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Clinical study of mode of invasion in tongue squamous cell carcinoma
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Original research
Clinical study of mode of invasion in tongue squamous cell carcinoma Nobuharu Yamamoto a,b,∗ , Ryuta Osaka a , Yukio Watabe a , Nobuo Takano a , Kenichi Matsuzaka c , Takahiko Shibahara a,b a b c
Department of Oral and Maxillofacial Surgery, Tokyo Dental College, 1-2-2, Masago, Mihama-Ku, Chiba 261-8502, Japan Oral Cancer Center, Tokyo Dental College, 5-11-13, Sugano, Ichikawa, Chiba 272-8513, Japan Department of Clinical Pathophysiology, Tokyo Dental College, 1-2-2, Masago, Mihama-Ku, Chiba 261-8502, Japan
a r t i c l e
i n f o
Article history: Received 25 October 2012 Received in revised form 11 February 2013 Accepted 26 February 2013 Keywords: Oral cancer Tongue squamous cell carcinoma Mode of invasion
a b s t r a c t Objective: The most commonly used system of classification for the evaluation of histological malignancy in oral squamous cell carcinoma is the Yamamoto–Kohama (Y–K) classification, which focuses on the shape of tumor cell cords at the tumor–host interface, an item also included in the Jakobsson and Anneroth classifications. In this clinical study, we investigated the relationship between mode of invasion as based on the Jakobsson and Y–K classifications and prognosis in patients with tongue squamous cell carcinoma treated at our department. Patients and methods: One hundred and sixty-eight of the 193 patients with tongue squamous cell carcinoma treated in at our department over an 11-year period between 2000 and 2010 were included in this study (25 were excluded as the mode of invasion could not be determined according to the Y–K classification). Results: According to the Jakobsson classification, 26, 33, 53, and 56 tumors were classified as grades 1–4, respectively. According to the Y–K classification, 26, 33, 53, 31, and 25 tumors were classified as grades 1–3, 4C, and 4D, respectively. Conclusion: Patients with grade 4C/4D tumors had many poor prognostic factors, including a pN-positive rate of 73.5%, mortality, recurrence, and late metastasis rate of 44.2%. The tumors in this group exhibited both endophytic and exophytic growth patterns, and the 5-year-survival rate was significantly lower than that in patients with other grade tumors. These results suggest that grade 4C/4D is a useful prognostic factor. © 2013 Asian Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
1. Introduction The malignancy of oral squamous cell carcinoma is usually determined histologically in accordance with the conventional World Health Organization (WHO) grading system [1], in which typing is mainly based on the degree of differentiation to stratified squamous epithelium. The attraction of this system is that histologic grade correlates to some extent with prognosis and lymph node metastasis. A number of alternatives exist, however, including the classifications of Jakobsson (Willem) [2,3] and Anneroth [4,5], in which malignancy is evaluated according to the sum of scores based on 6–8 factors at the tumor–host interface. Although many studies have demonstrated the usefulness of these two systems, they have yet to gain wide acceptance due to their complexity. At
many hospitals in Japan, particularly in the field of oral surgery, the Yamamoto–Kohama (Y–K) [6–8] classification is used. This system focuses on the shape of tumor cell cords at the tumor–host interface, which is also one of the items included in the Jakobsson and Anneroth classifications. A recent publication by WHO indicated that grade shows only a weak correlation with prognosis, and that a diffuse mode of invasion at the deep border is more important [9]. However, to our knowledge, no studies have compared the Y–K classification with these other systems, making an evaluation of their relative effectiveness difficult. In this clinical study, the relationship between mode of invasion as based on the Jakobsson and Y–K classifications and prognosis was investigated in patients with tongue squamous cell carcinoma treated at our department. 2. Patients and methods
∗ Corresponding author at: Department of Oral and Maxillofacial Surgery, Tokyo Dental College, 1-2-2, Masago, Mihama-Ku, Chiba 261-8502, Japan. Tel.: +81 47 322 0151; fax: +81 47 324 8533. E-mail address: [email protected] (N. Yamamoto).
One hundred and ninety-three patients with tongue squamous cell carcinoma who had been treated at the Department of Oral and Maxillofacial Surgery, Tokyo Dental College, over an 11-year period
2212-5558/$ – see front matter © 2013 Asian Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ajoms.2013.02.012
Please cite this article in press as: Yamamoto N, et al. Clinical study of mode of invasion in tongue squamous cell carcinoma. J Oral Maxillofac Surg Med Pathol (2013), http://dx.doi.org/10.1016/j.ajoms.2013.02.012
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Table 1 Clinicopathologic features of tongue cancer patient. Jakobsson classification
Grade 1
Grade 2
Grade 3
Grade 4
YK classification Case No.
Grade 1 26
Grade 2 33
Grade 3 53
Grade 4C 31
Grade 4D 25
168
15 11
22 11
36 17
21 10
17 8
111 57
0 0 2 0 8 9 6 0 1
1 1 3 2 6 11 7 2 0
0 1 6 5 10 18 8 5 0
0 0 3 2 9 12 5 0 0
0 1 1 4 12 6 1 0 0
1 3 15 13 45 56 27 7 1
16 9 1 0
13 17 3 0
23 24 4 2
10 11 5 5
4 12 7 2
66 73 20 9
20 2 4 0
25 7 1 0
36 9 8 0
12 8 10 1
11 5 9 0
104 31 32 1
16 4 2 4
11 12 9 1
20 13 12 8
7 5 8 11
3 7 4 11
57 41 35 35
7 0 0 19
17 4 2 10
40 6 2 5
17 7 7 0
14 3 7 1
95 20 18 35
13 3 10 0
13 5 15 0
15 9 28 1
7 0 24 0
9 4 12 0
57 21 89 1
18 1 2 1 2 2
18 7 2 2 1 3
21 15 7 6 1 3
6 10 3 5 1 6
7 6 1 8 0 3
70 39 15 22 5 17
1 25
1 32
7 46
13 18
12 13
34 134
22
26
41
20
17
126
1 2 1 0
1 3 2 1
2 2 5 3
4 3 3 1
3 1 3 1
11 11 14 6
Sex Male Female Age 10’s 20’s 30’s 40’s 50’s 60’s 70’s 80’s 90’s T classification T1 T2 T3 T4 N classification N0 N1 N2 N3 Stage I II III IV Differentiation Well Moderate Poor Other Clinical growth style Superficial Exophytic Endophytic Unclassified Treatment Ope Neoadjuvantchemo + ope Ope + adjuvantchemo Neoadjuvant + opeadjuvant Ope + radiation Ope + chemo + radiation pN (+) (−) Prognosis Well (disease-free survival) Poor Death Local Recurrence Late metastasis Metastasis + recurrence
between 2000 and 2010 were included in this study. Twenty-five of these patients who had early invasive cancer with no invasion of the muscle layer were excluded from the study because the property of the tumor parenchyma was unclear. All specimens were assigned an identification number and examined microscopically without knowledge of the clinical course of the patients. Mode of invasion was determined according to the Y–K classification. When a mixed mode of invasion was present, the mode of invasion was determined as that at the site with the highest grade. The diagnostic criteria for mode of invasion according to the Jakobsson classification are as follows: (1) grade 1, well defined borderline; (2) grade 2, cords, less marked borderline; (3) grade 3, group of cells, no distinct borderline; and (4) grade 4, diffuse
Total
growth. The diagnostic criteria for mode of invasion according to the Y–K classification are as follows: (1) grade 1, well defined borderline; (2) grade 2, cords, less marked borderline; (3) grade 3, group of cells, no distinct borderline; (4) grade 4C, deep invasion as cord-like, micro-tumor nests (cord-like type) with no distinct borderline; and (5) grade 4D, involving widespread type of diffuse invasion (diffuse type). The TNM classification was performed according to the 2009 UICC staging system [10], and cervical lymph node classification according to the General Rules for Clinical and Pathological Studies on Oral Cancer [11] published by the Japan Society for Oral Tumors. The clinical growth pattern was determined according to the Guidelines for the Management of Tongue Cancer [12]. Survival rates were calculated as of the end of August 2011.
Please cite this article in press as: Yamamoto N, et al. Clinical study of mode of invasion in tongue squamous cell carcinoma. J Oral Maxillofac Surg Med Pathol (2013), http://dx.doi.org/10.1016/j.ajoms.2013.02.012
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Fig. 1. Grade 2: cords, less marked borderline; grade 3: groups of cells, no distinct borderline; grade 4C: diffuse invasion of cord-like type; grade 4D: diffuse invasion of diffuse, widespread type.
3. Results (Table 1)
3.5. Clinical growth pattern
3.1. Mode of invasion
Fifty-seven tumors (33.9%) showed superficial growth (type 1), 21 (12.5%) exophytic growth (type 2), and 89 (53%) endophytic growth (type 3). In 1 tumor (0.6%), the growth pattern was unknown.
According to the Jakobsson classification, 26 (15.5%), 33 (19.6%), 53 (31.5%), and 56 (33.4%) of the tumors were classified as grade 1–4, respectively. According to the Y–K classification, 26 (15.5%), 33 (19.6%), 53 (31.5%), 31 (18.5%), and 25 (14.9%) of the tumors were classified as grades 1–3, 4C, and 4D, respectively. Fig. 1 shows representative histopathological images of grade 2, 3, 4C, and 4D tumors.
3.6. Treatment Seventy (41.7%), 76 (45.2%), 5 (3%), and 17 patients (10.1%) underwent surgery alone, surgery plus chemotherapy, surgery plus radiotherapy, and surgery plus chemoradiotherapy, respectively.
3.2. Age and sex 3.7. pN The overall mean age was 58.5 years (range, 19–90 years; 57.6 years for men and 60.2 years for women). One hundred and eleven (66.1%) and 57 patients (33.9%) were male and female, respectively, with a male-to-female ratio of 1.95:1.
Thirty-four (20.2%) and 134 patients (79.8%) were pN-positive and -negative, respectively. 3.8. Prognosis and survival rate (Fig. 2)
3.3. T classification, N classification, and stage classification Sixty-six (39.3%), 73 (43.5%), 20 (11.9%), and 9 tumors (5.4%) were classified as T1, T2, T3, and T4, respectively. One hundred and four (61.9%), 31 (18.5%), 32 (19%), and 1 tumor (0.6%) were classified as N0, N1, N2, and N3, respectively. Fifty-seven (33.9%), 41 (24.4%), 35 (20.8%), and 35 tumors (20.8%) were classified as stage I, II, III, and IV, respectively.
3.4. Differentiation Ninety-five (56.5%), 20 (11.9%), 18 (10.7%), and 35 tumors (20.8%) were well-differentiated, moderately differentiated, poorly differentiated, and other, respectively.
One hundred and twenty-five patients (74.4%) showed a good prognosis (disease-free survival), and 43 (25.6%) a poor prognosis. Of these 43 patients, 11 died, 12 had local recurrence, 14 developed late metastases, and 6 had local recurrence and late metastases. The 5-year survival rate in patients with Jakobsson’s grade 1 tumor was 92.9%, grade 2 tumor 96.9%, grade 3 tumor 97.8%, and grade 4 tumor 82.6%. The 5-year survival rate in patients with Jakobsson’s grade 4 tumor was 82.6%, which was significantly lower than that (96.3%) in those with Jakobsson’s grade 1, 2, or 3 tumors (p < 0.01). The 5-year survival rate in patients with Y–K grade 4C tumor was 78.5%, which was significantly lower than that (96.3%) in those with Y–K grade 1, 2, or 3 tumors (p < 0.01). The 5-year survival rate in patients with Y–K grade 4D tumors was 86.2%, which was also significantly lower than that (96.3%) in those with grade 1, 2, or 3 tumors (p < 0.05). The
Please cite this article in press as: Yamamoto N, et al. Clinical study of mode of invasion in tongue squamous cell carcinoma. J Oral Maxillofac Surg Med Pathol (2013), http://dx.doi.org/10.1016/j.ajoms.2013.02.012
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Fig. 2. Survival rates in tongue cancer according to Y–K classification using Kaplan–Meier method.
5-year survival rate in patients with Y–K classification grade 4C and 4D tumors showed no significant difference. 4. Discussion 4.1. Relationships between clinical and histopathological findings and mode of invasion The following relationships were observed between clinical findings and mode of invasion. Men had predominantly Jakobsson’s or Y–K grade 3 tumors. On initial examination, men in their 50s often had Jakobsson’s grade 4 or Y–K grade 4C/4D tumors, while those in their 60s frequently had Jakobsson’s or Y–K grade 3 tumors. T1 tumors were often associated without Jakobsson’s grade 4 or Y–K grade 4C/4D. N0, N1, and N2/N3 tumors were often associated with Jakobsson’s or Y–K grade 1–3, Jakobsson’s grade 3 or Y–K grade 3/4C, and Jakobsson’s grade 4 or Y–K grade 4C/4D tumors, respectively. Late-stage (stages III and IV) tumors were often associated with Jakobsson’s grade 4 and Y–K grade 4C/4D tumors, respectively. Superficial and exophytic growth patterns were frequently associated with Jakobsson’s or Y–K grade 1–3 tumors, and an endophytic growth pattern with Jakobsson’s grade3/4 or Y–K grade 3/4C/4D. The following relationships were noted between histopathological findings and mode of invasion. Early-invasive, well-, moderately-, and poorly differentiated states were often associated with Jakobsson’s or Y–K grade 1, Jakobsson’s or Y–K grade 3, Jakobsson’s grade 4 or Y–K grade 4C, and Jakobsson’s grade 4 or Y–K grade 4C/4D, respectively. Frequently, grade 1/2/3 tumors were highly keratinized, showing mild cellular atypia. On the other hand, Jakobsson’s grade 4 and Y–K grade 4D showed an increase in the degree of keratinization and cellular dysplasia. These results are in agreement with those of Yamamoto et al. [6] and Okamoto et al. [13], who noted that mode of invasion showed some degree of correlation with clinical growth pattern, degree of differentiation, degree of nuclear atypia, and mononuclear cell infiltration, but not mitotic activity. 4.2. Clinical course and mode of invasion 4.2.1. Local recurrence Some studies have reported high rates of local recurrence at the primary site [6,14]. In the present study, however, as well as in an earlier study by Okamoto et al. [13], no correlation was found between mode of invasion and local recurrence rate in any treatment group, and the recurrence rate for Jakobsson’s grade 4 or Y–K grade 4C/4D tumors was not high. Since Jakobsson’s grade 4 or Y–K grade 4C/4D tumors accounted for 21.2% of patients with T1 tumors, the extent of resection should be carefully determined.
In patients receiving preoperative combination therapy with bleomycin and radiation, the recurrence of the primary lesion depends on the effect of the combination therapy and extent of resection. Yamamoto et al. [15] noted that patients treated preoperatively with bleomycin alone achieved tumor reduction rates of more than 50%, and that tumor reduction rates were correlated with mode of invasion (Y–K grades 1–4), with correlation coefficients of 100%, 70%, 37.5%, and 36.4%, respectively. Amagasa et al. [16] indicated that bleomycin chemotherapy had little effect on highly aggressive diffuse tumors, as no patients with grade 4D tongue cancer achieved tumor disappearance. Many other studies have also reported that bleomycin or radiotherapy had little effect on Y–K grade 4C/4D tumors [17,18]. The present study showed no correlation between the effect of chemoradiotherapy and mode of invasion. In a histopathological study of surgical tongue cancer specimens, Inoue [19] showed that the histological picture varied from one area to another. Similarly, in the present study, microscopic examination of semi-serial sections revealed that, even in relatively early-stage tumors (i.e., T1 and T2), approximately 40% of sections differed in mode of tumor invasion. This suggests that the histological picture differs in different parts of the lesion in patients with advanced cancer, which means that one cannot exclude the possibility of grade 4C or 4D tumors in patients classified as having grade 3 tumors based on biopsy specimens, as these only represent one part of the lesion. Therefore, it remains unclear as to whether mode of invasion is closely related to the effect of chemoradiotherapy, making it difficult to predict the effect of such treatment based on mode of invasion alone. Further study is needed to elucidate the relationship between the effect of chemoradiotherapy and other clinico-histopathological findings. 4.2.2. Lymph node metastasis Miyagawa et al. [20] noted that while the incidence of lymph node metastasis in patients with Y–K grade 1–3 tumors was low, at 14.1%, that in patients with Y–K grade 4C and 4D tumors was high, at 66.7% and 75.0%, respectively. Yamamoto et al. [8] reported that the number of lymph node metastases was significantly higher in patients with grade 4 tumors. Tachibana [14] found that the mode of invasion was Y–K grade 4 in 69% (grade 4C in 48% and grade 4D in 21%) of node-positive tongue cancer patients. In the present study, the incidence of lymph node metastasis increased with the mode of invasion (Y–K grade 1 → grade 4) to a high 73.5% for Y–K grade 4 tumors (38.2% and 35.3% for grade 4C and 4D tumors, respectively). In addition, while 20.2% of the patients were pN-positive, a large majority (73.5%) of this group had grade 4C or 4D tumors involving more than one lymph node in more than one region. Thus, patients with grade 4C/4D tumors had many poor prognostic factors [21]. Prophylactic cervical lymph node dissection is indicated in patients at high risk of late lymph node metastasis. Therefore, we investigated the relationship between mode of invasion and late metastasis. Yamamoto et al. [22] noted that many Y–K grade 4 patients developed late cervical lymph node metastasis, and that the difficulty of controlling cervical lymph node recurrence indicated prophylactic lymph node dissection in grade 4D. In the present study, as in earlier studies by Okamoto et al. [17,25], the prognosis in patients with late nodal metastasis showed no significant difference with that in patients with nodal metastasis at initial treatment. It is for this reason that prophylactic lymph node dissection is not performed at our department on the assumption that patients will be closely followed up. However, patients who are past the time frame for prophylactic node dissection sometimes develop lymph node metastasis with extra-nodal invasion, leading to a poor prognosis. This indicates that Y–K grades 4C and 4D should be regarded as indicators for considering prophylactic node dissection.
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4.2.3. Survival rate Yamamoto et al. [7] reported that survival rates decreased as mode of invasion changed from Y–K grade 1 to grade 4D. In the present study, a significant difference in the survival rate was observed between patients with Y–K grade 1, 2, or 3 tumors and those with grade 4C or 4D tumors. This suggests that when a patient initially presents with a 4C or 4D tumor, that tumor should be radically resected to leave a sufficient safety margin as such tumors are highly invasive. 5. Conclusions We investigated the relationships between mode of tumor invasion, clinico-histopathological findings, and clinical course in 193 patients with primary tongue squamous cell carcinoma treated at our department during an 11-year period and came to the following conclusions: 1. Grade 4C and 4D tumors were often associated with stage IV tumors and an endophytic growth pattern. 2. Mode of invasion was related to degree of differentiation: grade 4C and 4D tumors accounted for a high proportion of poorly differentiated tumors. 3. In terms of the initial treatment modality for the primary lesion, no correlation was found between local recurrence rate and mode of invasion. 4. The incidence of cervical lymph node metastasis was correlated with mode of invasion: 5.9% for grades 1 and 2; 20.6% for grade 3; 38.2% for grade 4C; and 35.3% for grade 4D. The incidence of late metastasis was high, at 42.9 and 35.7% for grade 4C/4D and grade 3 tumors, respectively. 5. No significant difference was observed in the 5-year survival rate, which was relatively good, for grade 1–3 tumors; however, a significant difference was observed between grades 1 + 2 + 3 or grade 4C (p < 0.01) and 4D (p < 0.05). 6. No significant difference was observed in the 5-year survival rate between patients with Y–K grade 4C tumor and those with Y–K grade 4D. From the above, it was found that patients with Jakobsson grade 4 or Y–K grade 4C or 4D tumors had many poor prognostic factors, and that their 5-year survival rate was significantly low. However, no significant difference was found between Y–K grade 4C and 4D in terms of 5-year overall survival, so no significant correlation could be established between the Jakobsson and Y–K classifications on this point. Further study is needed to obtain a comprehensive analysis of prognostic factors in tongue squamous cell carcinoma, including depth of tumor invasion. This paper was presented in part at the 21st Annual Meeting of the Japanese Society for Oral Mucous Membrane (September 24, 2011, Kagoshima), the 56th Congress of the Japanese Society of Oral and Maxillofacial Surgeons (October 22, 2011, Osaka), and the 30th Annual Meeting of Japan Society for Oral Tumors (January 26, 2012, Omiya)
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Acknowledgments The authors would like to thank Associate Professor Jeremy Williams, Tokyo Dental College, for his assistance with the English of this manuscript. References [1] Kramer IRH, Pindborg JJ, Shear M. The World Health Organization histological typing of odontogenic tumours. Eur J Cancer B Oral Oncol 1993;29B: 169–71. [2] Jakobsson PA, Eneroth CM, Killander D, Moberger G, Martensson B. Histologic classification and grading of malignancy in carcinoma of the larynx. Acta Radiol Ther Phys Biol 1973;12:1–8. [3] Willen R, Nathanson A, Moberger G, Anneroth G. Squamous cell carcinoma of the gingiva, Histological classification and grading of malignancy. Acta Otolaryngol 1975;79:146–54. [4] Anneroth G, Batsakis J, Luna M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinoma. Scand J Dent Res 1987;95:229–49. [5] Anneroth G, Hansen LS. A methodologic study of histologic classification and grading of malignancy in oral squamous cell carcinoma. Scand J Dent Res 1984;92:448–68. [6] Yamamoto E, Sunakawa H, Kohama G. Studies on diffuse invasive squamous cell carcinoma of the oral cavity. Jpn J Oral Maxillofac Surg 1982;28:1472–9. [7] Yamamoto E, Kohama G, Sunagawa H, Iwai M, Hiratsuka H. Mode of invasion, Bleomycin sensitivity, and clinical course in squamous cell carcinoma of the oral cavity. Cancer 1983;51:2175–80. [8] Yamamoto E, Kohama G. Mode of invasion and lymph node metastasis in squamous cell carcinoma of the oral cavity. Head Neck Surg 1984;6:938–47. [9] Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization Classification of Tumours, Pathology & Genetics, Head and Neck Tumours. London: IARC Press; 2005168–75. [10] Sobin LH, Gospodarowicz MK, Wittekind Ch. TNM classification of malignant tumours. 7th ed. Geneva: UICC; 200925–9. [11] Japan Society for Oral Tumors. General rules for clinical and pathological studies on oral cancer. 1st ed. Tokyo: JSOT; 201034. [12] Japan Society for Oral Tumors. Tongue cancer handling guideline. J Jpn Soc Oral Tumor 2005;17:13–85. [13] Okamoto M, Ozeki S, Hara H, Sasaguri M, Tashiro H. Correlation between mode of invasion and prognosis of the carcinoma of the tongue. Jpn J Oral Maxillofac Surg 1987;33:615–22. [14] Tachibana T. A clinicopathological study of cervical lymph node metastases from oral squamous cell carcinoma. Pathol Int 1985;52:521–44. [15] Yamamoto E, Kohama G, Sunagawa H. Mode of invasion and Bleomycin susceptibility of the carcinoma of oral cavity. Jpn J Cancer Clinics 1981;27:1583–9. [16] Amagasa T, Shioda S, Iwaki H, Yokoo E, Sato K, Fujii E, et al. A clinical and histopathological study of anticancer effect of treatment with Bleomycin alone –with particular reference to histological disappearance of primary lesion-. J Jpn Soc Cancer Ther 1985;20:106–13. [17] Takashima H, Amatsu M. Clinical and histopathological studies on radiotherapy for hypopharyngeal carcinoma – factors determining the outcome of therapy-. J Jpn Soc Cancer Ther 1983;18:906–15. [18] Kohmura Y, Hosoda S, Kawabe Y, Isojima Z. Histopathologic observation of antitumor effect of Bleomycin and irradiation on cancers of tongue. Jpn J Cancer Chemother 1983;10:1320–7. [19] Inoue A. Histological studies of the cancer of the tongue. Fukuoka-igaku-zassi 1955;46:1039–59. [20] Miyakawa A, Kohama G, Yamamoto E, Sunakawa H, Adachi H, Hiratsuka H. Clinicopathological evaluation on metastasis to the cervical lymph node of oral cancer. Jpn J Oral Maxillofac Surg 1983;29:1555–61. [21] Okamoto M, Ozeki S, Hirakawa T, Hara H, Tashiro H. Evaluation of postoperative courses of the patients with oral cancer based on the mode of metastasis to the cervical lymph nodes. Jpn J Oral Maxillofac Surg 1985;31:554–62. [22] Yamamoto E, Kohama G, Densho S, Komatsu Y, Sunakawa H, Iwai M, et al. Cervical metastasis after excision of only primary lesion in non-advanced cancer of the tongue without local recurrence. Jpn J Oral Maxillofac Surg 1984;30:823–31.
Please cite this article in press as: Yamamoto N, et al. Clinical study of mode of invasion in tongue squamous cell carcinoma. J Oral Maxillofac Surg Med Pathol (2013), http://dx.doi.org/10.1016/j.ajoms.2013.02.012
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Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology journal homepage: www.elsevier.com/locate/jomsmp
Original research
Clinical study of mode of invasion in tongue squamous cell carcinoma Nobuharu Yamamoto a,b,∗ , Ryuta Osaka a , Yukio Watabe a , Nobuo Takano a , Kenichi Matsuzaka c , Takahiko Shibahara a,b a b c
Department of Oral and Maxillofacial Surgery, Tokyo Dental College, 1-2-2, Masago, Mihama-Ku, Chiba 261-8502, Japan Oral Cancer Center, Tokyo Dental College, 5-11-13, Sugano, Ichikawa, Chiba 272-8513, Japan Department of Clinical Pathophysiology, Tokyo Dental College, 1-2-2, Masago, Mihama-Ku, Chiba 261-8502, Japan
a r t i c l e
i n f o
Article history: Received 25 October 2012 Received in revised form 11 February 2013 Accepted 26 February 2013 Keywords: Oral cancer Tongue squamous cell carcinoma Mode of invasion
a b s t r a c t Objective: The most commonly used system of classification for the evaluation of histological malignancy in oral squamous cell carcinoma is the Yamamoto–Kohama (Y–K) classification, which focuses on the shape of tumor cell cords at the tumor–host interface, an item also included in the Jakobsson and Anneroth classifications. In this clinical study, we investigated the relationship between mode of invasion as based on the Jakobsson and Y–K classifications and prognosis in patients with tongue squamous cell carcinoma treated at our department. Patients and methods: One hundred and sixty-eight of the 193 patients with tongue squamous cell carcinoma treated in at our department over an 11-year period between 2000 and 2010 were included in this study (25 were excluded as the mode of invasion could not be determined according to the Y–K classification). Results: According to the Jakobsson classification, 26, 33, 53, and 56 tumors were classified as grades 1–4, respectively. According to the Y–K classification, 26, 33, 53, 31, and 25 tumors were classified as grades 1–3, 4C, and 4D, respectively. Conclusion: Patients with grade 4C/4D tumors had many poor prognostic factors, including a pN-positive rate of 73.5%, mortality, recurrence, and late metastasis rate of 44.2%. The tumors in this group exhibited both endophytic and exophytic growth patterns, and the 5-year-survival rate was significantly lower than that in patients with other grade tumors. These results suggest that grade 4C/4D is a useful prognostic factor. © 2013 Asian Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
1. Introduction The malignancy of oral squamous cell carcinoma is usually determined histologically in accordance with the conventional World Health Organization (WHO) grading system [1], in which typing is mainly based on the degree of differentiation to stratified squamous epithelium. The attraction of this system is that histologic grade correlates to some extent with prognosis and lymph node metastasis. A number of alternatives exist, however, including the classifications of Jakobsson (Willem) [2,3] and Anneroth [4,5], in which malignancy is evaluated according to the sum of scores based on 6–8 factors at the tumor–host interface. Although many studies have demonstrated the usefulness of these two systems, they have yet to gain wide acceptance due to their complexity. At
many hospitals in Japan, particularly in the field of oral surgery, the Yamamoto–Kohama (Y–K) [6–8] classification is used. This system focuses on the shape of tumor cell cords at the tumor–host interface, which is also one of the items included in the Jakobsson and Anneroth classifications. A recent publication by WHO indicated that grade shows only a weak correlation with prognosis, and that a diffuse mode of invasion at the deep border is more important [9]. However, to our knowledge, no studies have compared the Y–K classification with these other systems, making an evaluation of their relative effectiveness difficult. In this clinical study, the relationship between mode of invasion as based on the Jakobsson and Y–K classifications and prognosis was investigated in patients with tongue squamous cell carcinoma treated at our department. 2. Patients and methods
∗ Corresponding author at: Department of Oral and Maxillofacial Surgery, Tokyo Dental College, 1-2-2, Masago, Mihama-Ku, Chiba 261-8502, Japan. Tel.: +81 47 322 0151; fax: +81 47 324 8533. E-mail address: [email protected] (N. Yamamoto).
One hundred and ninety-three patients with tongue squamous cell carcinoma who had been treated at the Department of Oral and Maxillofacial Surgery, Tokyo Dental College, over an 11-year period
2212-5558/$ – see front matter © 2013 Asian Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ajoms.2013.02.012
Please cite this article in press as: Yamamoto N, et al. Clinical study of mode of invasion in tongue squamous cell carcinoma. J Oral Maxillofac Surg Med Pathol (2013), http://dx.doi.org/10.1016/j.ajoms.2013.02.012
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Table 1 Clinicopathologic features of tongue cancer patient. Jakobsson classification
Grade 1
Grade 2
Grade 3
Grade 4
YK classification Case No.
Grade 1 26
Grade 2 33
Grade 3 53
Grade 4C 31
Grade 4D 25
168
15 11
22 11
36 17
21 10
17 8
111 57
0 0 2 0 8 9 6 0 1
1 1 3 2 6 11 7 2 0
0 1 6 5 10 18 8 5 0
0 0 3 2 9 12 5 0 0
0 1 1 4 12 6 1 0 0
1 3 15 13 45 56 27 7 1
16 9 1 0
13 17 3 0
23 24 4 2
10 11 5 5
4 12 7 2
66 73 20 9
20 2 4 0
25 7 1 0
36 9 8 0
12 8 10 1
11 5 9 0
104 31 32 1
16 4 2 4
11 12 9 1
20 13 12 8
7 5 8 11
3 7 4 11
57 41 35 35
7 0 0 19
17 4 2 10
40 6 2 5
17 7 7 0
14 3 7 1
95 20 18 35
13 3 10 0
13 5 15 0
15 9 28 1
7 0 24 0
9 4 12 0
57 21 89 1
18 1 2 1 2 2
18 7 2 2 1 3
21 15 7 6 1 3
6 10 3 5 1 6
7 6 1 8 0 3
70 39 15 22 5 17
1 25
1 32
7 46
13 18
12 13
34 134
22
26
41
20
17
126
1 2 1 0
1 3 2 1
2 2 5 3
4 3 3 1
3 1 3 1
11 11 14 6
Sex Male Female Age 10’s 20’s 30’s 40’s 50’s 60’s 70’s 80’s 90’s T classification T1 T2 T3 T4 N classification N0 N1 N2 N3 Stage I II III IV Differentiation Well Moderate Poor Other Clinical growth style Superficial Exophytic Endophytic Unclassified Treatment Ope Neoadjuvantchemo + ope Ope + adjuvantchemo Neoadjuvant + opeadjuvant Ope + radiation Ope + chemo + radiation pN (+) (−) Prognosis Well (disease-free survival) Poor Death Local Recurrence Late metastasis Metastasis + recurrence
between 2000 and 2010 were included in this study. Twenty-five of these patients who had early invasive cancer with no invasion of the muscle layer were excluded from the study because the property of the tumor parenchyma was unclear. All specimens were assigned an identification number and examined microscopically without knowledge of the clinical course of the patients. Mode of invasion was determined according to the Y–K classification. When a mixed mode of invasion was present, the mode of invasion was determined as that at the site with the highest grade. The diagnostic criteria for mode of invasion according to the Jakobsson classification are as follows: (1) grade 1, well defined borderline; (2) grade 2, cords, less marked borderline; (3) grade 3, group of cells, no distinct borderline; and (4) grade 4, diffuse
Total
growth. The diagnostic criteria for mode of invasion according to the Y–K classification are as follows: (1) grade 1, well defined borderline; (2) grade 2, cords, less marked borderline; (3) grade 3, group of cells, no distinct borderline; (4) grade 4C, deep invasion as cord-like, micro-tumor nests (cord-like type) with no distinct borderline; and (5) grade 4D, involving widespread type of diffuse invasion (diffuse type). The TNM classification was performed according to the 2009 UICC staging system [10], and cervical lymph node classification according to the General Rules for Clinical and Pathological Studies on Oral Cancer [11] published by the Japan Society for Oral Tumors. The clinical growth pattern was determined according to the Guidelines for the Management of Tongue Cancer [12]. Survival rates were calculated as of the end of August 2011.
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Fig. 1. Grade 2: cords, less marked borderline; grade 3: groups of cells, no distinct borderline; grade 4C: diffuse invasion of cord-like type; grade 4D: diffuse invasion of diffuse, widespread type.
3. Results (Table 1)
3.5. Clinical growth pattern
3.1. Mode of invasion
Fifty-seven tumors (33.9%) showed superficial growth (type 1), 21 (12.5%) exophytic growth (type 2), and 89 (53%) endophytic growth (type 3). In 1 tumor (0.6%), the growth pattern was unknown.
According to the Jakobsson classification, 26 (15.5%), 33 (19.6%), 53 (31.5%), and 56 (33.4%) of the tumors were classified as grade 1–4, respectively. According to the Y–K classification, 26 (15.5%), 33 (19.6%), 53 (31.5%), 31 (18.5%), and 25 (14.9%) of the tumors were classified as grades 1–3, 4C, and 4D, respectively. Fig. 1 shows representative histopathological images of grade 2, 3, 4C, and 4D tumors.
3.6. Treatment Seventy (41.7%), 76 (45.2%), 5 (3%), and 17 patients (10.1%) underwent surgery alone, surgery plus chemotherapy, surgery plus radiotherapy, and surgery plus chemoradiotherapy, respectively.
3.2. Age and sex 3.7. pN The overall mean age was 58.5 years (range, 19–90 years; 57.6 years for men and 60.2 years for women). One hundred and eleven (66.1%) and 57 patients (33.9%) were male and female, respectively, with a male-to-female ratio of 1.95:1.
Thirty-four (20.2%) and 134 patients (79.8%) were pN-positive and -negative, respectively. 3.8. Prognosis and survival rate (Fig. 2)
3.3. T classification, N classification, and stage classification Sixty-six (39.3%), 73 (43.5%), 20 (11.9%), and 9 tumors (5.4%) were classified as T1, T2, T3, and T4, respectively. One hundred and four (61.9%), 31 (18.5%), 32 (19%), and 1 tumor (0.6%) were classified as N0, N1, N2, and N3, respectively. Fifty-seven (33.9%), 41 (24.4%), 35 (20.8%), and 35 tumors (20.8%) were classified as stage I, II, III, and IV, respectively.
3.4. Differentiation Ninety-five (56.5%), 20 (11.9%), 18 (10.7%), and 35 tumors (20.8%) were well-differentiated, moderately differentiated, poorly differentiated, and other, respectively.
One hundred and twenty-five patients (74.4%) showed a good prognosis (disease-free survival), and 43 (25.6%) a poor prognosis. Of these 43 patients, 11 died, 12 had local recurrence, 14 developed late metastases, and 6 had local recurrence and late metastases. The 5-year survival rate in patients with Jakobsson’s grade 1 tumor was 92.9%, grade 2 tumor 96.9%, grade 3 tumor 97.8%, and grade 4 tumor 82.6%. The 5-year survival rate in patients with Jakobsson’s grade 4 tumor was 82.6%, which was significantly lower than that (96.3%) in those with Jakobsson’s grade 1, 2, or 3 tumors (p < 0.01). The 5-year survival rate in patients with Y–K grade 4C tumor was 78.5%, which was significantly lower than that (96.3%) in those with Y–K grade 1, 2, or 3 tumors (p < 0.01). The 5-year survival rate in patients with Y–K grade 4D tumors was 86.2%, which was also significantly lower than that (96.3%) in those with grade 1, 2, or 3 tumors (p < 0.05). The
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Fig. 2. Survival rates in tongue cancer according to Y–K classification using Kaplan–Meier method.
5-year survival rate in patients with Y–K classification grade 4C and 4D tumors showed no significant difference. 4. Discussion 4.1. Relationships between clinical and histopathological findings and mode of invasion The following relationships were observed between clinical findings and mode of invasion. Men had predominantly Jakobsson’s or Y–K grade 3 tumors. On initial examination, men in their 50s often had Jakobsson’s grade 4 or Y–K grade 4C/4D tumors, while those in their 60s frequently had Jakobsson’s or Y–K grade 3 tumors. T1 tumors were often associated without Jakobsson’s grade 4 or Y–K grade 4C/4D. N0, N1, and N2/N3 tumors were often associated with Jakobsson’s or Y–K grade 1–3, Jakobsson’s grade 3 or Y–K grade 3/4C, and Jakobsson’s grade 4 or Y–K grade 4C/4D tumors, respectively. Late-stage (stages III and IV) tumors were often associated with Jakobsson’s grade 4 and Y–K grade 4C/4D tumors, respectively. Superficial and exophytic growth patterns were frequently associated with Jakobsson’s or Y–K grade 1–3 tumors, and an endophytic growth pattern with Jakobsson’s grade3/4 or Y–K grade 3/4C/4D. The following relationships were noted between histopathological findings and mode of invasion. Early-invasive, well-, moderately-, and poorly differentiated states were often associated with Jakobsson’s or Y–K grade 1, Jakobsson’s or Y–K grade 3, Jakobsson’s grade 4 or Y–K grade 4C, and Jakobsson’s grade 4 or Y–K grade 4C/4D, respectively. Frequently, grade 1/2/3 tumors were highly keratinized, showing mild cellular atypia. On the other hand, Jakobsson’s grade 4 and Y–K grade 4D showed an increase in the degree of keratinization and cellular dysplasia. These results are in agreement with those of Yamamoto et al. [6] and Okamoto et al. [13], who noted that mode of invasion showed some degree of correlation with clinical growth pattern, degree of differentiation, degree of nuclear atypia, and mononuclear cell infiltration, but not mitotic activity. 4.2. Clinical course and mode of invasion 4.2.1. Local recurrence Some studies have reported high rates of local recurrence at the primary site [6,14]. In the present study, however, as well as in an earlier study by Okamoto et al. [13], no correlation was found between mode of invasion and local recurrence rate in any treatment group, and the recurrence rate for Jakobsson’s grade 4 or Y–K grade 4C/4D tumors was not high. Since Jakobsson’s grade 4 or Y–K grade 4C/4D tumors accounted for 21.2% of patients with T1 tumors, the extent of resection should be carefully determined.
In patients receiving preoperative combination therapy with bleomycin and radiation, the recurrence of the primary lesion depends on the effect of the combination therapy and extent of resection. Yamamoto et al. [15] noted that patients treated preoperatively with bleomycin alone achieved tumor reduction rates of more than 50%, and that tumor reduction rates were correlated with mode of invasion (Y–K grades 1–4), with correlation coefficients of 100%, 70%, 37.5%, and 36.4%, respectively. Amagasa et al. [16] indicated that bleomycin chemotherapy had little effect on highly aggressive diffuse tumors, as no patients with grade 4D tongue cancer achieved tumor disappearance. Many other studies have also reported that bleomycin or radiotherapy had little effect on Y–K grade 4C/4D tumors [17,18]. The present study showed no correlation between the effect of chemoradiotherapy and mode of invasion. In a histopathological study of surgical tongue cancer specimens, Inoue [19] showed that the histological picture varied from one area to another. Similarly, in the present study, microscopic examination of semi-serial sections revealed that, even in relatively early-stage tumors (i.e., T1 and T2), approximately 40% of sections differed in mode of tumor invasion. This suggests that the histological picture differs in different parts of the lesion in patients with advanced cancer, which means that one cannot exclude the possibility of grade 4C or 4D tumors in patients classified as having grade 3 tumors based on biopsy specimens, as these only represent one part of the lesion. Therefore, it remains unclear as to whether mode of invasion is closely related to the effect of chemoradiotherapy, making it difficult to predict the effect of such treatment based on mode of invasion alone. Further study is needed to elucidate the relationship between the effect of chemoradiotherapy and other clinico-histopathological findings. 4.2.2. Lymph node metastasis Miyagawa et al. [20] noted that while the incidence of lymph node metastasis in patients with Y–K grade 1–3 tumors was low, at 14.1%, that in patients with Y–K grade 4C and 4D tumors was high, at 66.7% and 75.0%, respectively. Yamamoto et al. [8] reported that the number of lymph node metastases was significantly higher in patients with grade 4 tumors. Tachibana [14] found that the mode of invasion was Y–K grade 4 in 69% (grade 4C in 48% and grade 4D in 21%) of node-positive tongue cancer patients. In the present study, the incidence of lymph node metastasis increased with the mode of invasion (Y–K grade 1 → grade 4) to a high 73.5% for Y–K grade 4 tumors (38.2% and 35.3% for grade 4C and 4D tumors, respectively). In addition, while 20.2% of the patients were pN-positive, a large majority (73.5%) of this group had grade 4C or 4D tumors involving more than one lymph node in more than one region. Thus, patients with grade 4C/4D tumors had many poor prognostic factors [21]. Prophylactic cervical lymph node dissection is indicated in patients at high risk of late lymph node metastasis. Therefore, we investigated the relationship between mode of invasion and late metastasis. Yamamoto et al. [22] noted that many Y–K grade 4 patients developed late cervical lymph node metastasis, and that the difficulty of controlling cervical lymph node recurrence indicated prophylactic lymph node dissection in grade 4D. In the present study, as in earlier studies by Okamoto et al. [17,25], the prognosis in patients with late nodal metastasis showed no significant difference with that in patients with nodal metastasis at initial treatment. It is for this reason that prophylactic lymph node dissection is not performed at our department on the assumption that patients will be closely followed up. However, patients who are past the time frame for prophylactic node dissection sometimes develop lymph node metastasis with extra-nodal invasion, leading to a poor prognosis. This indicates that Y–K grades 4C and 4D should be regarded as indicators for considering prophylactic node dissection.
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4.2.3. Survival rate Yamamoto et al. [7] reported that survival rates decreased as mode of invasion changed from Y–K grade 1 to grade 4D. In the present study, a significant difference in the survival rate was observed between patients with Y–K grade 1, 2, or 3 tumors and those with grade 4C or 4D tumors. This suggests that when a patient initially presents with a 4C or 4D tumor, that tumor should be radically resected to leave a sufficient safety margin as such tumors are highly invasive. 5. Conclusions We investigated the relationships between mode of tumor invasion, clinico-histopathological findings, and clinical course in 193 patients with primary tongue squamous cell carcinoma treated at our department during an 11-year period and came to the following conclusions: 1. Grade 4C and 4D tumors were often associated with stage IV tumors and an endophytic growth pattern. 2. Mode of invasion was related to degree of differentiation: grade 4C and 4D tumors accounted for a high proportion of poorly differentiated tumors. 3. In terms of the initial treatment modality for the primary lesion, no correlation was found between local recurrence rate and mode of invasion. 4. The incidence of cervical lymph node metastasis was correlated with mode of invasion: 5.9% for grades 1 and 2; 20.6% for grade 3; 38.2% for grade 4C; and 35.3% for grade 4D. The incidence of late metastasis was high, at 42.9 and 35.7% for grade 4C/4D and grade 3 tumors, respectively. 5. No significant difference was observed in the 5-year survival rate, which was relatively good, for grade 1–3 tumors; however, a significant difference was observed between grades 1 + 2 + 3 or grade 4C (p < 0.01) and 4D (p < 0.05). 6. No significant difference was observed in the 5-year survival rate between patients with Y–K grade 4C tumor and those with Y–K grade 4D. From the above, it was found that patients with Jakobsson grade 4 or Y–K grade 4C or 4D tumors had many poor prognostic factors, and that their 5-year survival rate was significantly low. However, no significant difference was found between Y–K grade 4C and 4D in terms of 5-year overall survival, so no significant correlation could be established between the Jakobsson and Y–K classifications on this point. Further study is needed to obtain a comprehensive analysis of prognostic factors in tongue squamous cell carcinoma, including depth of tumor invasion. This paper was presented in part at the 21st Annual Meeting of the Japanese Society for Oral Mucous Membrane (September 24, 2011, Kagoshima), the 56th Congress of the Japanese Society of Oral and Maxillofacial Surgeons (October 22, 2011, Osaka), and the 30th Annual Meeting of Japan Society for Oral Tumors (January 26, 2012, Omiya)
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Please cite this article in press as: Yamamoto N, et al. Clinical study of mode of invasion in tongue squamous cell carcinoma. J Oral Maxillofac Surg Med Pathol (2013), http://dx.doi.org/10.1016/j.ajoms.2013.02.012