Clinicopathological risk factors for local recurrence in oral squamous cell carcinoma

Abstract

Local recurrence of oral squamous cell carcinoma (OSCC) after primary surgery has been considered to be a poor prognostic entity in terms of survival rate. The purpose of this study is to evaluate the incidence of local recurrence and to identify significant risk factors for the local recurrence in OSCC. The authors retrospectively reviewed records for 187 patients who underwent radical surgery for OSCC. The local recurrence rate was 16.0% (30/187 patients) in this study. The survival rate of patients with local recurrence was 33.3%, which was significantly lower than that (94.3%) of patients without local recurrence. Pattern of invasion (POI), neoadjuvant chemotherapy (NAC), and the status of the surgical margin were identified as factors influencing local recurrence. In particular, NAC and the status of the surgical margin were independent risk factors by multivariate analysis. The deep margin was resected at a close site in many NAC-treated patients, suggesting that NAC may lead to local recurrence and poor outcomes. No efficacy of NAC was observed, suggesting that the standard treatment of oral cancers is surgery alone.

Oral squamous cell carcinoma (OSCC) accounts for nearly 3% of all cancer cases in the world; its estimated incidence is around 275,000 cases/year, with two-thirds of these cases occurring in developing countries. OSCC continues to portend a poor prognosis, and remains a lethal disease for more than 50% of cases diagnosed annually. Of the known prognostic factors, TNM stage, histologic grade, and depth of tumour invasion are well recognized; however, the prognostic value of these clinicopathological factors is often uncertain and controversial.

Traditional treatment for OSCC comprises surgery and radiotherapy. Surgery is the most well established mode of initial definitive treatment for the majority of OSCC. Locoregional recurrence in patients with OSCC remains a problem and can affect survival. In particular, local recurrence of OSCC after primary surgery has been considered to be a bad prognostic entity in terms of survival rate. Several parameters may play a crucial role in determining therapeutic strategies; however, very few studies have focused on clinicopathological factors that may predict local recurrence in OSCC.

The purpose of this study is to evaluate the incidence of local recurrence and to identify significant risk factors for local recurrence in OSCC. This investigation may be helpful in the management of OSCC patients undergoing radical surgery.

Patients and methods

The authors retrospectively reviewed records for 187 patients who underwent radical surgery for OSCC between January 2001 and December 2010. The study cohort included patients with histologically confirmed diagnoses of OSCC and a minimum follow-up of 12 months. All study patients underwent extensive pretreatment evaluations, including blood chemistry, complete blood cell count, chest X-ray, computed tomography (CT) and/or magnetic resonance imaging (MRI) of the head and neck area, thoracoabdominal CT, and provided informed consent to participate in the study. Data collected included demographic information, site, TNM stage at diagnosis, tumour histologic grade, pattern of tumour invasion, treatment, status of the margin, recurrence, and the adjuvant therapy used for disease control.

Tumour stage was classified according to the TNM classification of the International Union against Cancer. Tumour histologic grade was defined according to the WHO classification. All pathological assessments were performed by two expert pathologists (SF and TI) who were unaware of the clinical outcomes. Pattern of invasion (POI) was examined at the host/tumour interface. POI types 1 through 4 have been previously defined by Bryne et al. POI type 1 represents tumour invasion in a broad pushing manner with a smooth outline. POI type 2 represents tumour invasion with broad pushing ‘fingers’ or separate large tumour islands, with a stellate appearance. POI type 3 represents invasive islands of tumour greater than 15 cells/island. POI type 4 represents invasive tumour islands smaller than 15 cells/island. This includes cord-like and single cell invasion. These evaluations were performed using biopsy specimens.

In the authors’ institute, surgery alone is preferred for the treatment of patients with oral cancer. Patients who hesitated in accepting surgical intervention or who did not have surgery available because of a busy schedule were selected for neoadjuvant chemotherapy (NAC). During the period of NAC, patients were encouraged to undergo surgery after completion of chemotherapy. All patients who received NAC underwent radical surgery. The regimen of NAC consisted of a combination of cisplatin-based multi drugs. In most patients, modifications in chemotherapy dosages were made for toxicity as indicated using standard criteria.

Primary tumours were excised with ≥1.5 cm safety margins (both superficial and deep margins). The extent of surgery was not modified according to tumour response with NAC. Surgery included removal of primary tumour and radical neck dissection was performed in patients who had clinically positive cervical lymph node metastasis. Elective neck dissection was not performed routinely. Postoperative adjuvant radiotherapy with a dose field of 60 Gy was given to patients with involved margins or extra-capsular lymph node spread. Local recurrence was defined as lesions arising in the oral cavity relative to primary tumour beyond 6 weeks within the first 5 years after the first definitive treatment. Locoregional recurrence arising in both the primary site and neck was also considered to be local recurrence. Recurrence arising only in the neck was defined as regional recurrence. Patients with recurrences that were considered potentially curable and operable underwent salvage surgery and radiotherapy. Patients with recurrences that were considered incurable were treated with palliative chemotherapy.

For pathological examination of the surgical margin, all permanent section histological slides of primary resection specimens were reviewed retrospectively. Regarding surgical margin distance, a large cohort study demonstrated that the pathological margin distance ≤4 mm was significantly associated with locoregional recurrence. In this study, the status of the surgical margin was classified as >4 and ≤4 mm in the superficial or deep margin, respectively.

Statistical analysis

Disease specific survival (DSS) rate was calculated using the actuarial life table method. Significance was evaluated using the log-rank test. Univariate logistic and multivariate logistic regression analyses were used to identify independent risk factors for local recurrence. Predictors that were not associated with local recurrence in univariate analysis were not included in multivariate analysis. Statistical analyses were performed using StatMate IV (Atms Co., Tokyo, Japan). In all analyses, P values <0.05 were considered to be significant.

Results

Patient characteristics are summarized in Table 1 . The male to female ratio was 1.2 with 102 male subjects. The mean age at diagnosis was 67.3 years (range 28–95 years). The most common primary site was the tongue (73/187 patients, 39.0%); 23.5% of patients had lower gingival cancer and 19.3% had upper gingival cancer.

Table 1
Patient characteristics and appearance of a local recurrence.
Characteristics No. of cases (%) No. of cases with a LR (%)
All cases 187 (100) 30 (16.0)
Gender
Male 102 (54.5) 15 (14.7)
Female 85 (45.5) 15 (17.6)
Age
≥68 111 (59.4) 20 (18.0)
≤67 76 (40.6) 10 (13.2)
Site
Tongue 73 (39.0) 8 (11.0)
Oral floor 26 (13.9) 3 (11.5)
Upper gingiva 36 (19.3) 8 (22.2)
Lower gingiva 44 (23.5) 9 (20.5)
Buccal mucosa 8 (4.3) 2 (25.0)
T stage
T1 52 (27.8) 6 (11.5)
T2 92 (49.2) 16 (17.4)
T3 14 (7.5) 2 (14.3)
T4 29 (15.5) 6 (20.7)
N stage
N0 141 (75.4) 20 (14.2)
N1 26 (13.9) 3 (11.5)
N2a 2 (1.1) 0 (0)
N2b 12 (6.4) 6 (50.0)
N2c 6 (3.2) 1 (16.7)
UICC stage
I 47 (25.1) 5 (10.6)
II 73 (39.1) 11 (15.1)
III 26 (13.9) 5 (19.2)
IV 41 (21.9) 9 (22.0)
Histologic grade
Well 166 (88.8) 25 (15.1)
Moderately 20 (10.7) 4 (20.0)
Poorly 1 (0.5) 1 (100)
POI
1 5 (2.7) 1 (20.0)
2 30 (16.0) 4 (13.3)
3 107 (57.2) 10 (9.3)
4 45 (24.1) 15 (33.3)
Preoperative treatment
Surgery alone 124 (66.3) 9 (7.3)
NAC 63 (33.7) 21 (33.3)
Surgical margin (superficial)
>4 mm 156 (83.4) 16 (10.3)
≤4 mm 31 (16.6) 14 (45.2)
Surgical margin (deep)
>4 mm 162 (86.6) 14 (8.6)
≤4 mm 25 (13.4) 16 (64.0)
Postoperative adjuvant radiotherapy
Yes 15 (8.0) 8 (53.3)
No 172 (92.0) 22 (12.8)
LR, local recurrence; POI, pattern of invasion; NAC, neoadjuvant chemotherapy.

The local recurrence rate was 16.0% (30/187 patients) during the follow-up period. The mean follow-up period was 36.7 months for the whole series (range 10–125 months). The mean period that elapsed before recurrence was 10.6 months (range 1–48 months), with most recurrences (21/30 patients, 70.0%) occurring during the first year after treatment (90% before 2 years). Site distribution of local recurrence cases was: 8 tongue (11.0%), 3 oral floor (11.5%), 8 upper gingiva (22.2%), 9 lower gingiva (20.5%), and 2 buccal mucosa (25.0%).

Univariate and multivariate logistic analyses for local recurrence

Univariate logistic analysis revealed that POI ( P < 0.001), NAC ( P < 0.001), the superficial margin ( P < 0.001), the deep margin ( P < 0.001), and postoperative adjuvant radiotherapy ( P < 0.001) were significantly associated with local recurrence ( Table 2 ). Gender, age, T-stage, N-stage, UICC stage, and histologic grade were not significantly associated with local recurrence. Multivariate analysis revealed that NAC (OR = 3.17, P = 0.047), the superficial margin (OR = 7.12, P < 0.001), and the deep margin (OR = 4.90, P = 0.011) were independent factors for local recurrence ( Table 3 ).

Table 2
Univariate logistic analysis for the factors influencing local recurrence.
Factor Odds ratio 95% CI P value
Gender
(male vs. female)
0.80 0.36–1.76 0.730
Age
(≥68 vs. ≤67)
1.45 0.64–3.30 0.492
T stage
(T1–2 vs. T3–4)
1.26 0.52–3.09 0.776
N stage
(N− vs. N+)
1.68 0.72–3.91 0.327
UICC stage
(I–II vs. III–IV)
1.72 0.78–3.78 0.253
Histologic grade
(well vs. moderately+poorly)
1.76 0.59–5.25 0.475
POI
(1+2+3 vs. 4)
4.23 1.87–9.60 <0.001
Preoperative treatment
(surgery alone vs. NAC)
6.60 2.80–15.57 <0.001
Superficial margin
(>4 mm vs. ≤4 mm)
7.20 3.00–17.31 <0.001
Deep margin
(>4 mm vs. ≤4 mm)
16.44 6.16–43.92 <0.001
Postoperative adjuvant radiotherapy
(no vs. yes)
7.79 2.57–23.61 <0.001
POI, pattern of invasion; NAC, neoadjuvant chemotherapy.

Table 3
Multivariate logistic regression analysis for the factors influencing local recurrence.
Factor Odds ratio 95% CI P value
POI
(1+2+3 vs. 4)
1.81 0.58–5.72 0.308
Preoperative treatment
(surgery alone vs. NAC)
3.17 1.02–9.86 0.047
Superficial margin
(>4 mm vs. ≤4 mm)
7.12 2.28–22.35 <0.001
Deep margin
(>4 mm vs. ≤4 mm)
4.90 1.44–16.70 0.011
Postoperative adjuvant radiotherapy
(no vs. yes)
2.55 0.77–8.47 0.125
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Jan 26, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Clinicopathological risk factors for local recurrence in oral squamous cell carcinoma
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