to] 71 4 (8)

Tumor site

 Tongue 24 (48)
 Oral floor 12 (24)
 Gingiva 7 (14)
 Retromolar trigone 4 (8)
 Buccal mucosa 2 (4)
 Hard palate 1 (2)

Table 2. Disease characteristics

Characteristic n (%)

Tumor size *

 cT1 15 (30)
 cT2 18 (36)
 cT3 10 (20)
 cT4 7 (14)

Degree of differentiation (n = 40) ([dagger])

 Well differentiated 21 (52.5)
 Moderately differentiated 14 (35)
 Poorly differentiated 5 (12.5)
 Unknown 10

Depth of invasion

 [less than or equal to] 5 mm 10 (20)
 5.1 to 10 mm 15 (30)
 [less than or equal to] 10.1 mm 25 (50)

Neck node involvement ([double dagger])

 cN0 36 (72)
 cN+ 14 (28)
 pN0 23 (46)
 pN+ 27 (54)

* cT indicates the preoperative clinical classification of tumor size.

([dagger]) Only cases with known differentiation are included in
these percentages.

([double dagger]) cN0 indicates no clinically detected involvement
of the cervical lymph nodes preoperatively; cN+ indicates detection
of lymph node involvement on palpation of the neck preoperatively;
pN0 indicates the absence of histologically detected metastasis in
neck dissection specimens postoperatively; pN+ indicates the presence
of histologically detected metastasis in neck dissection specimens
postoperatively.

Table 3. Comparison of pre- and postoperative N
status, * n

 pN0 pN+ Total

cN0 23 13 36
cN+ 0 14 14
Total 23 27 50

* cN0 indicates no clinically detected involvement of the
cervical lymph nodes preoperatively; cN+ indicates detection of
lymph node involvement on palpation of the neck preoperatively;
pN0 indicates the absence of histologically detected metastasis
in neck dissection specimens postoperatively; pN+ indicates the
presence of histologically detected metastasis in neck dissection
specimens postoperatively.

Table 4. Univariate analysis of associations between
node involvement and the three study parameters, n

Parameter pN0 pN+

Tumor size
 T1/T2 16 17
 T3/T4 7 10
 p Value NS *

Degree of differentiation ([dagger])

 Well differentiated 13 8
 Moderately differentiated 8 6
 Poorly differentiated 1 4
 p Value 0.027

Depth of invasion

 [less than or equal to] 5 mm 6 4
 5.1 to 10mm 9 6
 [greater than or equal to] 10.1 mm 8 17
 p Value 0.011

* Not statistically significant.

([dagger]) Tumor differentiation was unknown in 10 patients.

Table 5. Distribution of preoperative T and N
categories, * n

 cT1 cT2 cT3 cT4 Total

CN0 12 13 6 5 36
cN1 2 1 2 2 7
cN2a 0 2 0 0 2
cN2b 0 1 1 0 2
cN2c 0 1 0 0 1
cN3 1 0 1 0 2
Total 15 18 10 7 50

* cT and cN indicate the preoperative clinical evaluation of tumor
size and node status, respectively.
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Title Annotation:ORIGINAL ARTICLE
Author:Haksever, Mehmet; Inancli, Hasan Mete; Tuncel, Umit; Kurcuoglu, Sefik Sinan; Uyar, Melek; Genc, Omer
Publication:Ear, Nose and Throat Journal
Article Type:Report
Date:Mar 1, 2012
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