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Clinical characteristics of multiple primary carcinomas of the oral cavity
Oral Oncology 51 (2015) 182–189
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Clinical characteristics of multiple primary carcinomas of the oral cavity Yumi Mochizuki, Hiroyuki Harada ⇑, Minoru Ikuta, Hiroaki Shimamoto, Hirofumi Tomioka, Kae Tanaka, Hideaki Hirai, Ken Omura Department of Oral and Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan
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Article history: Received 11 August 2014 Received in revised form 17 November 2014 Accepted 20 November 2014 Available online 10 December 2014 Keywords: Multiple primary carcinomas Oral cavity Survival rate The cumulative incidence rate Squamous cell carcinoma
s u m m a r y Objectives: This study aimed to clarify the clinical characteristics of multiple primary carcinomas of the oral cavity. Materials and methods: We retrospectively reviewed the cases of 1015 patients who were treated during follow up for oral cancer at Tokyo Medical and Dental University between March 2001 and December 2012. We compared the clinical characteristics of 961 patients who developed single primary oral squamous cell carcinoma (SCC) during follow up and 54 patients who subsequently developed multiple primary carcinomas in the oral cavity. Results: Mean age at first diagnosis was significantly higher in patients with multiple primary carcinomas than single primary carcinoma. Multiple primary carcinomas showed a female predilection, were most prevalent in the gingiva, and tended to show earlier tumor and nodal stages than single primary carcinoma. The local recurrence rate was higher for multiple primary carcinomas than single primary carcinoma, and it increased with the number of multiple primary occurrences. The disease-specific survival rate at 10 years for patients with single primary carcinoma was 85.3% and that for patients with multiple primary carcinomas was 79.6%. The cumulative incidence rate for metachronous second multiple primary carcinomas after the onset of first carcinoma at 10 years was 8.0%. The recurrence of multiple primary carcinomas did not decrease the survival rate. Conclusion: Differences were found in the clinical characteristics between patients with single oral SCC and those with multiple primary oral carcinomas. Early diagnosis and treatment as well as close longterm follow up are needed for patients with multiple primary oral carcinomas. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Oral cancer, the sixth most prevalent cancer worldwide [1], is difficult to control even after treatment because of the high propensity for multiple primary carcinomas to develop [2–5]. The overall occurrence rate of multiple primary carcinomas in the oral cavity is between 6% and 27% [6–9], and its emergence has shown poor prognosis among patients who have already undergone treatment for early stage oral cancer [3,10,11]. Reducing its mortality and morbidity remains one of the most challenging problems. While molecular-based explanations of its pathomechanism have been reported, few studies have provided clinical information that is useful for daily practice. Oral and maxillofacial surgeons and head and neck oncologists would clearly benefit from knowing the Abbreviations: PVL, proliferative verrucous leukoplakia; SCC, squamous cell carcinoma. ⇑ Corresponding author. Tel.: +81 3 5803 5506; fax: +81 3 5803 0199. E-mail address: [email protected] (H. Harada). http://dx.doi.org/10.1016/j.oraloncology.2014.11.013 1368-8375/Ó 2014 Elsevier Ltd. All rights reserved.
characteristics of patients with this disease in order to identify and treat it expeditiously [12,13]. Therefore, this study aimed to examine the specific clinical features of, and discuss the clinical approach to managing, synchronous and metachronous multiple primary oral carcinomas. Materials and methods We retrospectively reviewed the medical records of patients with primary oral carcinoma who underwent surgical treatment at, and were followed by, the Department of Oral and Maxillofacial Surgery, Tokyo Medical and Dental University Hospital between March 2001 and December 2012. We studied only those patients who gave informed consent to be included in this study. The observation endpoints were set as June 30, 2014. Patients treated at another institute or with no pathology report or inadequate medical records were excluded. The study protocol was approved by our institution and was in accordance with the Declaration of Helsinki.
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Definitions of primary oral carcinoma Single primary carcinoma was defined as carcinoma that developed only once as a single primary lesion during the follow-up period. We limited this to oral squamous cell carcinoma (SCC). Multiple primary carcinomas were defined according to criteria modified from those of Warren and Gates in 1932 [14] and based on the ‘General Rules for Clinical and Pathological Studies on Oral Cancer’ proposed as a draft by the Japan Society for Oral Tumors [15], namely, more than 2 cancerous lesions separated by more than 1.5 cm of clinically non-cancerous epithelium in the oral cavity. As shown in Fig. 1, multiple primary carcinoma occurrence was categorized into synchronous or metachronous type and as first, second, or third multiple primary carcinomas. Synchronous multiple primary carcinomas were defined as more than 2 oral carcinomas separated by more than 1.5 cm of clinically non-cancerous epithelium synchronously or within 6 months of the original lesion. Metachronous multiple primary carcinomas were defined as more than 2 primary lesions that developed metachronously (after more than 6 months of each other) and were second or third occurrences. Local recurrence was defined as a lesion recurring within 1.5 cm of the original lesion. Distance between the lesions was determined by direct measurement from the newly onset lesion to the previous lesion and in reference to the patient’s medical records. If it was difficult to judge whether the distance was within 1.5 cm because of postoperative scar formation or irregular anatomy, the lesion was classified as a recurrent lesion. In view of the diagnostic criteria for proliferative verrucous leukoplakia (PVL) proposed by Cerero-Lapiedra et al. [16], we included patients with multiple primary OSCC who previously had PVL. Although in principle synchronous second and third multiple primary carcinomas are possible, they are rare and no such cases were observed in this study. Furthermore, because synchronous first multiple primary carcinomas greatly influence the survival of patients, we focus in this study on synchronous first multiple primary carcinomas and metachronous second and third primary carcinomas. For a detailed analysis of the features of multiple primary carcinomas, we studied differences in location, the interval between the first and later onsets of multiple primary carcinomas, cumulative incidence of second multiple primary carcinomas,
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recurrence, lymph node metastasis, and presence of mucosal changes after the onset of first multiple primary carcinomas. We compared differences in clinical features (age, sex, tobacco use, tumor location, TN classification, and stage) between the single primary carcinoma and the multiple primary carcinoma groups using the chi-squared or Fisher’s exact test for categorical data and we used one-way ANOVA for continuous variables. The disease-specific survival rates of the types of multiple primary carcinomas (i.e., synchronous first, metachronous, and metachronous third) were estimated by the Kaplan–Meier method. Also, differences in the disease-specific survival rates between patients with local recurrence and those with lymph nodes metastasis from the multiple primary carcinomas were analyzed by the log-rank test. Statistical analysis was performed using statistical PASW Statistics 18 software for Windows (SPSS Japan Inc., Tokyo, Japan). A p-value less than 0.05 was considered statistically significant. Results We analyzed data for 1015 patients: 961 with single primary carcinoma and 54 with multiple primary carcinomas. The median duration of follow-up was 64 (range, 4–146) months. Of the 54 patients with multiple primary carcinomas, 10 (20.4%) 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 and that between the onset of second and third multiple primary carcinomas (regardless of being synchronous or metachronous) was 63 (range, 28–124) months. Treatment protocols Of the 961 patients with single primary carcinoma, 843 underwent surgical treatment alone, 26 received brachytherapy (mean dose, 77.1 [range, 57.6–97.0] Gy), 38 received induction chemotherapy plus surgery (cisplatin and 5-FU, 34 cases; other, 4 cases),
Fig. 1. Flow diagram of patients who developed single primary carcinoma or multiple primary carcinomas during follow up after surgery for an initial occurrence of oral cancer. Number of recurrences are shown. Mean interval between primary tumor resection and recurrence was 22 (range, 2–86) months.
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and 54 received induction chemo-radiotherapy plus surgery (S-1, 36 cases; carboplatin, 9 cases; other, 9 cases; mean dose of external irradiation, 41.4 [30–56] Gy). When positive or close surgical margins were identified on histological examination of the surgical specimen, 43 received postoperative brachytherapy (mean dose, 75.5 [range, 62.0–91.0] Gy) and when advanced features at the primary site and/or cervical lymph nodes metastasis was identified, 81 received adjuvant chemotherapy (S-1, 33; cisplatin and 5-FU, 23 cases; other, 2) and 54 received adjuvant chemo-radiotherapy (S-1, 33; cisplatin and 5-FU, 19; other, 2; mean dose of external irradiation, 48.9 [range, 30–52] Gy). Of the 33 cases of metachronous second multiple primary carcinomas, 9 underwent brachytherapy (mean dose, 76.8 [range, 57.6–87.0] Gy) and 24 cases underwent surgery. Of the 11 cases of metachronous third multiple primary carcinomas, 3 underwent brachytherapy (mean dose, 67.2 [range, 57.6–77.0] Gy) and 8 underwent surgery. Age and sex Mean age at time of first diagnosis was significantly higher in patients with multiple primary carcinomas (median, 68.3 [range, 21–94] years) than in patients with single primary carcinoma (median, 61.6 [range, 28–86] years; F value = 9.511, p = 0.002). A total of 39 women and 15 men were diagnosed with multiple primary carcinomas, while 362 women and 599 men were diagnosed with single primary carcinoma. Multiple primary carcinomas occurred more frequently in women than men, while single primary carcinoma occurred more frequently in men than women (p < 0.001, Fisher’s exact test). Tobacco use Non-smokers accounted for 32 of 45 (71.1%) multiple primary carcinoma patients and 176 of 961 (18.3%) single primary carcinoma patients (v2 = 69.87, p < 0.001). Tumor location As Table 1 shows, the most common location for single primary carcinoma was the tongue (508/961, 52.9%), followed by the lower gingiva (162/961, 16.9%) and upper gingiva (94/961, 9.8%), while that for first multiple primary carcinomas was the lower gingiva, followed by the buccal mucosa. Mucosal change after the onset of first carcinoma was found in 14 of 33 patients (42.4%) with metachronous second multiple primary carcinomas and in 7 of 11 patients (63.6%) with metachronous third multiple primary carcinomas. Nine of 54 (16.7%; 2 men, 7 women) with multiple primary OSCC previously had PVL. T classification, cervical lymph node metastasis, and staging Table 2 shows T classification, cervical lymph node metastasis, and staging for single primary carcinoma and multiple primary carcinomas. The occurrence rate of T3–T4 disease with single primary carcinoma was 28.3% and that with multiple primary carcinomas at first occurrence was 5.6%. A significant difference in T classification was found between patients with single primary carcinoma and those with multiple primary carcinomas (v2 = 15.52, p = 0.001). Cervical lymph node metastasis showed no significant difference (Fisher’s exact test, p = 0.327), but did occur slightly more often with single primary carcinoma (287/ 961, 29.9%) than with multiple primary carcinomas (14/54, 25.9%). Although not statistically significant, the median age of patients with such metastasis (median, 69.0 [range, 57–81] years)
Table 1 Tumor location of single primary SCC and multiple primary carcinomas.
Tongue Lateral Inferior surface Dorsal surface Tongue + buccal mucosa Lower gingiva Lateral Mid gingiva Lower gingiva + Tongue Lower gingiva + Floor of mouth Lower gingiva + buccal mucosa Lower gingiva + buccal mucosa + upper gingiva Buccal mucosa Lateral Lip mucosa Buccal mucosa + lower lip Upper gingiva Unilateral Bilateral Upper gingiva + lower lip Floor of mouth Palate
Single primary SCC n = 961
Multiple primary SCC at first occurrence n = 54
461 4 3 0
11 2 0 1
185 4 0 0 0 0
14 1 1 3 1 1
85 3 0
6 0 1
113 0 0 69 34
4 1 1 2 4
Abbreviation: SCC, oral squamous cell carcinoma.
Table 2 Tumor staging for single primary SCC and multiple primary carcinomas.
T stage T1 T2 T3 T4
Single primary SCC n = 961
Multiple primary SCC at first occurrence n = 54
319 370 118 154
20 31 2 1
p = 0.001 (v2 = 15.52)
N N+ N
p value
p = 0.327 (Fisher’s exact test) 287 674
14 40
Abbreviation: SCC, oral squamous cell carcinoma.
was higher than that of patients without it (median, 68.0 [range, 28–86] years; F value = 0.101, p = 0.752). Local recurrence As Fig. 1 shows, local recurrence was seen in 87 of the 961 (9.1%) patients with single primary carcinoma. For patients with multiple primary carcinomas, the local recurrence rate was 37% (20/54): 10.0% (1/10) for synchronous first multiple primary carcinomas, 42.4% (14/33) for metachronous second multiple primary carcinomas, and 45.5% (5/11) for metachronous third multiple primary carcinomas. Cumulative incidence rate for secondary multiple primary carcinomas The cumulative incidence rates for metachronous second multiple primary carcinomas after the onset of first carcinoma at 5 and 10 years were 2.8% and 8.0%, respectively (Fig. 2). Disease-specific survival rates The disease-specific survival rate for patients with single primary carcinoma was 87.3% and 85.3% at 5 and 10 years, respectively, and for patients with multiple primary carcinomas
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Fig. 2. Cumulative incidence rate for metachronous second multiple primary carcinomas.
Fig. 3. Disease-specific survival rates of patients with single primary carcinoma and those with multiple primary carcinomas.
was 90.7% at 5 years and 79.6% at 10 years. The disease-specific survival rate for patients with multiple primary carcinomas was significantly lower (log-rank test, p = 0.017; Fig. 3). For patients with multiple primary carcinomas, the disease-specific survival rate for those with synchronous first multiple primary carcinomas decreased to 80.0% at 1 year and remained stable at 10 years. The rate for patients with metachronous second multiple primary carcinomas was 90.9% and 75.8% at 5 and 10 years, respectively, and for patients with metachronous third multiple primary carcinomas was 100% and 90.0%, respectively (Fig. 4). The disease-specific survival rate was significantly higher for patients with local recurrence (log-rank test, p = 0.045; Fig. 5) and significantly lower for patients with cervical lymph node metastasis (log-rank test, p = 0.004; Fig. 6). Six patients (6/14, 42.9%) did not undergo surgery because of advanced age and poor general health, and they ultimately died of cervical lymph node metastasis. Discussion The epidemiological data on multiple primary carcinomas remain relatively scarce. From the findings reported so far, it
appears that multiple primary carcinomas are less likely to occur as advanced disease (T3–T4) [10] or to co-occur with cervical lymph node metastasis (pN+) [10]. The occurrence rate of T3–T4 disease with single primary carcinoma was reported at 48.2% and that with multiple primary carcinomas at first occurrence 38.5%, while the corresponding occurrence rates of cervical lymph node metastasis were 53.6% and 38.5% [17]. In the present study, there was a tendency for cases of multiple primary carcinomas to show earlier tumor and nodal stages than cases of single primary carcinoma. It is well known that patients with multiple primary carcinomas have increased postoperative morbidity and mortality rates [11]. Although there have been few reports focusing on cancer in the oral region, one study found the disease-specific survival rate at 5 years for patients with single primary carcinoma was 87.0% and for patients with multiple primary carcinomas was 73.8% [17]. Our finding of a lower disease-specific survival rate for patients with multiple primary carcinomas is in agreement. Lai et al. [9] and González-García et al. [2] have both suggested that the biological behavior of tumors differ between single primary carcinoma and multiple primary carcinomas, and this may account for the differences.
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Fig. 4. Disease-specific survival rates of patients according to type of multiple primary carcinomas of the oral cavity.
Fig. 5. Disease-specific survival rates of patients with multiple primary carcinomas with and without local recurrence.
Fig. 6. Disease-specific survival rates of patients with multiple primary carcinomas with and without cervical lymph node metastasis.
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Location Oral mucosa is classified into (1) specialized epithelium (dorsal tongue), (2) keratinized (masticatory) epithelium, (3) non-keratinized (lining) epithelium, and (4) tongue epithelium (epithelium on the lateral border of the tongue). The locations of single primary carcinoma and multiple primary carcinomas have been reported to be different [3,4,18]. Our study revealed that single primary SCC lesions most frequently occurred in non-keratinized (lining) epithelium such as the floor of mouth, buccal mucosa, and the specialized mucosa of the tongue. In contrast, multiple primary carcinomas most frequently occurred in keratinized (masticatory) epithelium such as the gingiva and hard palate. Non-keratinized lining mucosa generally exhibits a lower host immunological response than keratinized mucosa [19]. The proportion of cases of single SCC in the areas of non-keratinized lining mucosa and specialized mucosa of the tongue was previously found to be high, and the carcinomas in these areas had identifiable etiological risk factors [20]. One of the reasons that single primary SCC is considered to show a higher incidence of cervical lymph nodes metastasis and higher nodal stages is that non-keratinized lining mucosa and the specialized mucosa of the tongue show local progression and easier dissemination of cancer cells through lymphatic drainage, resulting in regional lymph node metastasis [21]. The mucosal immune response of the keratinized mucosa defends against carcinogens and regional lymph nodes metastasis. The morbidity rate of multiple primary carcinomas, but not single primary carcinoma, in keratinized epithelium was found to be high, and lymph node metastasis from multiple primary carcinomas was not infrequent in keratinized epithelium [20]. PVL, first reported by Hansen et al. [22], is an oral epithelial disease with multifocal hyperkeratosis that eventually becomes exophytic, showing the presence of a verrucous lesion with proliferative confluence that becomes verrucous carcinoma or SCC [16,23]. It tends to show more aggressive biological behavior than other forms of leukoplakia [16], with high rates of malignant transformation (60–100%), recurrence (87–100%), and mortality (30–50%) [24]. In our study, 9 of 54 patients (16.7%) with multiple primary OSCCs were previously diagnosed with PVL. Among the few previous reports on this patient population, 10 of 19 (52.63%) patients with single primary OSCC developed from PVL had a second primary tumor [25] and 3 of 20 (15%) with multiple primary OSCCs had previously diagnosed PVL [26]. Further studies are needed to clarify the relationship between multiple primary OSCCs and PVL and the epidemiology of multiple primary OSCCs that have developed from PVL. Smokers are more likely to have synchronous carcinomas involving the entire aerodigestive tract, and 80% of the next occurrence of multiple primary carcinomas again involved the entire aerodigestive tract [13]. By contrast, patients with first multiple primary carcinomas in the oral cavity without tobacco or alcohol exposure (almost 70% of which were women) had the next occurrence of multiple primary carcinomas only in oral cavity [13,26– 28]. It has been suggested that the cancerization of multiple primary carcinomas had some relation with the molecular and genetic characteristics of the cancer cells in multiple primary carcinomas [29]. Further research into multiple primary carcinomas is needed from the perspective of the molecular and genetic characteristics of the cancer cells. The incidence rates of multiple primary carcinomas and its recurrences differ according to the definition of multiple primary carcinomas used [2]. In regard to the criterion of distance between lesions, some studies have defined multiple primary carcinomas as lesions separated by more than 2 cm in the oral cavity [2,26]. In our study, we used more than 1.5 cm as defined by the Japan Society
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for Oral Tumors. Given the typical size of the oral cavity of Japanese people, this definition is suitable for studying Japanese patients with multiple primary carcinomas in the oral cavity and has been applied by previous studies in Japan [30]. Treatment The treatment of choice for multiple primary carcinomas is surgery. The significance of negative surgical margins and surgical margins more than1 cm are less important in multiple primary carcinoma cases [2,31]. Mucosa with genetically changed but histologically normal cells has a high risk of malignant transformation and is referred to as ‘‘condemned mucosa’’ [33,34]. Because of the field cancerization of the oral mucosa [32–34], even when the entire tumor appears to be adequately excised, new multiple primary carcinomas may develop multicentrically from genetically altered cells in the ‘‘condemned mucosa’’ distant from the surgical site [35,36]. The condemned mucosa shows clinically recognizable stages of epithelial carcinogenesis [3]. Clinically recognizable premalignant mucosal changes such as leukoplakia or erythroplakia may transform into cancer earlier than in mucosa with no such recognizable changes [3]. In our study, a high incidence of mucosal change (25/54, 46.2%) was observed after the onset of first carcinoma. Some researchers have suggested that multiple primary carcinomas manifest as multiple independent lesions in the condemned mucosa due in part to genetic alteration and occasionally develop to coalesced multiple independent lesions [9,37]. Although limited surgical resection is occasionally performed to avoid severe dysfunction postoperatively [38], mucosa with changes such as leukoplakia or erythroplakia should be resected in an en bloc fashion whenever possible [12,13]. Chemokines and promigratory factors and wound-associated angiogenesis in the provisional surgical wound in the immediate postoperative period may promote local tumor formation [39]. Our study revealed a higher incidence of local recurrence for multiple primary carcinomas than for single primary carcinoma, and the local recurrence rate increased with the number of multiple primary occurrences (Fig. 1). The pathogenesis for the appearance of multiple primary carcinomas and recurrence has been explained by the concept of field cancerization [2]. Because genetically altered cells may be present in the mucosa adjacent to the surgical margins in the condemned mucosa, the adjacent mucosa of multiple primary carcinomas should be examined closely for emergence of another carcinoma. Hashibe et al. observed that radiotherapy became a risk factor for oral cancer at more than 10 years of follow up but was protective against second primary cancer within the first year [40]. They also stated that cancers in the irradiated head and neck area could be explained by potential mechanisms such as DNA damage [41]. However, according to González-García et al., it is difficult for them to conclude that postoperative radiotherapy induced multiple primary carcinomas because patients with more advanced disease in their study were all treated by postoperative radiotherapy and thus there was a selection bias [2]. Whether postoperative radiotherapy does induce multiple primary carcinomas should be investigated in specifically controlled clinical trials [2]. Prognosis The molecular and genetic characteristics and behavior of synchronous first multiple primary carcinomas are regarded as being more aggressive than those of metachronous multiple primary carcinomas and to have a lower disease-specific survival rate [30]. Patients may experience multiple primary carcinomas many times even if the previous tumor is not aggressive or treatment of the previous tumor is successful [8], or if they are younger and have a genetic predisposition to multiple primary carcinomas [10]. It
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was reported that patients with multiple primary carcinomas that arose first in the larynx were of advanced age [40]. Likewise, we found that patients with multiple primary carcinomas were older at first diagnosis than patients with single primary carcinoma. The impact of previous treatment on the tumor and the patient’s overall health status was found to affect the survival of patients with multiple primary carcinomas [21]. Although cervical lymph node metastasis occurred less frequently in our series, 6 patients with multiple primary carcinomas did not undergo surgery at the time of diagnosis because of poor general physical condition and intolerance for surgery, and they ultimately died from cervical lymph node metastasis. Thus, the survival of patients with multiple primary carcinomas was poorer than those with single primary carcinoma. We suggest that, whenever possible, at the least lymphadenectomy be performed for these patients. Our results showed that having more than 2 occurrences of multiple primary carcinomas or locoregional recurrence did not affect prognosis. Although the irregular anatomy and scar formation after surgery made it more difficult to diagnose and treat additional cancer [38], the findings of higher survival rates among patients with recurrent multiple primary carcinomas indicate that survival rates do not change as long as proper surgical resection is performed after each recurrence. These findings suggest that earlier diagnosis and treatment is effective. Second multiple primary carcinomas may occur long after onset of the first primary carcinoma [30]. Regueiro et al. [42] reported that the cumulative incidence rate for second multiple primary carcinomas after the onset of first carcinoma at 3 years was 3.6%. Boysen and Loven [34] reported that the annual incidence of second multiple primary carcinomas was higher in the oral region (4%) than in the head and neck region (3.6%). The cumulative incidence rate at 10 years was 8.0% in our series, which we believe is the first to be reported, and supports the need for close long-term follow up. Conclusions Characteristics were found to differ between patients with single primary oral SCC and those with multiple primary oral SCC. Patients with synchronous first multiple primary carcinomas had the worst prognosis. Multiple recurrences of multiple primary carcinomas did not affect prognosis. Overall health status and tolerance for cancer treatments affects the prognosis of patients with multiple primary carcinomas. Conflict of interest statement None declared. Acknowledgements The authors would like to thank all patients, nurses, and medical staff at Tokyo Medical and Dental University Hospital who enabled us to compile this report. References [1] Petersen PE. Strengthening the prevention of oral cancer: the WHO perspective. Community Dent Oral Epidemiol 2005;33(6):397–9. [2] González-García R, Naval-Gías L, Román-Romero L, Sastre-Pérez J, RodríguezCampo FJ. Local recurrences and second primary tumors from squamous cell carcinoma of the oral cavity: a retrospective analytic study of 500 patients. Head Neck 2009;31:1168–80. [3] Liao CT, Kang CJ, Chang JT, Wang HM, Ng SH, Hsueh C, et al. Survival of second and multiple primary tumors in patients with oral cavity squamous cell carcinoma in the betel quid chewing area. Oral Oncol 2007;43(8):811–9. [4] Cianfriglia F, Di Gregorio DA, Manieri A. Multiple primary tumours in patients with oral squamous cell carcinoma. Oral Oncol 1999;35(2):157–63.
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Clinical characteristics of multiple primary carcinomas of the oral cavity Yumi Mochizuki, Hiroyuki Harada ⇑, Minoru Ikuta, Hiroaki Shimamoto, Hirofumi Tomioka, Kae Tanaka, Hideaki Hirai, Ken Omura Department of Oral and Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan
a r t i c l e
i n f o
Article history: Received 11 August 2014 Received in revised form 17 November 2014 Accepted 20 November 2014 Available online 10 December 2014 Keywords: Multiple primary carcinomas Oral cavity Survival rate The cumulative incidence rate Squamous cell carcinoma
s u m m a r y Objectives: This study aimed to clarify the clinical characteristics of multiple primary carcinomas of the oral cavity. Materials and methods: We retrospectively reviewed the cases of 1015 patients who were treated during follow up for oral cancer at Tokyo Medical and Dental University between March 2001 and December 2012. We compared the clinical characteristics of 961 patients who developed single primary oral squamous cell carcinoma (SCC) during follow up and 54 patients who subsequently developed multiple primary carcinomas in the oral cavity. Results: Mean age at first diagnosis was significantly higher in patients with multiple primary carcinomas than single primary carcinoma. Multiple primary carcinomas showed a female predilection, were most prevalent in the gingiva, and tended to show earlier tumor and nodal stages than single primary carcinoma. The local recurrence rate was higher for multiple primary carcinomas than single primary carcinoma, and it increased with the number of multiple primary occurrences. The disease-specific survival rate at 10 years for patients with single primary carcinoma was 85.3% and that for patients with multiple primary carcinomas was 79.6%. The cumulative incidence rate for metachronous second multiple primary carcinomas after the onset of first carcinoma at 10 years was 8.0%. The recurrence of multiple primary carcinomas did not decrease the survival rate. Conclusion: Differences were found in the clinical characteristics between patients with single oral SCC and those with multiple primary oral carcinomas. Early diagnosis and treatment as well as close longterm follow up are needed for patients with multiple primary oral carcinomas. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Oral cancer, the sixth most prevalent cancer worldwide [1], is difficult to control even after treatment because of the high propensity for multiple primary carcinomas to develop [2–5]. The overall occurrence rate of multiple primary carcinomas in the oral cavity is between 6% and 27% [6–9], and its emergence has shown poor prognosis among patients who have already undergone treatment for early stage oral cancer [3,10,11]. Reducing its mortality and morbidity remains one of the most challenging problems. While molecular-based explanations of its pathomechanism have been reported, few studies have provided clinical information that is useful for daily practice. Oral and maxillofacial surgeons and head and neck oncologists would clearly benefit from knowing the Abbreviations: PVL, proliferative verrucous leukoplakia; SCC, squamous cell carcinoma. ⇑ Corresponding author. Tel.: +81 3 5803 5506; fax: +81 3 5803 0199. E-mail address: [email protected] (H. Harada). http://dx.doi.org/10.1016/j.oraloncology.2014.11.013 1368-8375/Ó 2014 Elsevier Ltd. All rights reserved.
characteristics of patients with this disease in order to identify and treat it expeditiously [12,13]. Therefore, this study aimed to examine the specific clinical features of, and discuss the clinical approach to managing, synchronous and metachronous multiple primary oral carcinomas. Materials and methods We retrospectively reviewed the medical records of patients with primary oral carcinoma who underwent surgical treatment at, and were followed by, the Department of Oral and Maxillofacial Surgery, Tokyo Medical and Dental University Hospital between March 2001 and December 2012. We studied only those patients who gave informed consent to be included in this study. The observation endpoints were set as June 30, 2014. Patients treated at another institute or with no pathology report or inadequate medical records were excluded. The study protocol was approved by our institution and was in accordance with the Declaration of Helsinki.
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Definitions of primary oral carcinoma Single primary carcinoma was defined as carcinoma that developed only once as a single primary lesion during the follow-up period. We limited this to oral squamous cell carcinoma (SCC). Multiple primary carcinomas were defined according to criteria modified from those of Warren and Gates in 1932 [14] and based on the ‘General Rules for Clinical and Pathological Studies on Oral Cancer’ proposed as a draft by the Japan Society for Oral Tumors [15], namely, more than 2 cancerous lesions separated by more than 1.5 cm of clinically non-cancerous epithelium in the oral cavity. As shown in Fig. 1, multiple primary carcinoma occurrence was categorized into synchronous or metachronous type and as first, second, or third multiple primary carcinomas. Synchronous multiple primary carcinomas were defined as more than 2 oral carcinomas separated by more than 1.5 cm of clinically non-cancerous epithelium synchronously or within 6 months of the original lesion. Metachronous multiple primary carcinomas were defined as more than 2 primary lesions that developed metachronously (after more than 6 months of each other) and were second or third occurrences. Local recurrence was defined as a lesion recurring within 1.5 cm of the original lesion. Distance between the lesions was determined by direct measurement from the newly onset lesion to the previous lesion and in reference to the patient’s medical records. If it was difficult to judge whether the distance was within 1.5 cm because of postoperative scar formation or irregular anatomy, the lesion was classified as a recurrent lesion. In view of the diagnostic criteria for proliferative verrucous leukoplakia (PVL) proposed by Cerero-Lapiedra et al. [16], we included patients with multiple primary OSCC who previously had PVL. Although in principle synchronous second and third multiple primary carcinomas are possible, they are rare and no such cases were observed in this study. Furthermore, because synchronous first multiple primary carcinomas greatly influence the survival of patients, we focus in this study on synchronous first multiple primary carcinomas and metachronous second and third primary carcinomas. For a detailed analysis of the features of multiple primary carcinomas, we studied differences in location, the interval between the first and later onsets of multiple primary carcinomas, cumulative incidence of second multiple primary carcinomas,
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recurrence, lymph node metastasis, and presence of mucosal changes after the onset of first multiple primary carcinomas. We compared differences in clinical features (age, sex, tobacco use, tumor location, TN classification, and stage) between the single primary carcinoma and the multiple primary carcinoma groups using the chi-squared or Fisher’s exact test for categorical data and we used one-way ANOVA for continuous variables. The disease-specific survival rates of the types of multiple primary carcinomas (i.e., synchronous first, metachronous, and metachronous third) were estimated by the Kaplan–Meier method. Also, differences in the disease-specific survival rates between patients with local recurrence and those with lymph nodes metastasis from the multiple primary carcinomas were analyzed by the log-rank test. Statistical analysis was performed using statistical PASW Statistics 18 software for Windows (SPSS Japan Inc., Tokyo, Japan). A p-value less than 0.05 was considered statistically significant. Results We analyzed data for 1015 patients: 961 with single primary carcinoma and 54 with multiple primary carcinomas. The median duration of follow-up was 64 (range, 4–146) months. Of the 54 patients with multiple primary carcinomas, 10 (20.4%) 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 and that between the onset of second and third multiple primary carcinomas (regardless of being synchronous or metachronous) was 63 (range, 28–124) months. Treatment protocols Of the 961 patients with single primary carcinoma, 843 underwent surgical treatment alone, 26 received brachytherapy (mean dose, 77.1 [range, 57.6–97.0] Gy), 38 received induction chemotherapy plus surgery (cisplatin and 5-FU, 34 cases; other, 4 cases),
Fig. 1. Flow diagram of patients who developed single primary carcinoma or multiple primary carcinomas during follow up after surgery for an initial occurrence of oral cancer. Number of recurrences are shown. Mean interval between primary tumor resection and recurrence was 22 (range, 2–86) months.
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and 54 received induction chemo-radiotherapy plus surgery (S-1, 36 cases; carboplatin, 9 cases; other, 9 cases; mean dose of external irradiation, 41.4 [30–56] Gy). When positive or close surgical margins were identified on histological examination of the surgical specimen, 43 received postoperative brachytherapy (mean dose, 75.5 [range, 62.0–91.0] Gy) and when advanced features at the primary site and/or cervical lymph nodes metastasis was identified, 81 received adjuvant chemotherapy (S-1, 33; cisplatin and 5-FU, 23 cases; other, 2) and 54 received adjuvant chemo-radiotherapy (S-1, 33; cisplatin and 5-FU, 19; other, 2; mean dose of external irradiation, 48.9 [range, 30–52] Gy). Of the 33 cases of metachronous second multiple primary carcinomas, 9 underwent brachytherapy (mean dose, 76.8 [range, 57.6–87.0] Gy) and 24 cases underwent surgery. Of the 11 cases of metachronous third multiple primary carcinomas, 3 underwent brachytherapy (mean dose, 67.2 [range, 57.6–77.0] Gy) and 8 underwent surgery. Age and sex Mean age at time of first diagnosis was significantly higher in patients with multiple primary carcinomas (median, 68.3 [range, 21–94] years) than in patients with single primary carcinoma (median, 61.6 [range, 28–86] years; F value = 9.511, p = 0.002). A total of 39 women and 15 men were diagnosed with multiple primary carcinomas, while 362 women and 599 men were diagnosed with single primary carcinoma. Multiple primary carcinomas occurred more frequently in women than men, while single primary carcinoma occurred more frequently in men than women (p < 0.001, Fisher’s exact test). Tobacco use Non-smokers accounted for 32 of 45 (71.1%) multiple primary carcinoma patients and 176 of 961 (18.3%) single primary carcinoma patients (v2 = 69.87, p < 0.001). Tumor location As Table 1 shows, the most common location for single primary carcinoma was the tongue (508/961, 52.9%), followed by the lower gingiva (162/961, 16.9%) and upper gingiva (94/961, 9.8%), while that for first multiple primary carcinomas was the lower gingiva, followed by the buccal mucosa. Mucosal change after the onset of first carcinoma was found in 14 of 33 patients (42.4%) with metachronous second multiple primary carcinomas and in 7 of 11 patients (63.6%) with metachronous third multiple primary carcinomas. Nine of 54 (16.7%; 2 men, 7 women) with multiple primary OSCC previously had PVL. T classification, cervical lymph node metastasis, and staging Table 2 shows T classification, cervical lymph node metastasis, and staging for single primary carcinoma and multiple primary carcinomas. The occurrence rate of T3–T4 disease with single primary carcinoma was 28.3% and that with multiple primary carcinomas at first occurrence was 5.6%. A significant difference in T classification was found between patients with single primary carcinoma and those with multiple primary carcinomas (v2 = 15.52, p = 0.001). Cervical lymph node metastasis showed no significant difference (Fisher’s exact test, p = 0.327), but did occur slightly more often with single primary carcinoma (287/ 961, 29.9%) than with multiple primary carcinomas (14/54, 25.9%). Although not statistically significant, the median age of patients with such metastasis (median, 69.0 [range, 57–81] years)
Table 1 Tumor location of single primary SCC and multiple primary carcinomas.
Tongue Lateral Inferior surface Dorsal surface Tongue + buccal mucosa Lower gingiva Lateral Mid gingiva Lower gingiva + Tongue Lower gingiva + Floor of mouth Lower gingiva + buccal mucosa Lower gingiva + buccal mucosa + upper gingiva Buccal mucosa Lateral Lip mucosa Buccal mucosa + lower lip Upper gingiva Unilateral Bilateral Upper gingiva + lower lip Floor of mouth Palate
Single primary SCC n = 961
Multiple primary SCC at first occurrence n = 54
461 4 3 0
11 2 0 1
185 4 0 0 0 0
14 1 1 3 1 1
85 3 0
6 0 1
113 0 0 69 34
4 1 1 2 4
Abbreviation: SCC, oral squamous cell carcinoma.
Table 2 Tumor staging for single primary SCC and multiple primary carcinomas.
T stage T1 T2 T3 T4
Single primary SCC n = 961
Multiple primary SCC at first occurrence n = 54
319 370 118 154
20 31 2 1
p = 0.001 (v2 = 15.52)
N N+ N
p value
p = 0.327 (Fisher’s exact test) 287 674
14 40
Abbreviation: SCC, oral squamous cell carcinoma.
was higher than that of patients without it (median, 68.0 [range, 28–86] years; F value = 0.101, p = 0.752). Local recurrence As Fig. 1 shows, local recurrence was seen in 87 of the 961 (9.1%) patients with single primary carcinoma. For patients with multiple primary carcinomas, the local recurrence rate was 37% (20/54): 10.0% (1/10) for synchronous first multiple primary carcinomas, 42.4% (14/33) for metachronous second multiple primary carcinomas, and 45.5% (5/11) for metachronous third multiple primary carcinomas. Cumulative incidence rate for secondary multiple primary carcinomas The cumulative incidence rates for metachronous second multiple primary carcinomas after the onset of first carcinoma at 5 and 10 years were 2.8% and 8.0%, respectively (Fig. 2). Disease-specific survival rates The disease-specific survival rate for patients with single primary carcinoma was 87.3% and 85.3% at 5 and 10 years, respectively, and for patients with multiple primary carcinomas
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Fig. 2. Cumulative incidence rate for metachronous second multiple primary carcinomas.
Fig. 3. Disease-specific survival rates of patients with single primary carcinoma and those with multiple primary carcinomas.
was 90.7% at 5 years and 79.6% at 10 years. The disease-specific survival rate for patients with multiple primary carcinomas was significantly lower (log-rank test, p = 0.017; Fig. 3). For patients with multiple primary carcinomas, the disease-specific survival rate for those with synchronous first multiple primary carcinomas decreased to 80.0% at 1 year and remained stable at 10 years. The rate for patients with metachronous second multiple primary carcinomas was 90.9% and 75.8% at 5 and 10 years, respectively, and for patients with metachronous third multiple primary carcinomas was 100% and 90.0%, respectively (Fig. 4). The disease-specific survival rate was significantly higher for patients with local recurrence (log-rank test, p = 0.045; Fig. 5) and significantly lower for patients with cervical lymph node metastasis (log-rank test, p = 0.004; Fig. 6). Six patients (6/14, 42.9%) did not undergo surgery because of advanced age and poor general health, and they ultimately died of cervical lymph node metastasis. Discussion The epidemiological data on multiple primary carcinomas remain relatively scarce. From the findings reported so far, it
appears that multiple primary carcinomas are less likely to occur as advanced disease (T3–T4) [10] or to co-occur with cervical lymph node metastasis (pN+) [10]. The occurrence rate of T3–T4 disease with single primary carcinoma was reported at 48.2% and that with multiple primary carcinomas at first occurrence 38.5%, while the corresponding occurrence rates of cervical lymph node metastasis were 53.6% and 38.5% [17]. In the present study, there was a tendency for cases of multiple primary carcinomas to show earlier tumor and nodal stages than cases of single primary carcinoma. It is well known that patients with multiple primary carcinomas have increased postoperative morbidity and mortality rates [11]. Although there have been few reports focusing on cancer in the oral region, one study found the disease-specific survival rate at 5 years for patients with single primary carcinoma was 87.0% and for patients with multiple primary carcinomas was 73.8% [17]. Our finding of a lower disease-specific survival rate for patients with multiple primary carcinomas is in agreement. Lai et al. [9] and González-García et al. [2] have both suggested that the biological behavior of tumors differ between single primary carcinoma and multiple primary carcinomas, and this may account for the differences.
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Fig. 4. Disease-specific survival rates of patients according to type of multiple primary carcinomas of the oral cavity.
Fig. 5. Disease-specific survival rates of patients with multiple primary carcinomas with and without local recurrence.
Fig. 6. Disease-specific survival rates of patients with multiple primary carcinomas with and without cervical lymph node metastasis.
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Location Oral mucosa is classified into (1) specialized epithelium (dorsal tongue), (2) keratinized (masticatory) epithelium, (3) non-keratinized (lining) epithelium, and (4) tongue epithelium (epithelium on the lateral border of the tongue). The locations of single primary carcinoma and multiple primary carcinomas have been reported to be different [3,4,18]. Our study revealed that single primary SCC lesions most frequently occurred in non-keratinized (lining) epithelium such as the floor of mouth, buccal mucosa, and the specialized mucosa of the tongue. In contrast, multiple primary carcinomas most frequently occurred in keratinized (masticatory) epithelium such as the gingiva and hard palate. Non-keratinized lining mucosa generally exhibits a lower host immunological response than keratinized mucosa [19]. The proportion of cases of single SCC in the areas of non-keratinized lining mucosa and specialized mucosa of the tongue was previously found to be high, and the carcinomas in these areas had identifiable etiological risk factors [20]. One of the reasons that single primary SCC is considered to show a higher incidence of cervical lymph nodes metastasis and higher nodal stages is that non-keratinized lining mucosa and the specialized mucosa of the tongue show local progression and easier dissemination of cancer cells through lymphatic drainage, resulting in regional lymph node metastasis [21]. The mucosal immune response of the keratinized mucosa defends against carcinogens and regional lymph nodes metastasis. The morbidity rate of multiple primary carcinomas, but not single primary carcinoma, in keratinized epithelium was found to be high, and lymph node metastasis from multiple primary carcinomas was not infrequent in keratinized epithelium [20]. PVL, first reported by Hansen et al. [22], is an oral epithelial disease with multifocal hyperkeratosis that eventually becomes exophytic, showing the presence of a verrucous lesion with proliferative confluence that becomes verrucous carcinoma or SCC [16,23]. It tends to show more aggressive biological behavior than other forms of leukoplakia [16], with high rates of malignant transformation (60–100%), recurrence (87–100%), and mortality (30–50%) [24]. In our study, 9 of 54 patients (16.7%) with multiple primary OSCCs were previously diagnosed with PVL. Among the few previous reports on this patient population, 10 of 19 (52.63%) patients with single primary OSCC developed from PVL had a second primary tumor [25] and 3 of 20 (15%) with multiple primary OSCCs had previously diagnosed PVL [26]. Further studies are needed to clarify the relationship between multiple primary OSCCs and PVL and the epidemiology of multiple primary OSCCs that have developed from PVL. Smokers are more likely to have synchronous carcinomas involving the entire aerodigestive tract, and 80% of the next occurrence of multiple primary carcinomas again involved the entire aerodigestive tract [13]. By contrast, patients with first multiple primary carcinomas in the oral cavity without tobacco or alcohol exposure (almost 70% of which were women) had the next occurrence of multiple primary carcinomas only in oral cavity [13,26– 28]. It has been suggested that the cancerization of multiple primary carcinomas had some relation with the molecular and genetic characteristics of the cancer cells in multiple primary carcinomas [29]. Further research into multiple primary carcinomas is needed from the perspective of the molecular and genetic characteristics of the cancer cells. The incidence rates of multiple primary carcinomas and its recurrences differ according to the definition of multiple primary carcinomas used [2]. In regard to the criterion of distance between lesions, some studies have defined multiple primary carcinomas as lesions separated by more than 2 cm in the oral cavity [2,26]. In our study, we used more than 1.5 cm as defined by the Japan Society
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for Oral Tumors. Given the typical size of the oral cavity of Japanese people, this definition is suitable for studying Japanese patients with multiple primary carcinomas in the oral cavity and has been applied by previous studies in Japan [30]. Treatment The treatment of choice for multiple primary carcinomas is surgery. The significance of negative surgical margins and surgical margins more than1 cm are less important in multiple primary carcinoma cases [2,31]. Mucosa with genetically changed but histologically normal cells has a high risk of malignant transformation and is referred to as ‘‘condemned mucosa’’ [33,34]. Because of the field cancerization of the oral mucosa [32–34], even when the entire tumor appears to be adequately excised, new multiple primary carcinomas may develop multicentrically from genetically altered cells in the ‘‘condemned mucosa’’ distant from the surgical site [35,36]. The condemned mucosa shows clinically recognizable stages of epithelial carcinogenesis [3]. Clinically recognizable premalignant mucosal changes such as leukoplakia or erythroplakia may transform into cancer earlier than in mucosa with no such recognizable changes [3]. In our study, a high incidence of mucosal change (25/54, 46.2%) was observed after the onset of first carcinoma. Some researchers have suggested that multiple primary carcinomas manifest as multiple independent lesions in the condemned mucosa due in part to genetic alteration and occasionally develop to coalesced multiple independent lesions [9,37]. Although limited surgical resection is occasionally performed to avoid severe dysfunction postoperatively [38], mucosa with changes such as leukoplakia or erythroplakia should be resected in an en bloc fashion whenever possible [12,13]. Chemokines and promigratory factors and wound-associated angiogenesis in the provisional surgical wound in the immediate postoperative period may promote local tumor formation [39]. Our study revealed a higher incidence of local recurrence for multiple primary carcinomas than for single primary carcinoma, and the local recurrence rate increased with the number of multiple primary occurrences (Fig. 1). The pathogenesis for the appearance of multiple primary carcinomas and recurrence has been explained by the concept of field cancerization [2]. Because genetically altered cells may be present in the mucosa adjacent to the surgical margins in the condemned mucosa, the adjacent mucosa of multiple primary carcinomas should be examined closely for emergence of another carcinoma. Hashibe et al. observed that radiotherapy became a risk factor for oral cancer at more than 10 years of follow up but was protective against second primary cancer within the first year [40]. They also stated that cancers in the irradiated head and neck area could be explained by potential mechanisms such as DNA damage [41]. However, according to González-García et al., it is difficult for them to conclude that postoperative radiotherapy induced multiple primary carcinomas because patients with more advanced disease in their study were all treated by postoperative radiotherapy and thus there was a selection bias [2]. Whether postoperative radiotherapy does induce multiple primary carcinomas should be investigated in specifically controlled clinical trials [2]. Prognosis The molecular and genetic characteristics and behavior of synchronous first multiple primary carcinomas are regarded as being more aggressive than those of metachronous multiple primary carcinomas and to have a lower disease-specific survival rate [30]. Patients may experience multiple primary carcinomas many times even if the previous tumor is not aggressive or treatment of the previous tumor is successful [8], or if they are younger and have a genetic predisposition to multiple primary carcinomas [10]. It
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was reported that patients with multiple primary carcinomas that arose first in the larynx were of advanced age [40]. Likewise, we found that patients with multiple primary carcinomas were older at first diagnosis than patients with single primary carcinoma. The impact of previous treatment on the tumor and the patient’s overall health status was found to affect the survival of patients with multiple primary carcinomas [21]. Although cervical lymph node metastasis occurred less frequently in our series, 6 patients with multiple primary carcinomas did not undergo surgery at the time of diagnosis because of poor general physical condition and intolerance for surgery, and they ultimately died from cervical lymph node metastasis. Thus, the survival of patients with multiple primary carcinomas was poorer than those with single primary carcinoma. We suggest that, whenever possible, at the least lymphadenectomy be performed for these patients. Our results showed that having more than 2 occurrences of multiple primary carcinomas or locoregional recurrence did not affect prognosis. Although the irregular anatomy and scar formation after surgery made it more difficult to diagnose and treat additional cancer [38], the findings of higher survival rates among patients with recurrent multiple primary carcinomas indicate that survival rates do not change as long as proper surgical resection is performed after each recurrence. These findings suggest that earlier diagnosis and treatment is effective. Second multiple primary carcinomas may occur long after onset of the first primary carcinoma [30]. Regueiro et al. [42] reported that the cumulative incidence rate for second multiple primary carcinomas after the onset of first carcinoma at 3 years was 3.6%. Boysen and Loven [34] reported that the annual incidence of second multiple primary carcinomas was higher in the oral region (4%) than in the head and neck region (3.6%). The cumulative incidence rate at 10 years was 8.0% in our series, which we believe is the first to be reported, and supports the need for close long-term follow up. Conclusions Characteristics were found to differ between patients with single primary oral SCC and those with multiple primary oral SCC. Patients with synchronous first multiple primary carcinomas had the worst prognosis. Multiple recurrences of multiple primary carcinomas did not affect prognosis. Overall health status and tolerance for cancer treatments affects the prognosis of patients with multiple primary carcinomas. Conflict of interest statement None declared. Acknowledgements The authors would like to thank all patients, nurses, and medical staff at Tokyo Medical and Dental University Hospital who enabled us to compile this report. References [1] Petersen PE. Strengthening the prevention of oral cancer: the WHO perspective. Community Dent Oral Epidemiol 2005;33(6):397–9. [2] González-García R, Naval-Gías L, Román-Romero L, Sastre-Pérez J, RodríguezCampo FJ. Local recurrences and second primary tumors from squamous cell carcinoma of the oral cavity: a retrospective analytic study of 500 patients. Head Neck 2009;31:1168–80. [3] Liao CT, Kang CJ, Chang JT, Wang HM, Ng SH, Hsueh C, et al. Survival of second and multiple primary tumors in patients with oral cavity squamous cell carcinoma in the betel quid chewing area. Oral Oncol 2007;43(8):811–9. [4] Cianfriglia F, Di Gregorio DA, Manieri A. Multiple primary tumours in patients with oral squamous cell carcinoma. Oral Oncol 1999;35(2):157–63.
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