Clinical features of multiple primary carcinomas of the oral cavity

[This retracts the article DOI: 10.3892/etm.2016.3999.].


Introduction
The occurrence of second or multiple primary cancers in the oral cavity, pharynx and larynx has been extensively examined in patients with oral squamous cell carcinoma (SCC) (1)(2)(3)(4). In these previous studies, the incidence of second or multiple primary cancers was reported to range between 10 and 24%, and the 5-year survival rate of the patients who developed second or multiple primary cancers was significantly lower, as compared with the patients who did not develop these tumors (1,3). In total, ~1/3 of the second or multiple primary cancers arose in the oral cavity, which may have been partly due to the continuous exposure of the epithelial surface of the oral cavity to carcinogens, including those found in tobacco and alcohol (5).
Improvements in the cancer cure rate due to advancements in early diagnosis and treatment, extension of life expectancy, genetic disposition, exposure to several dietary and environmental carcinogens, hormonal imbalance, impaired host immunosurveillance, radiation carcinogenesis and oncogenic virus infection tends to increase the incidence of double and multiple primary cancers, in which two or more cancers occur in the same individual (6). The measures for multiple primary cancers as defined by Warren and Ehrenreich (7) in 1944 are: i) the two neoplasms must be malignant, ii) the two neoplasms must be anatomically separated and not connected by epithelial or submucosal neoplastic changes and iii) the possibility of the second tumor representing a metastasis from the index tumor must be excluded. Numerous studies in the literature have investigated the incidence of second primary head and neck malignancies (8)(9)(10); however, there is minimal data concerning patients who exhibit at least three oral primary carcinomas (7)(8)(9). As such, the present study was undertaken to investigate the clinical characteristics of multiple primary carcinomas of the oral cavity.

Materials and methods
Ethics statement. This study was conducted subject to ethical approval granted by Ethics Committee of Henan Provincial People's Hospital (HPPH/2015/PLW/053). Informed consent was obtained from the patient and his family.
Definitions of primary oral carcinomas. Single primary carcinoma was defined as a carcinoma that developed only once as a single primary lesion during the follow-up period. In the present study, this type was defined as an oral squamous cell carcinoma (OSCC). Multiple primary carcinomas were defined according to modified criteria outlined by Warren and Ehrenreich (7). In brief, >2 cancerous lesions separated by >1.5 cm of clinically non-cancerous epithelium in the oral cavity were set as the criteria. Furthermore, multiple primary carcinoma occurrence was categorized into a synchronous or metachronous type, and at first, second or third multiple primary carcinomas (Fig. 1). In addition, synchronous multiple primary carcinomas were defined as >2 oral carcinomas separated by >1.5 cm of clinically non-cancerous epithelium synchronously or within 6 months of the original wound. Metachronous multiple primary carcinomas were defined as >2 primary lesions that developed metachronously (after >6 months apart from each other), and were categorized as second or third occurrences. Local recurrence was defined as a lesion recurring within 1.5 cm of the original wound. The space between the lesions was determined by direct measurement from the newly onset lesion to the previous one, and in reference to the patient's medical records. In cases where it was difficult to evaluate whether the distance was within 1.5 cm due to post-operative scar formation or an irregular anatomy, the lesion was classified as a recurrent lesion. In line with the diagnostic criteria for proliferative verrucous leukoplakia (PVL) proposed by Cerero-Lapiedra et al (11), patients with multiple primary OSCC who previously had PVL were included.
Since synchronous first multiple primary carcinomas influence patient selection in this regard, the present study focused on synchronous first, multiple primary carcinomas and metachronous second and third primary carcinomas. For a detailed analysis of the features of multiple primary carcinomas, the differences in location, the interval between the initial and subsequent onsets of multiple primary carcinomas, cumulative incidence of second multiple primary carcinomas, recurrence, lymph node metastasis and the presence of mucosal changes following the onset of first multiple primary carcinomas were examined.
Statistical analysis. Statistical analysis was performed using statistical SPSS 18 software for Windows (SPSS Japan Inc., Tokyo, Japan). Differences in the clinical features, including age, gender, tobacco use, tumor location, TNM classification and phase, between the single primary and the multiple primary carcinoma groups were analyzed using the χ 2 or Fisher's exact tests for categorical data, and one-way analysis of variance was used for continuous variables. Log-rank test was performed to distinguish disease-specific survival rate of patients with multiple primary carcinomas. P<0.05 was considered to indicate a statistically significant difference.

Results
Primary data analysis. Data from 1,024 patients were analyzed, of which 961 presented with single primary carcinoma and 54 presented with multiple primary carcinomas. The average duration of follow-up was 64 (range, 4-146) months. Of the 54 patients with multiple primary carcinomas, 10 (18.5%) had synchronous first multiple primary carcinomas, 33 (61.1%) had metachronous, second multiple primary carcinomas and 11 (20.4%) had metachronous third multiple primary carcinomas (Fig. 1). The median interval between onset of first multiple primary carcinomas (regardless of being synchronous or metachronous) and onset of second multiple primary carcinomas was 90 (range, 13-141) months. The median interval between the onset of second and third multiple primary carcinomas (regardless of being synchronous or metachronous) was 63 (range, 28-124) months. Age and gender differences. A total of 39 women and 15 men were diagnosed with multiple primary carcinomas, whereas 362 women and 599 men were diagnosed with single primary carcinoma. Multiple primary carcinomas occurred more frequently in women than in men, whereas single primary carcinoma occurred significantly more frequently in men than in women, as determined by Fisher's exact test (P<0.001).
Cumulative incidence and survival rates discretion. Cumulative incidence rates for metachronous second multiple primary carcinomas following the onset of first carcinoma at 5 and 10 years were 2.8 and 8.0%, respectively (Fig. 2). Disease-specific survival rates for patients with single primary carcinoma were 87.3 and 85.3% at 5 and 10 years, respectively, and for patients with multiple primary carcinomas were 90.7% at 5 years and 79.6% at 10 years. The disease-specific survival rate of patients with multiple primary carcinomas was significantly lower (log-rank test, P=0.017; Fig. 3), as compared with patients with single primary carcinoma. Four of the patients with multiple cancers succumbed to oral cancer, whereas one succumbed to a non-cancerous illness, three had an unknown outcome and 18 survived. Therefore, the outcome associated with multiple cancers was similar to that associated with oral cancer alone. It remains difficult to evaluate multiple cancers as a prognostic factor. Multiple primary tumors were registered according to the criteria outlined by Neglia et al (12) and Moertel et al (13): i) All the tumors were histologically malignant; ii) were distinct masses, separated by normal tissue (≥2 cm); iii) the possibility that the tumors were metastatic was histologically excluded; and iv) secondary lung lesions were solitary and histologically distinct from the primary tumor. Multiple tumors were classified according to their chronological sequence: Synchronous, occurring simultaneously or within 6 months of each other; and metachronous, arising ≥6 months after the first diagnosis (14,15).

Discussion
With regard to field carcinogenesis (16), multiple independent oral squamous cell carcinomas were observed in 11.2% of the patients. These cancers were considered to have developed as a result of field carcinogenesis, and it was stated that the entire oral cavity was susceptible to the development of multiple lesions. Although there are minimal previous studies (13)(14)(15) that have focused on cancer in the oral region, Fushimi et al (17) identified that the disease-specific survival rate at 5 years for patients with single primary carcinoma was 87.0%; whereas this value was 73.8% for patients with multiple primary carcinomas.
Regueiro et al (18) reported that the cumulative incidence rate for second multiple primary carcinomas following the onset of a first carcinoma at 3 years was 3.6%. In addition, Boysen and Loven (19) demonstrated that the annual incidence of second multiple primary carcinomas was higher in the oral region (4%), as compared with the head and neck region (3.6%). Cumulative incidence rate at 10 years was 8.0% in the present study, which to the best of our knowledge is the first to be reported, and supports the requirement for close long-term follow-up. However, it should be noted that distinct discretion was not observed in regards to age and gender as compared to other relevant factors (18,20,21).
According to the field cancerization concept, oral, pharyngeal, esophageal and gastric cancers are exposed to the same carcinogenic environment (15)(16)(17)22). In particular, the presence of multiple or double cancers influences the selection and results of treatment modalities for oral cancer (16,18,23,24). In the present study, ~10% of all patients developed multiple cancers, including oral cancer. Therefore, careful, long-term follow-up is required for recurrence and metastasis, and the development of a primary cancer elsewhere through appropriate examinations. For the early detection of primary and double cancers, a visit to an oral cancer outpatient clinic, the application of vital staining, strengthening of magnification endoscopy with vital dye staining in close cooperation with the endoscopist prior to and following surgery, and systemic examination including positron emission tomography scanning and genetic profiling are all important (6,8,11,13,25).  In conclusion, multiple primary squamous cell carcinomas of the oral cavity are more common in white females, and tend to favor the gingiva. The reason that these patients continue to develop novel primary cancer remains unclear, and does not seem to correlate with smoking, although some are associated with specific conditions such as PVL or lichen planus. It was demonstrated that survival was improved in the present patients by close monitoring and follow-up, and early treatment as novel dysplasias and carcinomas develop. Notably, the development of lymph node metastasis was induced with a poor prognosis in these patients, with a survival rate of <10%.