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Revised FIGO staging for carcinoma of the cervix
International Journal of Gynecology and Obstetrics 105 (2009) 107–108
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
SPECIAL COMMUNICATION
Revised FIGO staging for carcinoma of the cervix Sergio Pecorelli a,b,c, Lucia Zigliani c, Franco Odicino a,c,⁎ a b c
Department of Obstetrics and Gynecology Oncology, University of Brescia, Brescia, Italy Chairman, FIGO Committee on Gynocologic Oncology; and Editor, FIGO Annul Report, FIGO Annual Report Editorial Office FIGO Annual Report Editorial Office, European Institute of Oncology, Milan Italy
Cervical cancer staging is the oldest staging in the literature, dating back to 1928 when, for the first time, physicians grouped cancer of the cervix uteri into different stages according to the extent of tumor growth. At this time the scientific gynecologic community also believed that a uniform staging instrument and common nomenclature were needed. In 1950, the Annual Report Editorial Committee met in New York during the International Gynecological Congress and the 4th American Congress of Obstetrics and Gynecology. On that occasion it was felt that several modifications to the classification and staging should be adopted, and it was recommended that this new classification be termed “The International Classification of the Stages of Carcinoma of the Uterine Cervix.” Since then the staging for cervical cancer has undergone 7 revisions, the most recent in 1994. Almost all of these changes were relevant to Stage I [1] and its division into substages, including the Society of Gynecologic Oncologists' criteria of 3 mm to define microinvasion [2]. The main controversies surrounding cervical cancer staging that have contributed to the present revision are described here. 1. Surgical versus clinical staging This has been an important issue for many years. Firstly, clinical staging is less accurate than surgical staging despite the significant advances in imaging techniques and better assessment of tumor size [3–6]. Secondly, according to the FIGO staging system, cervical cancer staging is primarily a local disease in the pelvis. Finally, surgical staging cannot be employed worldwide, especially in low-resource countries where late stages are common and surgical facilities are scarce. Nevertheless, we know that when staging is performed surgically the stage is often more advanced [7]. Correlation between the FIGO (clinical) stage and the pT (TNM) in patients treated with up-front surgery shows inaccuracy in the clinical staging, especially in Stages IB2 and II (IIA and IIB) [8–10]. Surgical staging of local disease (i.e., tumor size assessment, vaginal and parametrial involvement) is good in early stage disease amenable to surgical treatment. On the contrary, the assessment of size and parametria are difficult in locally advanced and late stage disease, i.e. in ⁎ Corresponding author. FIGO Annual Report Editorial Office, Division of Epidemiology and Biostatistics, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy. Fax: +39 0257489872. E-mail address: fi[email protected] (L. Zigliani).
those patients who are not candidates for up-front surgery. These patients are the vast majority of cervical cancer patients in low-resource settings. The FIGO Committee on Gynecologic Oncology agrees on the possible important benefits of a pre-treatment surgical staging, but cost-effectiveness and some scientific issues are still a matter of investigation and debate in a disease that can be cured with the same efficacy by other non-surgical treatment modalities. 2. Stage IA (early invasion, size of microinvasion) According to some pathological assessments, early (minimal) stromal invasion should be considered as Stage IA1 and not deleted. If we take 50–100 sections of a conization specimen with cervical intraepithelial neoplasia (CIN) 3, microscopic epithelial buds that emanate from the base of the CIN might be found. Lesions may not be seen if only 10–15 sections are obtained. These patients are equally treated with conization and the outcome is the same in either case. These meaningless lesions—pathologically identifiable as early stromal invasion (ESI)—represent approximately 80% of Stage IA1 and tend to dilute its prognostic value [11]. The decision not to revise the definition of Stage IA, in particular Stage IA1, arises from the difficulty in reaching a worldwide common interpretation of the pathological data. Other important difficulties arise from the definition of multifocality, how to measure it, and how to combine data observed in the different foci. 3. Stage IIA, IIB, and IIIB substages There are data indicating that size subdivision (with a 4 cm cut-off in maximum diameter) is appropriate for Stage IIA [12–15,10]; while for Stage IIB there are no available data in the literature supporting a subdivision regarding tumor size. The decision not to subdivide Stage IIB and IIIB according to uni- or bilateral parametrial extension is also based on the fact that the treatment is identical in both situations and this subdivision would not affect management. 4. Lymphovascular space invasion Lymphovascular space invasion (LVSI) has been taken into consideration when staging cervical cancer. Nevertheless, this important risk factor was not included in the staging nomenclature because of its
0020-7292/$ – see front matter © 2009 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. doi:10.1016/j.ijgo.2009.02.009
108
S. Pecorelli et al. / International Journal of Gynecology and Obstetrics 105 (2009) 107–108
subjective definition influencing the assessment of its extension, and thus its significance. However, LVSI should be reported. 5. Lymph nodal status Cervical cancer has a poor prognosis in the presence of lymph nodal metastasis, and this is particularly evident in early stage disease [16– 20]. Despite improvements in imaging techniques and pilot studies dealing with minimally invasive surgical-pathological assessment of lymph nodal status, the FIGO Committee on Gynecologic Oncology decided not to perform lymph nodal assessment per se regarding the staging [21–25]. However, the FIGO Committee encourages the use of imaging techniques for the evaluation of the extension and size of the lesion(s). 6. Microinvasive and invasive adenocarcinoma Microinvasive and invasive adenocarcinoma should be staged as squamous cell carcinoma of the cervix. 7. Approved changes to cervical cancer staging The following changes to the staging for cervical cancer were proposed and approved by the Enlarged Committee, and subsequently approved by UICC, AJCC, and FIGO. 1. Deletion of Stage 0: FIGO has decided to delete Stage 0 from the staging of all tumors, since it is a pre-invasive lesion. 2. Stage IIA: Several reports in the literature and data analyses from the FIGO Annual Report database consistently demonstrate that, in Stage IIA patients, size, defined as the maximum tumor diameter, has an effect on prognosis similar to that observed in Stage IB [26]. Therefore, definitions of Stage IIA substages have been included: • Stage IIA1: tumor size of less than or equal to 4 cm with involvement of less than the upper two-thirds of the vagina. • Stage IIA2: tumor size of more than 4 cm with involvement of less than the upper two-thirds of the vagina. The new staging is effective from January 2009. The Enlarged Committee has also taken into consideration further clinical and investigational recommendations: 1. Cervical cancer remains a clinically staged disease; nevertheless, research in the field of surgical staging is encouraged. 2. When available, all surgical-pathological findings (such as LVSI) should be reported to the FIGO Annual Report Editorial Office or in other scientific publications, although not included in the staging system. 3. The use of diagnostic imaging techniques to assess the size of the primary tumor is encouraged but is not mandatory. For those institutions with access to MRI/CT scanning, radiological tumor volume and parametrial invasion should be recorded and sent to the FIGO Annual Report Editorial Office for data entry and inclusion in the Annual Report. Other investigations (i.e., examination under anesthesia, cystoscopy, sigmoidoscopy, intravenous pielography) are optional and no longer mandatory. 4. Vaginal carcinoma may occur within 5 years after treatment, and sustained complete response in cervical carcinoma is regarded as primary vaginal cancer. 8. Conclusions The aim of reaching a useful, as well as a unified, cancer staging system depends on its ability to cope with new epidemiological and clinical evidence, i.e. the increase in population screening for cancer, the discovery of new treatments, and the use of new molecular biomarkers.
There is an increasing demand that more biological prognostic factors (histological grades, LVSI, serum biomarkers, etc) be included in the staging system, with the aim to better identify patients at high and low risk of dying of their disease [1]. For this reason, scientists should improve their understanding of tumor biology as well as their ability to tailor treatment. References [1] de Oliveira CF, Mota F. Cervical Cancer – pre-therapeutic investigations and clinical staging versus surgical staging. CME J Gynecol Oncol 2001;6:246–56. [2] Tropé C, Kristensen G, Onsrud M, Bosze P. Controversies in cervical cancer staging. CME J Gynecol Oncol 2001;6:240–5. [3] Amendola MA, Hricak H, Mitchell DG, Snyder B, Chi DS, Long III HJ, et al. Utilization of diagnostic studies in the pretreatment evaluation of invasive cervical cancer in the United States: results of intergroup protocol ACRIN 6651/GOG 183. J Clin Oncol 2005;23(30):7454–9. [4] Hricak H. First open trial of the American College of Radiology Imaging Network: proper imaging approach for invasive cervical cancer. Radiology 2002;225(3):634–5. [5] Mitchell DG, Snyder B, Coakley F, Reinhold C, Thomas G, Amendola M, et al. Early invasive cervical cancer: tumor delineation by magnetic resonance imaging, computed tomography, and clinical examination, verified by pathologic results, in the ACRIN 6651/GOG 183 Intergroup Study. J Clin Oncol 2006;24(36):5687–94. [6] Hricak H, Gatsonis C, Coakley FV, Snyder B, Reinhold C, Schwartz LH, et al. Early invasive cervical cancer: CT and MR imaging in preoperative evaluation - ACRIN/ GOG comparative study of diagnostic performace and interobserver variability. Radiology 2007;245(2):491–8. [7] Lagasse LD, Creasman WT, Shingleton HM, Ford JH, Blessing JA. Results and complications of operative staging in cervical cancer: experience of the Gynecologic Oncology Group. Gynecol Oncol 1980;9(1):90–8. [8] Boyle P, la Vecchia C, Walker A, editors. Annual Report on the Results of Treatment in Gynecological Cancer. Twenty-fourth volume, vol. 6(1). J Epidemiol Biostat; 2001. p. 1–184. [9] Pecorelli S, editor. 25th Annual Report on the Results of Treatment in Gynecological Cancer, vol. 83(Suppl 1). Int J Gynecol Obstet; 2003. p. S1–230. [10] Pecorelli S, editor. 26th Annual Report on the Results of Treatment in Gynecological Cancer, vol. 95(Suppl 1). Int J Gynecol Obstet; 2006. p. S1–258. [11] Burghardt E, Ostör A, Fox H. The new FIGO definition of cervical cancer stage IA: a critique. Gynecol Oncol 1997;65(1):1–5. [12] Piver MS, Chung WS. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma. Obstet Gynecol 1975;46(5):507–10. [13] Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F. Prospective surgicalpathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study. Gynecol Oncol 1990;38(3):352–7. [14] Perez CA, Grigsby PW, Chao KS, Mutch DG, Lockett MA. Tumor size, irradiation dose, and long-term outcome of carcinoma of uterine cervix. Int J Radiat Oncol Biol Phys 1998;41(2):307–17. [15] Horn LC, Fischer U, Raptis G, Bilek K, Hentschel B. Tumor size is of prognostic value in surgically treated FIGO stage II cervical cancer. Gynecol Oncol 2007;107(2):310–5. [16] Cheng X, Cai S, Li Z, Tang M, Xue M, Zang R. The prognosis of women with stage IB1-IIB node-positive cervical carcinoma after radical surgery. World J Surg Oncol 2004;18;2:47. [17] Graflund M, Sorbe B, Karlsson M. Immunohistochemical expression of p53, bcl-2, and p21(WAF1/CIP1) in early cervical carcinoma: correlation with clinical outcome. Int J Gynecol Cancer 2002;12(3):290–8. [18] Aoki Y, Sasaki M, Watanabe M, Sato T, Tsuneki I, Aida H, et al. High-risk group in nodepositive patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation. Gynecol Oncol 2000;77(2):305–9. [19] Sakuragi N, Satoh C, Takeda N, Hareyama H, Takeda M, Yamamoto R, et al. Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with Stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy. Cancer 1999;85(7):1547–54. [20] Benedetti-Panici P, Maneschi F, D'Andrea G, Cutillo G, Rabitti C, Congiu M, et al. Early cervical carcinoma: the natural history of lymph node involvement redefined on the basis of thorough parametrectomy and giant section study. Cancer 2000;88(10):2267–74 [Erratum in: Cancer 2000;89(2):473]. [21] Narayan K, McKenzie AF, Hicks RJ, Fisher R, Bernshaw D, Bau S. Relation between FIGO stage, primary tumor volume, and presence of lymph node metastases in cervical cancer patients referred for radiotherapy. Int J Gynecol Cancer 2003;13(5):657–63. [22] Grigsby PW, Siegel BA, Dehdashti F. Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 2001;19(17): 3745–9. [23] Kawagoe T, Kashimura M, Matsuura Y, Sugihara K, Toki N, Aoki T. Clinical significance of tumor size in stage IB and II carcinoma of the uterine cervix. Int J Gynecol Cancer 1999;9(5):421–6. [24] Togashi K, Morikawa K, Kataoka ML, Konishi J. Cervical cancer. J Magn Reson Imaging 1998;8(2):391–7. [25] Grigsby PW. 4th International Cervical Cancer Conference: update on PET and cervical cancer. Gynecol Oncol 2005;99(3 Suppl 1):S173–5. [26] Hong JH, Tsai CS, Lai CH, Chang TC, Wang CC, Chou HH, et al. Risk stratification of patients with advanced squamous cell carcinoma of cervix treated by radiotherapy alone. Int J Radiat Oncol Biol Phys 2005;63(2):492–9.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o
SPECIAL COMMUNICATION
Revised FIGO staging for carcinoma of the cervix Sergio Pecorelli a,b,c, Lucia Zigliani c, Franco Odicino a,c,⁎ a b c
Department of Obstetrics and Gynecology Oncology, University of Brescia, Brescia, Italy Chairman, FIGO Committee on Gynocologic Oncology; and Editor, FIGO Annul Report, FIGO Annual Report Editorial Office FIGO Annual Report Editorial Office, European Institute of Oncology, Milan Italy
Cervical cancer staging is the oldest staging in the literature, dating back to 1928 when, for the first time, physicians grouped cancer of the cervix uteri into different stages according to the extent of tumor growth. At this time the scientific gynecologic community also believed that a uniform staging instrument and common nomenclature were needed. In 1950, the Annual Report Editorial Committee met in New York during the International Gynecological Congress and the 4th American Congress of Obstetrics and Gynecology. On that occasion it was felt that several modifications to the classification and staging should be adopted, and it was recommended that this new classification be termed “The International Classification of the Stages of Carcinoma of the Uterine Cervix.” Since then the staging for cervical cancer has undergone 7 revisions, the most recent in 1994. Almost all of these changes were relevant to Stage I [1] and its division into substages, including the Society of Gynecologic Oncologists' criteria of 3 mm to define microinvasion [2]. The main controversies surrounding cervical cancer staging that have contributed to the present revision are described here. 1. Surgical versus clinical staging This has been an important issue for many years. Firstly, clinical staging is less accurate than surgical staging despite the significant advances in imaging techniques and better assessment of tumor size [3–6]. Secondly, according to the FIGO staging system, cervical cancer staging is primarily a local disease in the pelvis. Finally, surgical staging cannot be employed worldwide, especially in low-resource countries where late stages are common and surgical facilities are scarce. Nevertheless, we know that when staging is performed surgically the stage is often more advanced [7]. Correlation between the FIGO (clinical) stage and the pT (TNM) in patients treated with up-front surgery shows inaccuracy in the clinical staging, especially in Stages IB2 and II (IIA and IIB) [8–10]. Surgical staging of local disease (i.e., tumor size assessment, vaginal and parametrial involvement) is good in early stage disease amenable to surgical treatment. On the contrary, the assessment of size and parametria are difficult in locally advanced and late stage disease, i.e. in ⁎ Corresponding author. FIGO Annual Report Editorial Office, Division of Epidemiology and Biostatistics, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy. Fax: +39 0257489872. E-mail address: fi[email protected] (L. Zigliani).
those patients who are not candidates for up-front surgery. These patients are the vast majority of cervical cancer patients in low-resource settings. The FIGO Committee on Gynecologic Oncology agrees on the possible important benefits of a pre-treatment surgical staging, but cost-effectiveness and some scientific issues are still a matter of investigation and debate in a disease that can be cured with the same efficacy by other non-surgical treatment modalities. 2. Stage IA (early invasion, size of microinvasion) According to some pathological assessments, early (minimal) stromal invasion should be considered as Stage IA1 and not deleted. If we take 50–100 sections of a conization specimen with cervical intraepithelial neoplasia (CIN) 3, microscopic epithelial buds that emanate from the base of the CIN might be found. Lesions may not be seen if only 10–15 sections are obtained. These patients are equally treated with conization and the outcome is the same in either case. These meaningless lesions—pathologically identifiable as early stromal invasion (ESI)—represent approximately 80% of Stage IA1 and tend to dilute its prognostic value [11]. The decision not to revise the definition of Stage IA, in particular Stage IA1, arises from the difficulty in reaching a worldwide common interpretation of the pathological data. Other important difficulties arise from the definition of multifocality, how to measure it, and how to combine data observed in the different foci. 3. Stage IIA, IIB, and IIIB substages There are data indicating that size subdivision (with a 4 cm cut-off in maximum diameter) is appropriate for Stage IIA [12–15,10]; while for Stage IIB there are no available data in the literature supporting a subdivision regarding tumor size. The decision not to subdivide Stage IIB and IIIB according to uni- or bilateral parametrial extension is also based on the fact that the treatment is identical in both situations and this subdivision would not affect management. 4. Lymphovascular space invasion Lymphovascular space invasion (LVSI) has been taken into consideration when staging cervical cancer. Nevertheless, this important risk factor was not included in the staging nomenclature because of its
0020-7292/$ – see front matter © 2009 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. doi:10.1016/j.ijgo.2009.02.009
108
S. Pecorelli et al. / International Journal of Gynecology and Obstetrics 105 (2009) 107–108
subjective definition influencing the assessment of its extension, and thus its significance. However, LVSI should be reported. 5. Lymph nodal status Cervical cancer has a poor prognosis in the presence of lymph nodal metastasis, and this is particularly evident in early stage disease [16– 20]. Despite improvements in imaging techniques and pilot studies dealing with minimally invasive surgical-pathological assessment of lymph nodal status, the FIGO Committee on Gynecologic Oncology decided not to perform lymph nodal assessment per se regarding the staging [21–25]. However, the FIGO Committee encourages the use of imaging techniques for the evaluation of the extension and size of the lesion(s). 6. Microinvasive and invasive adenocarcinoma Microinvasive and invasive adenocarcinoma should be staged as squamous cell carcinoma of the cervix. 7. Approved changes to cervical cancer staging The following changes to the staging for cervical cancer were proposed and approved by the Enlarged Committee, and subsequently approved by UICC, AJCC, and FIGO. 1. Deletion of Stage 0: FIGO has decided to delete Stage 0 from the staging of all tumors, since it is a pre-invasive lesion. 2. Stage IIA: Several reports in the literature and data analyses from the FIGO Annual Report database consistently demonstrate that, in Stage IIA patients, size, defined as the maximum tumor diameter, has an effect on prognosis similar to that observed in Stage IB [26]. Therefore, definitions of Stage IIA substages have been included: • Stage IIA1: tumor size of less than or equal to 4 cm with involvement of less than the upper two-thirds of the vagina. • Stage IIA2: tumor size of more than 4 cm with involvement of less than the upper two-thirds of the vagina. The new staging is effective from January 2009. The Enlarged Committee has also taken into consideration further clinical and investigational recommendations: 1. Cervical cancer remains a clinically staged disease; nevertheless, research in the field of surgical staging is encouraged. 2. When available, all surgical-pathological findings (such as LVSI) should be reported to the FIGO Annual Report Editorial Office or in other scientific publications, although not included in the staging system. 3. The use of diagnostic imaging techniques to assess the size of the primary tumor is encouraged but is not mandatory. For those institutions with access to MRI/CT scanning, radiological tumor volume and parametrial invasion should be recorded and sent to the FIGO Annual Report Editorial Office for data entry and inclusion in the Annual Report. Other investigations (i.e., examination under anesthesia, cystoscopy, sigmoidoscopy, intravenous pielography) are optional and no longer mandatory. 4. Vaginal carcinoma may occur within 5 years after treatment, and sustained complete response in cervical carcinoma is regarded as primary vaginal cancer. 8. Conclusions The aim of reaching a useful, as well as a unified, cancer staging system depends on its ability to cope with new epidemiological and clinical evidence, i.e. the increase in population screening for cancer, the discovery of new treatments, and the use of new molecular biomarkers.
There is an increasing demand that more biological prognostic factors (histological grades, LVSI, serum biomarkers, etc) be included in the staging system, with the aim to better identify patients at high and low risk of dying of their disease [1]. For this reason, scientists should improve their understanding of tumor biology as well as their ability to tailor treatment. References [1] de Oliveira CF, Mota F. Cervical Cancer – pre-therapeutic investigations and clinical staging versus surgical staging. CME J Gynecol Oncol 2001;6:246–56. [2] Tropé C, Kristensen G, Onsrud M, Bosze P. Controversies in cervical cancer staging. CME J Gynecol Oncol 2001;6:240–5. [3] Amendola MA, Hricak H, Mitchell DG, Snyder B, Chi DS, Long III HJ, et al. Utilization of diagnostic studies in the pretreatment evaluation of invasive cervical cancer in the United States: results of intergroup protocol ACRIN 6651/GOG 183. J Clin Oncol 2005;23(30):7454–9. [4] Hricak H. First open trial of the American College of Radiology Imaging Network: proper imaging approach for invasive cervical cancer. Radiology 2002;225(3):634–5. [5] Mitchell DG, Snyder B, Coakley F, Reinhold C, Thomas G, Amendola M, et al. Early invasive cervical cancer: tumor delineation by magnetic resonance imaging, computed tomography, and clinical examination, verified by pathologic results, in the ACRIN 6651/GOG 183 Intergroup Study. J Clin Oncol 2006;24(36):5687–94. [6] Hricak H, Gatsonis C, Coakley FV, Snyder B, Reinhold C, Schwartz LH, et al. Early invasive cervical cancer: CT and MR imaging in preoperative evaluation - ACRIN/ GOG comparative study of diagnostic performace and interobserver variability. Radiology 2007;245(2):491–8. [7] Lagasse LD, Creasman WT, Shingleton HM, Ford JH, Blessing JA. Results and complications of operative staging in cervical cancer: experience of the Gynecologic Oncology Group. Gynecol Oncol 1980;9(1):90–8. [8] Boyle P, la Vecchia C, Walker A, editors. Annual Report on the Results of Treatment in Gynecological Cancer. Twenty-fourth volume, vol. 6(1). J Epidemiol Biostat; 2001. p. 1–184. [9] Pecorelli S, editor. 25th Annual Report on the Results of Treatment in Gynecological Cancer, vol. 83(Suppl 1). Int J Gynecol Obstet; 2003. p. S1–230. [10] Pecorelli S, editor. 26th Annual Report on the Results of Treatment in Gynecological Cancer, vol. 95(Suppl 1). Int J Gynecol Obstet; 2006. p. S1–258. [11] Burghardt E, Ostör A, Fox H. The new FIGO definition of cervical cancer stage IA: a critique. Gynecol Oncol 1997;65(1):1–5. [12] Piver MS, Chung WS. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinoma. Obstet Gynecol 1975;46(5):507–10. [13] Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F. Prospective surgicalpathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study. Gynecol Oncol 1990;38(3):352–7. [14] Perez CA, Grigsby PW, Chao KS, Mutch DG, Lockett MA. Tumor size, irradiation dose, and long-term outcome of carcinoma of uterine cervix. Int J Radiat Oncol Biol Phys 1998;41(2):307–17. [15] Horn LC, Fischer U, Raptis G, Bilek K, Hentschel B. Tumor size is of prognostic value in surgically treated FIGO stage II cervical cancer. Gynecol Oncol 2007;107(2):310–5. [16] Cheng X, Cai S, Li Z, Tang M, Xue M, Zang R. The prognosis of women with stage IB1-IIB node-positive cervical carcinoma after radical surgery. World J Surg Oncol 2004;18;2:47. [17] Graflund M, Sorbe B, Karlsson M. Immunohistochemical expression of p53, bcl-2, and p21(WAF1/CIP1) in early cervical carcinoma: correlation with clinical outcome. Int J Gynecol Cancer 2002;12(3):290–8. [18] Aoki Y, Sasaki M, Watanabe M, Sato T, Tsuneki I, Aida H, et al. High-risk group in nodepositive patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation. Gynecol Oncol 2000;77(2):305–9. [19] Sakuragi N, Satoh C, Takeda N, Hareyama H, Takeda M, Yamamoto R, et al. Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with Stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy. Cancer 1999;85(7):1547–54. [20] Benedetti-Panici P, Maneschi F, D'Andrea G, Cutillo G, Rabitti C, Congiu M, et al. Early cervical carcinoma: the natural history of lymph node involvement redefined on the basis of thorough parametrectomy and giant section study. Cancer 2000;88(10):2267–74 [Erratum in: Cancer 2000;89(2):473]. [21] Narayan K, McKenzie AF, Hicks RJ, Fisher R, Bernshaw D, Bau S. Relation between FIGO stage, primary tumor volume, and presence of lymph node metastases in cervical cancer patients referred for radiotherapy. Int J Gynecol Cancer 2003;13(5):657–63. [22] Grigsby PW, Siegel BA, Dehdashti F. Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 2001;19(17): 3745–9. [23] Kawagoe T, Kashimura M, Matsuura Y, Sugihara K, Toki N, Aoki T. Clinical significance of tumor size in stage IB and II carcinoma of the uterine cervix. Int J Gynecol Cancer 1999;9(5):421–6. [24] Togashi K, Morikawa K, Kataoka ML, Konishi J. Cervical cancer. J Magn Reson Imaging 1998;8(2):391–7. [25] Grigsby PW. 4th International Cervical Cancer Conference: update on PET and cervical cancer. Gynecol Oncol 2005;99(3 Suppl 1):S173–5. [26] Hong JH, Tsai CS, Lai CH, Chang TC, Wang CC, Chou HH, et al. Risk stratification of patients with advanced squamous cell carcinoma of cervix treated by radiotherapy alone. Int J Radiat Oncol Biol Phys 2005;63(2):492–9.