An Analysis of Distant Metastases in Oral Squamous Cell Carcinoma

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1 Original Araki Yasui et al. : Distant Metastases in Oral Squamous Cell Carcinoma Journal of Hard Tissue Biology 19[1] (2010) p The Hard Tissue Biology Network Association Printed in Japan, All rights reserved. CODEN-JHTBFF, ISSN Online ISSIN X An Analysis of Distant Metastases in Oral Squamous Cell Carcinoma Araki Yasui 1,2), Yasuo Okada 3), Izumi Mataga 1) and Masataka Katagiri 4) 1) Department of Oral & Maxillofacial Surgery, The Nippon Dental University, School of Life Dentistry at Niigata, 1-8 Hamauracho, Chuo-ku, Niigata City, Niigata , Japan. 2) Yasui Dental Clinic, Higashi-dori, Akita City, Akita , Japan. 3) Department of Pathology, The Nippon Dental University, School of Life Dentistry at Niigata, 1-8 Hamaura-cho, Chuo-ku, Niigata City, Niigata , Japan. 4) The Nippon Dental University, Fujimi, Chiyoda-ku, Tokyo, , Japan. (Accepted for publication, March 10, 2010) Abstract: Metastases to distant organs are well known to be factors influencing prognosis in patients with oral cancer. Therefore, it is very important to detect the metastasis of cancer as early as possible and to investigate the factors associated with the mechanism of metastasis. This study evaluated the risk of distant metastasis by the degree of histological malignancy among 59 patients with oral squamous cell carcinoma (SCC) who were treated at our department during the past five years. The degree of histological malignancy of initial biopsy specimens was evaluated by Anneroth s classification and its relationship with metastasis was analyzed. Distant metastasis occurred in 7 of 59 patients (11.9%) and was located predominantly in the lung and bone. There was a significant correlation between the degree of histological malignancy and distant metastasis (P<0.05); however, there was no significant difference between T classification and metastasis in the distant organs. It is considered that histological malignancy is useful for predicting the prognosis and deciding additional treatments for oral SCC. When a total score on histological malignancy grading exceeds 14, metastasis in the distant organs should be carefully considered. Key words: Oral region, Squamous cell carcinoma, Distant metastasis, Histological malignancy grading Introduction Patients and Methods Since not only the suppression of primary lesion but also the Patients presence or absence of metastasis in the distant organs may greatly Fifty-nine from 65 patients with primary oral SCC who were influence the outcome of oral cancer, suppression of metastasis admitted and underwent treatment in our department during the has become an important subject 1). However, the therapeutic past five years, and who were conducted at least ten-year followup, regimen has been selected mainly based on the stage of clinical were selected as subjects for this study. Regarding the progression in most cases. Therefore, metastasis may occur even treatment method, treatment with a combination of surgery, in T1 and T2 cases and it is often difficult to suppress distant chemotherapy and radiotherapy was applied to 24 cases, surgery metastasis due to insufficient prediction, with rather unfavorable alone to 13 cases, treatment combined with surgery and therapeutic results. Thus, an adequate therapeutic regimen needs chemotherapy to 12 cases, treatment combined with chemotherapy to be established by clarifying possible factors involved in distant and radiotherapy to 9 cases, and treatment combined with surgery metastasis in individual cases. In the present study, we clinically and radiotherapy to 1 case. The primary SCC sites of these patients evaluated the relationship between T classification and the distant were the tongue in 23 cases, mandibular gingiva in 15 cases, floor metastasis in patients with oral squamous cell carcinoma (SCC) of the mouth in 8 cases, buccal mucosa in 7 cases and maxillary encountered during the past five years in our department. gingiva in 6 cases. Moreover we histopathologically observed the biopsy specimens of primary lesion and evaluated the relationship between the Procedures degree of histological malignancy based on Anneroth s In relation to metastasis, T classification was examined classification 2) and metastasis in the distant organs. clinically, while the degree of histological malignancy of biopsy specimens of primary lesion was evaluated according to Corresponding to: Araki Yasui, DDS, PhD. Yasui Dental Clinic, Higasi-dori, Akita City, Akita , Japan. Tel: , Fax: yasui-dc@sa2.gyao.ne.jp Anneroth s classification 2). A total of 6 parameters were evaluated: namely, 3 parameters including the degree of keratinization, 27

2 J.Hard Tissue Biology Vol. 19(1):27-32, 2010 Primary site Mandibular Buccal Maxillary T classification* Tongue gingiva Oral floor mucosa gingiva Total T1 0/9 0/2 1/5 0/1-1/17 ( 5.9 %) T2 1/9 0/8 0/2 0/5 0/2 1/26 ( 3.8 %) T3 2/5 1/2-0/1 1/3 4/11 (36.4 %) T4-0/3 0/1-1/1 1/5 (20.0 %) Total 3/23 1/15 1/8 0/7 2/6 7/59 (11.9 %) *The extent of the primary tumor : UICC 2002 Table 1. Relationship between T classification and metastasis Table 2. Patient characteristics with distant organs metastasis Case Gender Age Primary Site T* pn** Metastasis to Histological No. (yrs) distant organs malignancy 1 M 66 oral floor T1 pn1 lung (1yr 2mos. after ope.) 14 2 M 60 tongue T2 pn0 lung (2yrs 8mos. after ope.) 14 3 F 60 tongue T3 pn1 lung (3mos. after ope.) 19 lumbar vertebrae (7mos. after ope.) 4 F 60 tongue T3 pn2c lung (2yrs 3mos. after ope.) 15 5 M 45 maxillary gingiva T3 pn2b lung, clavicle, rib, ilium 19 (9mos. after ope.) 6 M 59 mandibular gingiva T3 pn2b lung (3mos. after ope.) 16 7 M 65 maxillary gingiva T4 - lung (First visit) 21 scapula (2mos. after first visit) *The extent of the primary tumor : UICC 2002 **The pathological assessment of the regional lymph nodes : UICC 2002 Table 3. Relationship between T classification and the degree of histological malignancy T classification* Histological malignancy T ± 2.40 T ± 2.10 T ± 3.11 T ± 3.27 *The extent of the primary tumor : UICC 2002 The data are expressed as the mean ± standard deviation nuclear polymorphism and number of mitoses as factors for tumor cell population, and 3 parameters including pattern of invasion, stage of invasion and degree of lymphoplasmocytic infiltration as factors for tumor-host relationship. Biopsy specimens of the primary lesion were stained by Hematoxylin-Eosin (HE). Statistical analysis Each value of histological malignancy was expressed as mean ± standard deviation (SD). Relationships between metastasis and histological malignancy were tested using the Mann-Whitney U- test. P<0.05 was considered statistically significant. Statistical analyses were performed using Stat View (Abacus Concepts Inc., Berkeley, CA, USA, 1998). Results Metastatic rate and the affected site Metastases were noted in 7 out of 59 cases (11.9%), counting 4 cases of solitary metastasis and 3 cases of multiple metastases in 7 cases, with 12 sites of metastases in total. The metastases were located predominantly in the lung and bone (Tables 1, 2). Relationship between T classification and metastasis According to T classification, there were 17 cases of T1, 26 cases of T2, 11 cases of T3 and 5 cases of T4. The metastatic rate in T1 cases was 5.9% and that of T2 cases was 3.8%, while the rate in T3 cases was as high as 36.4% and that of T4 cases was 20%. However, there was no significant difference. Regarding 28

3 Araki Yasui et al. : Distant Metastases in Oral Squamous Cell Carcinoma Table 4. Relationship between histological malignancy and metastasis Histological Metastasis No metastasis malignancy (7 cases) (52 cases) Total scores ± ± 2.17 P<0.05 Degree of keratinization 2.43 ± ± 0.62 P<0.05 Nuclear polymorphism 3.00 ± ± 0.63 P<0.05 Number of mitoses 2.00 ± ± 0.42 P<0.05 Pattern of invasion 3.14 ± ± 0.72 P<0.05 Stage of invasion 3.86 ± ± 1.33 P<0.05 Lymphoplasmocytic infiltration 2.43 ± ± 0.62 Mean scores 2.81 ± ± 0.36 P<0.05 The data are expressed as the mean ± standard deviation Figure 1. Sixty-year-old man with carcinoma of the tongue in case No.2. (A) Left side of tongue tumor at first visit. (B) Macroscopic findings of autopsy. (C) Initial biopsy shows well differentiated SCC. Total score of Anneroth s histological malignancy was 14 points, and each score of 6 parameters was as follows: keratinization 2, nuclear polymorphism 2, number of mitoses 1, pattern of invasion 2, stage of invasion 4, lymphoplasmocytic infiltration 3 (HE 200). (D) Histopathological findings of autopsy specimen of metastasis tumor in lung (HE 200). Bars: 100µm the site of primary lesion, the metastatic rate was 3/23 (13.0%) in the tongue, 1/15 (6.7%) in the mandibular gingiva, 1/8 (12.5%) in the oral floor, 0/7 (0%) in the buccal mucosa and 2/6 (33.3%) in the maxillary gingiva. Although no metastasis was observed in T1 cases of primary lesion in the tongue, mandibular gingiva and buccal mucosa, metastasis was observed in T1 cases of primary lesion in the oral floor. The relationship between T classification and the degree of histological malignancy was examined: the degree of histological malignancy in T1, T2, T3 and T4 cases was ± 2.40, ± 2.10, ± 3.11, and ± 3.27, respectively. Thus, the larger T classification, the higher the histological malignancy observed (Tables 1 3). Relationship between degree of histological malignancy and metastasis Regarding the relationship between the degree of histological malignancy and metastasis, both total and mean scores were significantly higher in the cases with metastasis (16.86 ± 2.78) than in the cases without metastasis (12.21 ± 2.17) (P<0.05). In the former cases, mean values for all 6 parameters were higher 29

4 J.Hard Tissue Biology Vol. 19(1):27-32, 2010 than those in the latter. Among the 6 parameters, a significant prediction. Jakobsson et al. 15) evaluated 8 parameters in total: 4 difference was observed in the degree of keratinization (P<0.05), parameters including structure, keratinization tendency, nuclear nuclear polymorphism (P< 0.05), number of mitoses (P<0.05), aberrations and number of mitoses as factors for tumor cell pattern of invasion (P<0.05), and stage of invasion (P<0.05). No population, and 4 parameters including mode of invasion, stage distant metastatis was observed in the patients whose total score of invasion, vascular invasion and degree of lymphoplasmocytic on histological malignancy grading was lower than 13, while infiltration as factors for tumor-host relationship, which indicated distant metastasis was observed in 7 of the 26 patients (26.9%), a distinct relation between the degree of histological malignancy whose total score was higher than 14 (Table 4, Fig. 1). and recurrence or survival rate in patients with carcinoma of the larynx. In 1975, however, Willén et al. 16) evaluated 6 of the 8 Discussion parameters by excluding the structure because of resemblance to In cases of oral SCC, metastasis may occur even in T1 or T2 the mode of invasion and the vascular invasion because of its cases of primary tumor, which is a problem when establishing a difficulty in judging induced by possible individual differences therapeutic regimen. However, predictive factors for metastasis in the vascular distribution. Thereafter, they reported that a relation of oral SCC have not been established. In the present study, existed between metastasis and prognosis in SCC of the gingiva. metastasis was examined clinically and histopathologically in Lund et al. 17) and Holm et al. 18) reported a relation of histological patients with oral cancer in order to elucidate the factors involved malignancy evaluated by multiple factors to the prognosis in SCC in the mechanism of metastasis. The metastatic rate was reported of the tongue. Further, Yamamoto et al. 19) focused on the mode of to be from 7.5 to 57% in patients with oral SCC 3-8). Metastasis invasion for the parameter and subdivided Grade 4 proposed by was detected in 11.9% as a whole in this study, which was lower Jakobsson et al. 15) into Grade 4C and 4D. They subsequently than the results reported by other authors. As for the metastatic reported a possible relation between metastasis in the cervical rate by different sites of primary lesion, no metastasis was observed lymph nodes and histological malignancy judged by these in the buccal mucosa. This may be explained by the fact that the modified prognostic factors. We also reported a possible relation primary tumor was confined to the buccal mucosa region and did between metastasis in the cervical lymph nodes and histological not extend to the gingiva in this study. malignancy evaluated by multiple factors 20). In 1987, Anneroth The most common organ of distant metastasis of oral SCC et al. 2) reviewed these reports published after Broders s study 13), was lung and this tendency corresponded to other reports 1, 3-10). and a total of 6 parameters (3 parameters including degree of The second most frequent organ of metastases was reported to be keratinization, nuclear polymorphism and number of mitoses as liver 4, 5). Merino et al. 7) reported that 33 metastases in liver were factors for tumor cell population, and 3 parameters including found in 546 cases with SCC of the head and neck region but pattern of invasion, stage of invasion and degree of only one case was found in 116 oral SCC cases. The frequency lymphoplasmocytic infiltration as factors for tumor-host of liver metastases from oral SCC appears to be limited and no relationship) were assessed in 4 grades from 1 to 4 points each metastasis was found in this study. and the total number of points was used as a predictor for the Although the metastatic rate was higher in T3 (36.4%) and T4 degree of histological malignancy. As compared with conventional cases (20.0%) as compared to T1 and T2 cases (4 to 6%), no reports on assessment, the border between various score results significant difference was noted among them. This suggested can be depicted clearly in simplified figures and tables with misprediction of metastasis can be induced when considering T distinctly indicated number of cancer cells and mitoses as well as classification alone as a predictive factor for metastasis. Some the clarified degree of depth achieved by anatomical evaluation, authors found a significant correlation between local extension all of which enable us to evaluate the degree of histological of tumor and risk of distant metastases 1, 7, 10), whereas others did malignancy in a simpler and more objective way. Therefore, not find this 11, 12). Thus, a systematic assessment, including other among various assessment methods, the method of evaluating the factors, appears to be necessary. degree of histological malignancy according to the classification A possible relation of the degree of malignancy judged by proposed by Anneroth et al. 2) was used in the present study. A histopathological findings to prognosis of oral SCC has been significant correlation was found between the degree of investigated since Broders 13) reported the degree of keratinization histological malignancy and metastasis, indicating that histological of cancer cells in relation to prognosis of oral cancer in In malignancy could serve as a predictor for metastasis. 1966, Arthur and Fenner 14) reported a significant correlation The therapeutic regimen should be judged by the factors of between prognosis of tongue cancer and histological parameters not only T classification but also the evaluation of the degree of such as the keratinization, mitosis, hyperchromatism, and cell histological malignancy. Anneroth et al. 21) reported that the SCC irregularity. Their report led to the tendency in research to establish cases of the floor of the mouth were histopathologically divided the systematic assessment of multiple factors for prognosis into two groups with low malignancies (mean points ranging from 30

5 Araki Yasui et al. : Distant Metastases in Oral Squamous Cell Carcinoma 1.0 to 2.5) and high malignancies (mean points ranging from 2.6 to 4.0) and they showed a statistical significance between clinical stage and mean of malignancy score. In this study, the degree of 10. Probert JC, Thompson RW and Bagshaw MA. Patterns of spread of distant metestases in head and neck cancer. Cancer 33: , 1974 histological malignancy of the cases with metastasis was ± 2.78 ( ), and that of the cases without metastasis was ± 2.17 ( ). The total score of histological malignancy of the metastatic group was significantly higher than 11. Ellis ER, Mendenhall WM, Rao PV, Parsons JT, Spangler AE and Million RR. Does node location affect the incidence of distant metastases in head and neck squamous cell carcinoma? Int J Radiat Oncol Biol Phys 17: , 1989 that of the non-metastatic group. These results suggested that 14 points is the critical score in judging histological malignancy and that metastasis should be carefully considered when the degree of histological malignancy exceeds a total score of 14. Nevertheless, further investigation of predictive factors for metastasis of oral SCC is required 12. Leemans CR, Tiwari R, Nauta JJ, van der Waal I and Snow GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer 71: , Broders AC. Squamous-cell epithelioma of the lip. JAMA 74: , Arthur JF and Fenner ML. The influence of histological References grading of prognosis in carcinoma of the tongue (A computer 1. León X, Quer M, Orús C, Venegas MdP and López M. Distant metestases in head and neck cancer patients who achieved loco-regional control. Head Neck 22: , 2000 analysis of 299 cases). Clin Radiol 17: , Jakobsson PÅ, Eneroth C-M, Killander D, Moberger G and Mårtensson B. Histologic classification and grading of 2. Anneroth G, Batsakis J and Luna M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinomas. Scand J Dent Res 95: , 1987 malignancy in carcinoma of the larynx. Acta Radiol Ther Phys Biol 12: 1-8, Willén R, Nathanson A, Moberger G and Anneroth G. Squamous cell carcinoma of the gingiva: Histological 3. Braund RR and Martin HE. Distant metastasis in cancer of the upper respiratory and alimentary tracts. Surg Gynec & Obst 73: 63-71, 1941 classification and grading of malignancy. Acta Otolaryngol 79: , Lund C, Søgaard H, Elbrønd O, Jørgensen K and Andersen 4. Peltier LF, Thomas LB, Barclay THC and Kremen AJ. The incidence of distant metestases among patients dying with head and neck cancers. Surgery 30: , 1951 AP. Epidermoid carcinoma of the tongue: Histologic grading in the clinical evaluation. Acta Radiol 14: , Holm L-E, Lundquist P-G, Silfverswärd C and Sobin A. 5. Topazian DS. Distant metastasis of oral carcinoma. OS, OM & OP 14: , 1961 Histological grading of malignancy in squamous cell carcinoma of the oral tongue. Acta Otolaryngol 94: , 6. O brien PH, Carlson R, Steubner EA and Stanley CT. Distant metestases in epidermoid cell carcinoma of the head and neck. Cancer 27: , Yamamoto E, Miyakawa A and Kohama G. Mode of invasion and lymph node metastasis in squamous cell carcinoma of 7. Merino OR, Lindberg RD and Fletcher GH. An analysis of distant metestases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 40: , 1977 the oral cavity. Head Neck Surg 6: , Okada Y, Mataga I, Katagiri M and Ishii K. An analysis of cervical lymph nodes metastasis in oral squamous cell 8. Dennington ML, Carter DR and Meyers AD. Distant metastases in head and neck epidermoid carcinoma. Laryngoscope 90: , 1980 carcinoma: Relationship between grade of histological malignancy and lymph nodes metastasis. Int J Oral Maxillofac Surg 32: , Liao C-T, Wang H-M, Chang J T-C, Ng S-H, Hsueh C, Lee L-Y, Lin C-H, Chen I-H, Huang S-F and Yen T-C. Analysis of risk factors for distant metastases in squamous cell carcinoma of the oral cavity. Cancer 110: , Anneroth G, Batsakis JG and Luna M. Malignancy grading of squamous cell carcinoma in the floor of the mouth related to clinical evaluation. Scand J Dent Res 94: ,

6 J.Hard Tissue Biology Vol. 19(1):27-32,