ORIGINAL STUDY
Prognostic Factors of Surgically Treated Early-Stage Small Cell Neuroendocrine Carcinoma of the Cervix Lei Yuan, MD, PhD, Hongyuan Jiang, MD, Yin Lu, MD, Sun-wei Guo, PhD, and Xishi Liu, MD, PhD
Objective: Small cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare malignancy and has a high mortality despite of aggressive surgical treatment. The aims of this study were to determine the prognostic factors associated with the survival of surgically treated patients with early-stage SCNECC and to see whether carboplatin plus paclitaxel (TC) therapy after surgery can improve their survival. Methods: Thirty-eight women with FIGO stages IA2 (n = 1), IB1 (n = 31), IB2 (n = 3), and IIA1 (n = 3) were treated with radical hysterectomy, followed by adjuvant TC or non-TC, with or without radiotherapy, in our hospital between 2004 and 2013. Medical charts and clinical data were retrieved and retrospectively reviewed. The Kaplan-Meier method and Cox regression model were used for survival analysis. Results: The mean age of patients were 40.4 T 7.0 years. The preoperative detection rate of SCNECC was only 34.2%. The overall 1-, 2-, and 5-year survival rate was 81.6%, 54.7%, and 43%, respectively, whereas the 1-, 2-, and 5-year cumulative recurrence rate was 37.8%, 44.2%, and 49.3%, respectively. For overall survival (OS), the univariate survival analysis indicated that tumor homology, parametrial invasion, chemotherapy regimens, and chemotherapy courses were risk factors. For disease-free survival, the univariate survival analysis identified lymph node involvement, tumor homology, parametrial invasion, chemotherapy regimens, and chemotherapy courses as risk factors. However, when multivariable Cox regression model was used, only parametrial invasion and postoperative chemotherapy regimen were identified as risk factors for both OS (P = 0.037 and P = 0.016) and disease-free survival (P = 0.044 and P = 0.018). Conclusions: Small cell neuroendocrine carcinoma of the cervix is a deadly variant of cervical cancer. Postoperative TC chemotherapy may improve the OS and disease-free survival in women with early-stage SCNECC. Key Words: Small cell neuroendocrine carcinoma of the cervix (SCNECC), Prognosis, Chemotherapy Received April 18, 2015, and accepted for publication April 26, 2015. (Int J Gynecol Cancer 2015;25: 1315Y1321)
Department of Gynecology, Obstetrics & Gynecology Hospital, Fudan University, Shanghai, China.
Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000496 International Journal of Gynecological Cancer
Address correspondence and reprint requests to Xishi Liu, MD, PhD, Department of Gynecology, Obstetrics & Gynecology Hospital, Fudan University, 419 Fangxie Rd, Shanghai 200011, PR China. E-mail: [email protected]. Lei Yuan and Hongyuan Jiang contributed equally to this work. Support: This project is sponsored by Shanghai Natural Science Fund (13ZR1451900 [Lei Yuan]). The authors declare that there are no conflicts of interest.
& Volume 25, Number 7, September 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
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Yuan et al
carcinoma of the cervix (NECC) is a class N euroendocrine of rare gynecologic malignancy with an incidence of 1%
to 3%.1,2 It is highly aggressive and prone to hematologic and lymphatic metastasis at an early stage. Because of the variation in terminology that has evolved over time, it is difficult to define the characteristics of NECC since it was first described by Reagan et al3 in 1957. In 1997, a workgroup sponsored by the National Cancer Institute and the College of American Pathologists recommended uniform terminology for these tumors with 4 categories: typical carcinoid tumor, atypical carcinoid tumor, large cell neuroendocrine carcinoma, and small cell carcinoma.4 Among these tumors, small cell neuroendocrine carcinoma of the cervix (SCNECC) is more common than other types of NECC with worse prognosis in patients with advanced stage based on a 14% 5-year survival rate.5 Because of the low incidence of SCNECC, previous studies have mostly been clinical case reports or case series, making it difficult to draw conclusions on overall management. As a result, risk factors determining the prognosis of SCNECC have not been illustrated and the optimal treatment strategy still remains unclear.6,7 The role of chemotherapy has been advocated as potentially beneficial in treating SCNECC, given its intrinsic biological behavior of early metastasis. Cohen and colleagues8 showed that chemotherapy (as primary, adjuvant or with concurrent radiation) was associated with improved survival in stage IIB-IVA SCNECC compared with those who did not receive chemotherapy. Similar findings were reported by a Taiwanese study that 5 or more consecutive courses of etoposide and cisplatin (EP) chemotherapy could result in better survival for patients with stage IIB-IV SCNECC.7 However, what is the effect of chemotherapy on early-stage patients? Unfortunately, a few bodies of evidence have yet been obtained by previous studies. A Korean report by Lee et al9 showed that in patients with stage IB-IIA, adjuvant chemotherapy tended to favor 5-year survival, but the difference did not reach statistically significance when compared with those with nonchemotherapy. Considering the curative potentials for earlystage SCNECC, it is imperative for us to fully delineate the role of adjuvant chemotherapy in treating early-stage patients. Furthermore, closely tied into this is the question of chemotherapy regimens, even the widely used guidelines such as National Comprehensive Cancer Network or FIGO did not provide suggestions on SCNECC. Because there was no published guideline for chemotherapeutic treatment on SCNECC up to date, the knowledge regarding the treatment regimens is still fragmentary; because previous studies have not been able to show which regimen is better, and thus, the selection of different regimen mostly depends on surgeons’ own values, or preferences7,9 In the current study, we investigated the clinicopathologic features and prognostic factors for patients with surgically treated early-stage SCNECC and to see in particular whether carboplatin plus paclitaxel (TC) therapy after surgery can improve their survival.
MATERIALS AND METHODS Patient Selection A total of 38 patients with early-stage SCNECC (FIGO staging IA2-IIA) who had been admitted and surgically treated
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from January 2004 to December 2013 in the Obstetrics and Gynecology Hospital of Fudan University were enrolled into this study. All patients received radical hysterectomy, and 37 of 38 received adjuvant chemotherapy with/without radiation. Among the patients with postoperative chemotherapy, TC regimen and non-TC regimen (a single-agent or combination chemotherapy including bleomycin, etoposide, 5-FU, cisplatin) were administrated. A follow-up of 12 to 124 months were completed for those 38 patients. Clinical and pathological data, including patient’s age, chief complaint, preoperative diagnosis, tumor size and stage, tumor homology (simple SCNECC or mixed SCNECC with adenocarcinoma or squamous carcinoma), lymph node involvement, depth of stromal invasion, lymphovascular infiltration, parametrial invasion, surgical margin involvement, and postoperative treatment modalities, were collected for analysis. This study was approved by the institutional ethics review board of Obstetrics and Gynecology Hospital, Fudan University.
Pathological Diagnosis The diagnosis of all patients with SCNECC was confirmed by histologic morphology and immunohistochemical staining of tissue samples that were read by 2 experienced pathologists. The SCNECC histology was defined as having a markedly high nuclear/cytoplasmic ratio and hyperchromatic nuclei with fine granular chromatin and inconspicuous or rarely conspicuous nucleoli. Frequent nuclear moulding might be present. Mixed type cases included small cell carcinoma that accounted for at least 10% of the tumor area.4 Furthermore, at least one of the biomarkers derived from the immunohistochemical staining, including neuron-specific enolase, chromogranin, synaptophysin, and neural cell adhesion molecule CD56, is positive.
Statistical Analysis The primary end point was any cancer-related death, and the secondary one was cancer recurrence. Overall survival (OS) was calculated from the date of radical hysterectomy to death, or censored at last follow-up. Disease-free survival (DFS) was calculated from the date of radical hysterectomy to cancer recurrence, or censored at last follow-up. OS and DFS were evaluated using the Kaplan-Meier method and log-rank tests. The Cox proportional hazards model was used to estimate the independent prognostic factors for OS and DFS. The significance level for all analyses was 0.05. All analyses were carried out using SPSS 16.0 software (SPSS, Chicago, IL).
RESULTS The Clinical and Pathological Features of SCNECC Thirty-eight patients with an average age of 40.4 T 7.0 years were identified with chief complaints of irregular vaginal bleeding (26 cases; 68.4%), leukorrhagia, or occasional findings on physical examination (12 cases; 31.6%). Among these patients, there was 1 case of FIGO stage IA2 (2.6%), 31 cases of stage IB1 (81.6%), 3 cases of stage IB2 (7.9%), and 3 cases of stage IIA (7.9%). All patients * 2015 IGCS and ESGO
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International Journal of Gynecological Cancer
& Volume 25, Number 7, September 2015 Surgically Treated Early-Stage SCNECC
TABLE 1. Baseline characteristics (n = 38)
TABLE 1. (Continued) Cases (%)
Cases (%) Age (y) G40 Q40 Preoperative pathological diagnosis (via colposcopic biopsy or Loop Electrosurgical Excision Procedure) NECC Squamous carcinoma Adenocarcinoma/adenosquamous carcinoma Poorly differentiated carcinoma FIGO stage Ia2 IB1 IB2 IIA Tumor size, cm G2 2-4 Q4 Tumor homology Simple SCNECC Mixed SCNECC with adenocarcinoma squamous carcinoma Lymphovascular infiltration Positive Negative Pelvic lymph node metastasis Positive Negative Deep stromal infiltration Positive Negative Parametrial infiltration Positive Negative Postoperative radiotherapy Yes No Postoperative Chemotherapy Yes No Chemotherapy regimensi and courses TC chemotherapy G4 courses Q4 courses
23 (60.5) 15 (39.5)
Non-TC chemotherapy G4 courses Q4 courses
14 (37.8) 8 6
*Thirty-seven patients received chemotherapy.
13 (34.2) 12 (31.6) 12 (31.6) 1 (2.6) 1 (2.6) 31 (81.6) 3 (7.9) 3 (7.9) 14 (36.8) 20 (52.6) 4 (10.5) 29 (76.3) 9 (23.7)
26 (68.4) 12 (31.6) 13 (34.2) 25 (65.8) 17 (46.7) 21 (55.3) 5 (13.2) 33 (86.8) 24 (63.2) 14 (38.8) 37 (97.4) 1 (2.6) 23 (62.2) 5 18
underwent radical hysterectomy and pelvic lymph node dissection through laparotomy or laparoscopy. The clinical and pathological characteristics were summarized in Table 1. Of 38 patients enrolled in this study, only 13 patients were preoperatively diagnosed as having SCNECC; therefore, the preoperative detection rate of SCNECC was only 34.2%. Thirty-seven of 38 patients underwent postoperative chemotherapy or chemoradiotherapy as adjuvant therapy. Twenty-four patients (63.2%) received postoperative radiotherapy, and 14 patients (38.8%) did not. Of the 37 patients receiving postoperative chemotherapy, 23 patients (62.2%) received TC regimen, and the remaining 14 patients (37.8%) received non-TC regimen (a single-agent or combination chemotherapy including bleomycin, etoposide, 5-FU, cisplatin). Among them, 18 patients (48.6%) received less than 4 courses of chemotherapy treatment, whereas 19 patients (51.4%) received 4 or more courses of chemotherapy. The clinical and pathological characteristics were summarized in Table 1. The median OS of 38 SCNECC patients was 55 months, with a median DFS of 36 months. One-year, 2-year, and 5-year OS rates were 81.6%, 54.7%, and 43%, respectively, and 1-, 2-, and 5-year cumulative recurrence rates were 37.8%, 44.2%, and 49.3%, respectively (see Fig. 1).
Risk Factors Affecting OS and DFS in Surgically Treated Patients With Early-Stage SCNECC Univariate analysis showed that tumor homology (P = 0.033), parametrial invasion (P = 0.034), chemotherapy regimens (P = 0.006), and chemotherapy courses (P = 0.004) were high risk factors for OS. Meanwhile, tumor homology (P = 0.027), pelvic lymph node involvement (P = 0.046), parametrial invasion (P = 0.008), chemotherapy regimens (P = 0.002), and chemotherapy courses (P = 0.003) were the high-risk factors for DFS (see Table 2). Variables associated with OS and DFS on univariate analysis (P e 0.2) were initially included in a Cox proportional hazards model for multivariate analysis, which used stepwise elimination to identify variables independently predictive of OS and DFS. As log-rank test identified that chemotherapy regimens were significantly correlated with chemotherapy courses (P G 0.05), whereas collinearity among variables should be eliminated in a Cox proportional hazards model, we then kept a major independent variable from these 2 (that was chemotherapy regimens) into the multivariate analysis and reanalyzed it. Parametrial invasion and chemotherapy regimen
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FIGURE 1. Survival curves of all 38 patients with early-stage SCNECC. A, OS. B, Cumulative recurrence rate. were indicated as risk factors for both DFS and OS in patients (Table 3). This suggested that postoperative TC therapy was an independent prognostic factor for improved survival.
Comparison of Survival Curves in Patients With Early-Stage SCNECC With Different Adjuvant Chemotherapy Regimens and Chemotherapy Courses There was a significant difference in patients’ survival when different adjuvant chemotherapy regimens (TC vs. nonTC) were compared. The relationship between chemotherapy regimens and OS/DFS in patients is shown in Figures 2 and 3. The 2- and 5-year cumulative survival rates in patients receiving TC regimen as postoperative chemotherapy were 72.6% and 65.3%, respectively. Meanwhile, patients receiving non-TC regimen showed a low 2-year cumulative survival rate of 21.8%, and all patients died within 5 years after surgery. Furthermore, the 2-year recurrence rate of patients receiving TC regimen was as low as 27.3%, whereas those receiving non-TC regimen experienced a tumor recurrence rate of 74.3%. Four and more consecutive chemotherapy courses tended to favor both DFS and OS in both TC (Fig. 3A, B) and non-TC groups (Fig. 3C, D), but the difference did not reach statistically significance when compared with those with less than 4 courses.
DISCUSSION Small cell neuroendocrine carcinoma of the cervix is a rare, highly malignant primary carcinoma of the cervix. Epidemiologic studies showed that the incidence of SCNECC accounts for only 1% to 3% of total number of cervical cancer cases; however, the mortality rate reaches 1.84 times higher than that of invasive squamous cervical cancer at the same stage.10 One reason for why it is so aggressive may be due to the difficulty in early diagnosis, because it was not until 2003 a World Health Organization classification had been recommended. The extremely low preoperative detection rate of 34.2% by colposcopic biopsy or LEEP in our study
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demonstrated the difficulty in early diagnosis, to some extent. The other reason might be the different biological behavior of SCNECC from squamous cell carcinoma, which generally does not invade the cervical surface epithelium, but infiltrates interstitial tissues diffusely. Thus, even patients with early stage could experience lymphovascular infiltration, resulting in poor prognosis. This was particular true in our study, with 68.4% of all cases experienced vascular invasion, whereas 34.2% ones had pelvic lymph node metastasis at an early FIGO stage of Ia2-IIa. Previous studies have suggested that large tumor size, lymph node metastasis, smoking, deep cervical stromal invasion, and pure small cell histology are possible indicators of a poor prognosis in SCNECC.2,6,11 However, given the rare incidence, most previous studies enrolled all stages (I-IV) of patients with SCNECC and did univariate analysis because of sample size limitations. However, it does not take much insight to the fact that there might be intrinsic difference between early-stage patients and advanced ones regarding not
TABLE 2. Univariate analysis of risk factors
Age (G40 y/Q40 y) FIGO stage Tumor size, cm Tumor homology (simple/mixed) Lymphovascular infiltration Pelvic lymph node involvement Deep stromal invasion Parametrial invasion Postoperative chemotherapy Chemotherapy regimens* (TC/non-TC) Chemotherapy courses* (G4/Q4)
DFS (P)
OS (P)
0.261 0.810 0.175 0.027 0.079 0.046 0.110 0.008 0.809 0.002 0.003
0.318 0.778 0.374 0.033 0.112 0.088 0.111 0.009 0.810 0.006 0.004
*Thirty-seven patients received chemotherapy.
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International Journal of Gynecological Cancer
& Volume 25, Number 7, September 2015 Surgically Treated Early-Stage SCNECC
TABLE 3. Multivariate analysis of risk factors DFS
Parametrial invasion Chemotherapy regimens (TC/non-TC)
OS
HR (95% CI)
P
HR (95% CI)
P
3.078 (1.412Y10.783) 3.49 (1.245Y9.784)
0.044 0.018
3.107 (1.072Y9.004) 3.38 (1.25Y9.104)
0.037 0.016
CI, confidence interval; HR, hazard ratio.
only prognostic factors but also optimal treatment strategies. Therefore, we performed current study focusing on patients with early-stage SCNECC (FIGO staging Ia2-IIa). In our study, the univariate analysis showed that tumor homology, parametrial infiltration, chemotherapy regimens, and chemotherapy course are risk factors for OS, whereas tumor homology, lymph node involvement, parametrial infiltration, chemotherapy regimens, and chemotherapy courses are high-risk factors for DFS. Partially consistent with the other studies, smoking was not included as one of the risk factors for analysis because fewer Asian female smokers were included. We then further used Cox proportional hazard model for multivariate analysis and demonstrated that parametrial infiltration and chemotherapy regimens were the only 2 risk factors for both OS and DFS. Significantly higher OS and DFS were found in patients receiving TC regimen than in patients receiving non-TC regimen postoperatively. The 2- and 5-year cumulative survival rates in patients receiving TC regimen were 72.6% and 65.3%, whereas patients receiving non-TC regimen showed a low 2-year cumulative survival rate of 21.8%, and all patients died within 5 years after surgery. In addition, 4 and more consecutive chemotherapy courses tended to favor survival, although the effect did not attain statistical significance, possibly due to the small sample size. Although there are few clinical data supporting the use of adjuvant multimodality treatment in early-stage SCNECC, most clinicians favor to use chemotherapy and/or radiation
because of the strong evidence supporting concurrent chemoradiation in other subtypes of cervical cancer and the high incidence of distant metastases in patients with SCNECC.8,9,12 In a Japanese study of 28 SCNECC patients with FIGO IB1IIB, postoperative chemotherapy has been proved to reach better PFS when compared with nonchemotherapy ones.13 However, optimal chemotherapy regimen for early-stage patients still remains to be determined. Current treatment decisions have largely extrapolated treatment approaches from the management of small cell lung cancer in light of the pathological and behavioral similarities between these tumors. For example, vincristine, adriamycin, and cyclophosphamide and EP, the first-line therapy in treating small cell lung cancer, are also commonly used in SCNECC. In fact, there is no definite proof to distinguish the optimal chemotherapy regimen. Most studies only compared patients between those with and without adjuvant chemotherapy.12,14 Furthermore, even a study did compare different regimens and reveal the advantage of EP regimen, survival benefit was only demonstrated to be improved for patients with advanced stage (FIGO IIB-IV), but not the early ones.7 To our knowledge, this is the first study to demonstrate a potential benefit in survival associated with adjuvant TC therapy in early-stage SCNECC. With well tolerance and definitive effect, TC regimen has been recommended for many gynecologic malignancies, such as epithelial ovarian cancer, uterine cancer, and so on. Based on multivariate regression analysis, our study indicated that as far as the
FIGURE 2. Comparison of survival curves in patients with early-stage SCNECC with different postoperative chemotherapy regimens. A, OS. B, DFS. * 2015 IGCS and ESGO
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& Volume 25, Number 7, September 2015
FIGURE 3. Comparison of survival curves in patients with early-stage SCNECC with different chemotherapy courses (Q4 courses vs. G4 courses) in different groups. A, OS in the TC group. B, DFS in the TC group. C, OS in the non-TC group. (D) DFS in the non-TC group. specific type of SCNECC is concerned, the TC regimen may be more advantageous as adjuvant chemotherapy than any others for patients with early-stage SCNECC after surgery. Although it is a retrospective study and with limited sample size, this study focused on a pure subgroup of SCNECC patientsVearly-stage (FIGO Ia2-IIa) patients and nearly all patients received systemic comprehensive treatment with radical hysterectomy plus adjuvant chemotherapy/or chemoradiation therapy. The results of the present study are of potential clinical value because it indicated the preferred treatment strategies for patients with early-stage SCNECC, that is, primary radical hysterectomy in addition with adjuvant TC therapy. A multicenter randomized controlled trial is further warranted to confirm our findings in these patients in the future.
REFERENCES 1. Viswanathan AN, Deavers MT, Jhingran A, et al. Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence. Gynecol Oncol. 2004;93:27Y33. 2. Crowder S, Tuller E. Small cell carcinoma of the female genital tract. Semin Oncol. 2007;34:57Y63.
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3. Reagan JW, Hamonic MJ, Wentz WB. Analytical study of the cells in cervical squamous-cell cancer. Lab Invest. 1957;6: 241Y250. 4. Albores-Saavedra J, Gersell D, Gilks CB, et al. Terminology of endocrine tumors of the uterine cervix: results of a workshop sponsored by the College of American Pathologists and the National Cancer Institute. Arch Pathol LabMed. 1997;121:34Y39. 5. Abeler VM, Holm R, Nesland JM, et al. Small cell carcinoma of the cervix. A clinicopathologic study of 26 patients. Cancer. 1994;73:672Y677. 6. Chan JK, Loizzi V, Burger RA, et al. Prognostic factors in neuroendocrine small cell cervical carcinoma: a multivariate analysis. Cancer. 2003;97:568Y574. 7. Wang KL, Chang TC, Jung SM, et al. Primary treatment and prognostic factors of small cell neuroendocrine carcinoma of the uterine cervix: a Taiwanese Gynecologic Oncology Group study. Eur J Cancer. 2012;48:1484Y1494. 8. Cohen JG, Kapp DS, Shin JY, et al. Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients. Am J Obstet Gynecol. 2010;203:347.e1Ye6. 9. Lee JM, Lee KB, Nam JH, et al. Prognostic factors in FIGO stage IB-IIA small cell neuroendocrine carcinoma of the uterine * 2015 IGCS and ESGO
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& Volume 25, Number 7, September 2015 Surgically Treated Early-Stage SCNECC
cervix treated surgically: results of a multi-center retrospective Korean study. Ann Oncol. 2008;19:321Y326. 10. McCusker ME, Cote´ TR, Clegg LX, et al. Endocrine tumors of the uterine cervix: incidence, demographics, and survival with comparison to squamous cell carcinoma. Gynecol Oncol. 2003;88:333Y339. 11. Kasamatsu T, Sasajima Y, Onda T, et al. Surgical treatment for neuroendocrine carcinoma of the cervix. Int J Gynecol Obstet. 2007;99:225Y228. 12. Wang KL, Yang YC, Wang TY, et al. Neuroendocrine carcinoma of the uterine cervix: a clinicopathologic retrospective study
of 31 cases with prognostic implications. J Chemother. 2006; 18:209Y216. 13. Kuji S, Hirashima Y, Nakayama H, et al. Diagnosis, clinicopathologic features, treatment, and prognosis of small cell carcinoma of the uterine cervix; Kansai Clinical Oncology Group/Intergroup study in Japan. Gynecol Oncol. 2013;129: 522Y527. 14. Zivanovic O, Leitao MM Jr, Park KJ, et al. Small cell neuroendocrine carcinoma of the cervix: analysis of outcome, recurrence pattern and the impact of platinum-based combination chemotherapy. Gynecol Oncol. 2009;112: 590Y593.
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Prognostic Factors of Surgically Treated Early-Stage Small Cell Neuroendocrine Carcinoma of the Cervix Lei Yuan, MD, PhD, Hongyuan Jiang, MD, Yin Lu, MD, Sun-wei Guo, PhD, and Xishi Liu, MD, PhD
Objective: Small cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare malignancy and has a high mortality despite of aggressive surgical treatment. The aims of this study were to determine the prognostic factors associated with the survival of surgically treated patients with early-stage SCNECC and to see whether carboplatin plus paclitaxel (TC) therapy after surgery can improve their survival. Methods: Thirty-eight women with FIGO stages IA2 (n = 1), IB1 (n = 31), IB2 (n = 3), and IIA1 (n = 3) were treated with radical hysterectomy, followed by adjuvant TC or non-TC, with or without radiotherapy, in our hospital between 2004 and 2013. Medical charts and clinical data were retrieved and retrospectively reviewed. The Kaplan-Meier method and Cox regression model were used for survival analysis. Results: The mean age of patients were 40.4 T 7.0 years. The preoperative detection rate of SCNECC was only 34.2%. The overall 1-, 2-, and 5-year survival rate was 81.6%, 54.7%, and 43%, respectively, whereas the 1-, 2-, and 5-year cumulative recurrence rate was 37.8%, 44.2%, and 49.3%, respectively. For overall survival (OS), the univariate survival analysis indicated that tumor homology, parametrial invasion, chemotherapy regimens, and chemotherapy courses were risk factors. For disease-free survival, the univariate survival analysis identified lymph node involvement, tumor homology, parametrial invasion, chemotherapy regimens, and chemotherapy courses as risk factors. However, when multivariable Cox regression model was used, only parametrial invasion and postoperative chemotherapy regimen were identified as risk factors for both OS (P = 0.037 and P = 0.016) and disease-free survival (P = 0.044 and P = 0.018). Conclusions: Small cell neuroendocrine carcinoma of the cervix is a deadly variant of cervical cancer. Postoperative TC chemotherapy may improve the OS and disease-free survival in women with early-stage SCNECC. Key Words: Small cell neuroendocrine carcinoma of the cervix (SCNECC), Prognosis, Chemotherapy Received April 18, 2015, and accepted for publication April 26, 2015. (Int J Gynecol Cancer 2015;25: 1315Y1321)
Department of Gynecology, Obstetrics & Gynecology Hospital, Fudan University, Shanghai, China.
Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000496 International Journal of Gynecological Cancer
Address correspondence and reprint requests to Xishi Liu, MD, PhD, Department of Gynecology, Obstetrics & Gynecology Hospital, Fudan University, 419 Fangxie Rd, Shanghai 200011, PR China. E-mail: [email protected]. Lei Yuan and Hongyuan Jiang contributed equally to this work. Support: This project is sponsored by Shanghai Natural Science Fund (13ZR1451900 [Lei Yuan]). The authors declare that there are no conflicts of interest.
& Volume 25, Number 7, September 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
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International Journal of Gynecological Cancer
Yuan et al
carcinoma of the cervix (NECC) is a class N euroendocrine of rare gynecologic malignancy with an incidence of 1%
to 3%.1,2 It is highly aggressive and prone to hematologic and lymphatic metastasis at an early stage. Because of the variation in terminology that has evolved over time, it is difficult to define the characteristics of NECC since it was first described by Reagan et al3 in 1957. In 1997, a workgroup sponsored by the National Cancer Institute and the College of American Pathologists recommended uniform terminology for these tumors with 4 categories: typical carcinoid tumor, atypical carcinoid tumor, large cell neuroendocrine carcinoma, and small cell carcinoma.4 Among these tumors, small cell neuroendocrine carcinoma of the cervix (SCNECC) is more common than other types of NECC with worse prognosis in patients with advanced stage based on a 14% 5-year survival rate.5 Because of the low incidence of SCNECC, previous studies have mostly been clinical case reports or case series, making it difficult to draw conclusions on overall management. As a result, risk factors determining the prognosis of SCNECC have not been illustrated and the optimal treatment strategy still remains unclear.6,7 The role of chemotherapy has been advocated as potentially beneficial in treating SCNECC, given its intrinsic biological behavior of early metastasis. Cohen and colleagues8 showed that chemotherapy (as primary, adjuvant or with concurrent radiation) was associated with improved survival in stage IIB-IVA SCNECC compared with those who did not receive chemotherapy. Similar findings were reported by a Taiwanese study that 5 or more consecutive courses of etoposide and cisplatin (EP) chemotherapy could result in better survival for patients with stage IIB-IV SCNECC.7 However, what is the effect of chemotherapy on early-stage patients? Unfortunately, a few bodies of evidence have yet been obtained by previous studies. A Korean report by Lee et al9 showed that in patients with stage IB-IIA, adjuvant chemotherapy tended to favor 5-year survival, but the difference did not reach statistically significance when compared with those with nonchemotherapy. Considering the curative potentials for earlystage SCNECC, it is imperative for us to fully delineate the role of adjuvant chemotherapy in treating early-stage patients. Furthermore, closely tied into this is the question of chemotherapy regimens, even the widely used guidelines such as National Comprehensive Cancer Network or FIGO did not provide suggestions on SCNECC. Because there was no published guideline for chemotherapeutic treatment on SCNECC up to date, the knowledge regarding the treatment regimens is still fragmentary; because previous studies have not been able to show which regimen is better, and thus, the selection of different regimen mostly depends on surgeons’ own values, or preferences7,9 In the current study, we investigated the clinicopathologic features and prognostic factors for patients with surgically treated early-stage SCNECC and to see in particular whether carboplatin plus paclitaxel (TC) therapy after surgery can improve their survival.
MATERIALS AND METHODS Patient Selection A total of 38 patients with early-stage SCNECC (FIGO staging IA2-IIA) who had been admitted and surgically treated
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from January 2004 to December 2013 in the Obstetrics and Gynecology Hospital of Fudan University were enrolled into this study. All patients received radical hysterectomy, and 37 of 38 received adjuvant chemotherapy with/without radiation. Among the patients with postoperative chemotherapy, TC regimen and non-TC regimen (a single-agent or combination chemotherapy including bleomycin, etoposide, 5-FU, cisplatin) were administrated. A follow-up of 12 to 124 months were completed for those 38 patients. Clinical and pathological data, including patient’s age, chief complaint, preoperative diagnosis, tumor size and stage, tumor homology (simple SCNECC or mixed SCNECC with adenocarcinoma or squamous carcinoma), lymph node involvement, depth of stromal invasion, lymphovascular infiltration, parametrial invasion, surgical margin involvement, and postoperative treatment modalities, were collected for analysis. This study was approved by the institutional ethics review board of Obstetrics and Gynecology Hospital, Fudan University.
Pathological Diagnosis The diagnosis of all patients with SCNECC was confirmed by histologic morphology and immunohistochemical staining of tissue samples that were read by 2 experienced pathologists. The SCNECC histology was defined as having a markedly high nuclear/cytoplasmic ratio and hyperchromatic nuclei with fine granular chromatin and inconspicuous or rarely conspicuous nucleoli. Frequent nuclear moulding might be present. Mixed type cases included small cell carcinoma that accounted for at least 10% of the tumor area.4 Furthermore, at least one of the biomarkers derived from the immunohistochemical staining, including neuron-specific enolase, chromogranin, synaptophysin, and neural cell adhesion molecule CD56, is positive.
Statistical Analysis The primary end point was any cancer-related death, and the secondary one was cancer recurrence. Overall survival (OS) was calculated from the date of radical hysterectomy to death, or censored at last follow-up. Disease-free survival (DFS) was calculated from the date of radical hysterectomy to cancer recurrence, or censored at last follow-up. OS and DFS were evaluated using the Kaplan-Meier method and log-rank tests. The Cox proportional hazards model was used to estimate the independent prognostic factors for OS and DFS. The significance level for all analyses was 0.05. All analyses were carried out using SPSS 16.0 software (SPSS, Chicago, IL).
RESULTS The Clinical and Pathological Features of SCNECC Thirty-eight patients with an average age of 40.4 T 7.0 years were identified with chief complaints of irregular vaginal bleeding (26 cases; 68.4%), leukorrhagia, or occasional findings on physical examination (12 cases; 31.6%). Among these patients, there was 1 case of FIGO stage IA2 (2.6%), 31 cases of stage IB1 (81.6%), 3 cases of stage IB2 (7.9%), and 3 cases of stage IIA (7.9%). All patients * 2015 IGCS and ESGO
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International Journal of Gynecological Cancer
& Volume 25, Number 7, September 2015 Surgically Treated Early-Stage SCNECC
TABLE 1. Baseline characteristics (n = 38)
TABLE 1. (Continued) Cases (%)
Cases (%) Age (y) G40 Q40 Preoperative pathological diagnosis (via colposcopic biopsy or Loop Electrosurgical Excision Procedure) NECC Squamous carcinoma Adenocarcinoma/adenosquamous carcinoma Poorly differentiated carcinoma FIGO stage Ia2 IB1 IB2 IIA Tumor size, cm G2 2-4 Q4 Tumor homology Simple SCNECC Mixed SCNECC with adenocarcinoma squamous carcinoma Lymphovascular infiltration Positive Negative Pelvic lymph node metastasis Positive Negative Deep stromal infiltration Positive Negative Parametrial infiltration Positive Negative Postoperative radiotherapy Yes No Postoperative Chemotherapy Yes No Chemotherapy regimensi and courses TC chemotherapy G4 courses Q4 courses
23 (60.5) 15 (39.5)
Non-TC chemotherapy G4 courses Q4 courses
14 (37.8) 8 6
*Thirty-seven patients received chemotherapy.
13 (34.2) 12 (31.6) 12 (31.6) 1 (2.6) 1 (2.6) 31 (81.6) 3 (7.9) 3 (7.9) 14 (36.8) 20 (52.6) 4 (10.5) 29 (76.3) 9 (23.7)
26 (68.4) 12 (31.6) 13 (34.2) 25 (65.8) 17 (46.7) 21 (55.3) 5 (13.2) 33 (86.8) 24 (63.2) 14 (38.8) 37 (97.4) 1 (2.6) 23 (62.2) 5 18
underwent radical hysterectomy and pelvic lymph node dissection through laparotomy or laparoscopy. The clinical and pathological characteristics were summarized in Table 1. Of 38 patients enrolled in this study, only 13 patients were preoperatively diagnosed as having SCNECC; therefore, the preoperative detection rate of SCNECC was only 34.2%. Thirty-seven of 38 patients underwent postoperative chemotherapy or chemoradiotherapy as adjuvant therapy. Twenty-four patients (63.2%) received postoperative radiotherapy, and 14 patients (38.8%) did not. Of the 37 patients receiving postoperative chemotherapy, 23 patients (62.2%) received TC regimen, and the remaining 14 patients (37.8%) received non-TC regimen (a single-agent or combination chemotherapy including bleomycin, etoposide, 5-FU, cisplatin). Among them, 18 patients (48.6%) received less than 4 courses of chemotherapy treatment, whereas 19 patients (51.4%) received 4 or more courses of chemotherapy. The clinical and pathological characteristics were summarized in Table 1. The median OS of 38 SCNECC patients was 55 months, with a median DFS of 36 months. One-year, 2-year, and 5-year OS rates were 81.6%, 54.7%, and 43%, respectively, and 1-, 2-, and 5-year cumulative recurrence rates were 37.8%, 44.2%, and 49.3%, respectively (see Fig. 1).
Risk Factors Affecting OS and DFS in Surgically Treated Patients With Early-Stage SCNECC Univariate analysis showed that tumor homology (P = 0.033), parametrial invasion (P = 0.034), chemotherapy regimens (P = 0.006), and chemotherapy courses (P = 0.004) were high risk factors for OS. Meanwhile, tumor homology (P = 0.027), pelvic lymph node involvement (P = 0.046), parametrial invasion (P = 0.008), chemotherapy regimens (P = 0.002), and chemotherapy courses (P = 0.003) were the high-risk factors for DFS (see Table 2). Variables associated with OS and DFS on univariate analysis (P e 0.2) were initially included in a Cox proportional hazards model for multivariate analysis, which used stepwise elimination to identify variables independently predictive of OS and DFS. As log-rank test identified that chemotherapy regimens were significantly correlated with chemotherapy courses (P G 0.05), whereas collinearity among variables should be eliminated in a Cox proportional hazards model, we then kept a major independent variable from these 2 (that was chemotherapy regimens) into the multivariate analysis and reanalyzed it. Parametrial invasion and chemotherapy regimen
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FIGURE 1. Survival curves of all 38 patients with early-stage SCNECC. A, OS. B, Cumulative recurrence rate. were indicated as risk factors for both DFS and OS in patients (Table 3). This suggested that postoperative TC therapy was an independent prognostic factor for improved survival.
Comparison of Survival Curves in Patients With Early-Stage SCNECC With Different Adjuvant Chemotherapy Regimens and Chemotherapy Courses There was a significant difference in patients’ survival when different adjuvant chemotherapy regimens (TC vs. nonTC) were compared. The relationship between chemotherapy regimens and OS/DFS in patients is shown in Figures 2 and 3. The 2- and 5-year cumulative survival rates in patients receiving TC regimen as postoperative chemotherapy were 72.6% and 65.3%, respectively. Meanwhile, patients receiving non-TC regimen showed a low 2-year cumulative survival rate of 21.8%, and all patients died within 5 years after surgery. Furthermore, the 2-year recurrence rate of patients receiving TC regimen was as low as 27.3%, whereas those receiving non-TC regimen experienced a tumor recurrence rate of 74.3%. Four and more consecutive chemotherapy courses tended to favor both DFS and OS in both TC (Fig. 3A, B) and non-TC groups (Fig. 3C, D), but the difference did not reach statistically significance when compared with those with less than 4 courses.
DISCUSSION Small cell neuroendocrine carcinoma of the cervix is a rare, highly malignant primary carcinoma of the cervix. Epidemiologic studies showed that the incidence of SCNECC accounts for only 1% to 3% of total number of cervical cancer cases; however, the mortality rate reaches 1.84 times higher than that of invasive squamous cervical cancer at the same stage.10 One reason for why it is so aggressive may be due to the difficulty in early diagnosis, because it was not until 2003 a World Health Organization classification had been recommended. The extremely low preoperative detection rate of 34.2% by colposcopic biopsy or LEEP in our study
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demonstrated the difficulty in early diagnosis, to some extent. The other reason might be the different biological behavior of SCNECC from squamous cell carcinoma, which generally does not invade the cervical surface epithelium, but infiltrates interstitial tissues diffusely. Thus, even patients with early stage could experience lymphovascular infiltration, resulting in poor prognosis. This was particular true in our study, with 68.4% of all cases experienced vascular invasion, whereas 34.2% ones had pelvic lymph node metastasis at an early FIGO stage of Ia2-IIa. Previous studies have suggested that large tumor size, lymph node metastasis, smoking, deep cervical stromal invasion, and pure small cell histology are possible indicators of a poor prognosis in SCNECC.2,6,11 However, given the rare incidence, most previous studies enrolled all stages (I-IV) of patients with SCNECC and did univariate analysis because of sample size limitations. However, it does not take much insight to the fact that there might be intrinsic difference between early-stage patients and advanced ones regarding not
TABLE 2. Univariate analysis of risk factors
Age (G40 y/Q40 y) FIGO stage Tumor size, cm Tumor homology (simple/mixed) Lymphovascular infiltration Pelvic lymph node involvement Deep stromal invasion Parametrial invasion Postoperative chemotherapy Chemotherapy regimens* (TC/non-TC) Chemotherapy courses* (G4/Q4)
DFS (P)
OS (P)
0.261 0.810 0.175 0.027 0.079 0.046 0.110 0.008 0.809 0.002 0.003
0.318 0.778 0.374 0.033 0.112 0.088 0.111 0.009 0.810 0.006 0.004
*Thirty-seven patients received chemotherapy.
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TABLE 3. Multivariate analysis of risk factors DFS
Parametrial invasion Chemotherapy regimens (TC/non-TC)
OS
HR (95% CI)
P
HR (95% CI)
P
3.078 (1.412Y10.783) 3.49 (1.245Y9.784)
0.044 0.018
3.107 (1.072Y9.004) 3.38 (1.25Y9.104)
0.037 0.016
CI, confidence interval; HR, hazard ratio.
only prognostic factors but also optimal treatment strategies. Therefore, we performed current study focusing on patients with early-stage SCNECC (FIGO staging Ia2-IIa). In our study, the univariate analysis showed that tumor homology, parametrial infiltration, chemotherapy regimens, and chemotherapy course are risk factors for OS, whereas tumor homology, lymph node involvement, parametrial infiltration, chemotherapy regimens, and chemotherapy courses are high-risk factors for DFS. Partially consistent with the other studies, smoking was not included as one of the risk factors for analysis because fewer Asian female smokers were included. We then further used Cox proportional hazard model for multivariate analysis and demonstrated that parametrial infiltration and chemotherapy regimens were the only 2 risk factors for both OS and DFS. Significantly higher OS and DFS were found in patients receiving TC regimen than in patients receiving non-TC regimen postoperatively. The 2- and 5-year cumulative survival rates in patients receiving TC regimen were 72.6% and 65.3%, whereas patients receiving non-TC regimen showed a low 2-year cumulative survival rate of 21.8%, and all patients died within 5 years after surgery. In addition, 4 and more consecutive chemotherapy courses tended to favor survival, although the effect did not attain statistical significance, possibly due to the small sample size. Although there are few clinical data supporting the use of adjuvant multimodality treatment in early-stage SCNECC, most clinicians favor to use chemotherapy and/or radiation
because of the strong evidence supporting concurrent chemoradiation in other subtypes of cervical cancer and the high incidence of distant metastases in patients with SCNECC.8,9,12 In a Japanese study of 28 SCNECC patients with FIGO IB1IIB, postoperative chemotherapy has been proved to reach better PFS when compared with nonchemotherapy ones.13 However, optimal chemotherapy regimen for early-stage patients still remains to be determined. Current treatment decisions have largely extrapolated treatment approaches from the management of small cell lung cancer in light of the pathological and behavioral similarities between these tumors. For example, vincristine, adriamycin, and cyclophosphamide and EP, the first-line therapy in treating small cell lung cancer, are also commonly used in SCNECC. In fact, there is no definite proof to distinguish the optimal chemotherapy regimen. Most studies only compared patients between those with and without adjuvant chemotherapy.12,14 Furthermore, even a study did compare different regimens and reveal the advantage of EP regimen, survival benefit was only demonstrated to be improved for patients with advanced stage (FIGO IIB-IV), but not the early ones.7 To our knowledge, this is the first study to demonstrate a potential benefit in survival associated with adjuvant TC therapy in early-stage SCNECC. With well tolerance and definitive effect, TC regimen has been recommended for many gynecologic malignancies, such as epithelial ovarian cancer, uterine cancer, and so on. Based on multivariate regression analysis, our study indicated that as far as the
FIGURE 2. Comparison of survival curves in patients with early-stage SCNECC with different postoperative chemotherapy regimens. A, OS. B, DFS. * 2015 IGCS and ESGO
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FIGURE 3. Comparison of survival curves in patients with early-stage SCNECC with different chemotherapy courses (Q4 courses vs. G4 courses) in different groups. A, OS in the TC group. B, DFS in the TC group. C, OS in the non-TC group. (D) DFS in the non-TC group. specific type of SCNECC is concerned, the TC regimen may be more advantageous as adjuvant chemotherapy than any others for patients with early-stage SCNECC after surgery. Although it is a retrospective study and with limited sample size, this study focused on a pure subgroup of SCNECC patientsVearly-stage (FIGO Ia2-IIa) patients and nearly all patients received systemic comprehensive treatment with radical hysterectomy plus adjuvant chemotherapy/or chemoradiation therapy. The results of the present study are of potential clinical value because it indicated the preferred treatment strategies for patients with early-stage SCNECC, that is, primary radical hysterectomy in addition with adjuvant TC therapy. A multicenter randomized controlled trial is further warranted to confirm our findings in these patients in the future.
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