Objective
To determine the clinicopathologic factors associated with survival in neuroendocrine small cell cervical cancer patients.
Study Design
Patients were identified from a review of literature with an additional 52 patients from four hospitals. Kaplan-Meier and Cox regression methods were used for analyses.
Results
Of 188 patients, 135 had stages I-IIA, 45 stages IIB-IVA, and 8 stage IVB disease. A total of 55.3% underwent surgery, 16.0% had chemoradiation, 12.8% radiation, and 3.2% chemotherapy alone. The 5-year disease-specific survival in stage I-IIA, IIB-IVA, and IVB disease was 36.8%, 9.8%, and 0%, respectively ( P < .001). Adjuvant chemotherapy or chemoradiation was associated with improved survival in patients with stages IIB-IVA disease compared with those who did not receive chemotherapy (17.8% vs 6.0%; P = .04). On multivariable analysis, early-stage disease and use of chemotherapy or chemoradiation were independent prognostic factors for improved survival.
Conclusion
Use of adjuvant chemotherapy or chemoradiation was associated with higher survival in small cell cervical cancer patients.
Neuroendocrine small cell cervical carcinoma is an aggressive, but rare form of cervical cancer with an incidence of less than 3% of all cervical cancers. Earlier reports have shown that the majority of patients present with advanced stage disease, have lymph node metastasis, and are at a high risk for recurrence and disease progression. In a retrospective study of 21 patients with small cell cervical cancer, the 2- and 5-year survival rates were only 43% and 29%, respectively. In fact, of the patients with greater than IB1 disease, there were no survivors beyond 30 months. Compared with patients with squamous cell carcinomas, women with small cell tumors have 1.84 times greater risk of death. Women with small cell cervical cancer have a worse prognosis than other histologic cell types. Of those with stage IB1 disease, the 10-year survival was 55% in small cell compared with 76% and 88% in adenocarcinoma and squamous cell patients, respectively. To date, most studies on neuroendocrine cervical carcinoma are comprised of only small series and case reports, making it difficult to draw conclusions on overall management. Given the aggressive nature of neuroendocrine small cell cervical cancer, it is imperative to identify potential treatments that can improve the outcomes of these patients. As such, we performed an analysis of 188 women comprised of patients from our own institutions and abstracted on a case by case basis from series in the English literature, to determine the prognostic factors and potential therapeutic modalities that may improve survival in neuroendocrine cervical cancer patients.
Materials and Methods
Fifty-two patients with neuroendocrine small cell cervical carcinoma who received diagnoses from 1979-2005 were identified from tumor registry databases at 4 hospitals (University of California-San Francisco, Stanford University, University of California-Irvine Medical Center, and Long Beach Memorial Medical Center). After institutional review board approval from these institutions, data were collected from hospital charts, office records, and tumor registry files. The remaining 136 patients were collected from case-series reported in the literature. A literature search was performed in Pubmed using “small cell carcinoma,” and “neuroendocrine and cervix,” and “oat cell carcinoma and cervix.” These papers were then analyzed for those which provided individual patient data on demographics, clinicopathologic characteristics, treatment, and outcome information and 44 papers met these criteria. Every attempt was made to include only patients meeting the criteria for high-grade small cell carcinomas of the cervix as characterized by the workshop sponsored by the College of American Pathologists and the National Cancer Institute. Cases that were clearly carcinoid tumors or large cell neuroendocrine tumors of the cervix were excluded. Of the cases, 50% were confirmed with either immunohistochemical staining or electron microscopy. Of the other cases, 89% came from large academic institutions with expert gynecologic pathologists. By reviewing the individual patient demographic and tumor characteristics, an attempt was made to exclude cases that may have been included in 2 or more publications. The individual patient data were abstracted from the text and tables in the publications and not extrapolated from the figures. Statistical analysis was performed using NCSS 2001. Kaplan-Meier life table analyses were used to analyze the significant clinical and pathologic risk factors for survival. Independent prognostic factors predictive of survival were analyzed with Cox regression methods. All tests were 2-tailed with P values < .05 considered significant.
Results
Of 188 patients, 135 had stage I-IIA, 45 had IIB-IVA, and 8 had stage IVB disease. The median age was 42 years (range, 20–87 years). Demographic characteristics of the patients are shown in Table 1 . Vaginal bleeding at presentation was noted in 21.8% of patients and 8% had pain and pressure. Of 115 patients with tumor size documented, 80.0% had tumor ≥2 cm in size. Other clinicopathologic characteristics are shown in Table 2 .
| Variables | n (%) | 5-year DSS | P value |
|---|---|---|---|
| Age at diagnosis, y | .78 | ||
| ≤40 | 92 (48.9) | 30.1% | |
| >40 | 96 (51.1) | 28.6% | |
| Race | .44 | ||
| White | 42 (61.8) | 28.7% | |
| Hispanic | 3 (4.4) | 33.3% | |
| Black | 4 (5.9) | 50.0% | |
| Others | 19 (27.9) | 0.0% | |
| Stage | < .001 | ||
| I-IIA | 135 (71.8) | 36.8% | |
| IIB-IV | 53 (28.2) | 8.9% | |
| Radical hysterectomy | < .001 | ||
| Yes | 89 (52.4) | 38.2% | |
| No | 81 (47.6) | 23.8% | |
| Chemotherapy | |||
| Stage I-IV disease | .56 | ||
| Chemotherapy | 81 (43.1) | 38.1% | |
| No chemotherapy | 85 (45.2) | 30.3% | |
| Stage I-IIA disease | .91 | ||
| Chemotherapy | 57 (46.7) | 47.3% | |
| No chemotherapy | 65 (53.3) | 38.7% | |
| Stage IIB-IVA disease | .043 a | ||
| Chemotherapy | 17 (37.8) | 17.8% | |
| No chemotherapy | 20 (44.4) | 12.0% |
a Three-year survival listed, unable to calculate 5-y DSS due to death of all patients in at least 1 group by 60 mo.
| Variables | n (%) | 5-year DSS | P value |
|---|---|---|---|
| Tumor size | .06 | ||
| <2 cm | 23 (20.0) | 67.4% | |
| ≥2 cm | 92 (80.0) | 34.4% | |
| Tumor histology | .014 | ||
| Pure | 82 (73.2) | 14.3% | |
| Mixed | 30 (26.8) | 30.9% | |
| Lymphovascular space invasion | .26 | ||
| Yes | 50 (26.6) | 40.7% | |
| No | 22 (11.7) | 52.0% | |
| Lymph node involvement a | |||
| Pelvic lymphadenectomy | .12 | ||
| No | 37 (34.6) | 55.7% | |
| Yes | 70 (65.4) | 32.8% | |
| Pelvic lymph node involvement | |||
| No | 44 (65.7) | 31.7% | .20 |
| Yes | 23 (34.3) | 27.8% | |
| Paraaortic lymphadenectomy | |||
| No | 56 (57.1) | 46.7% | .65 |
| Yes | 42 (42.9) | 36.2% | |
| Paraaortic lymph node involvement | |||
| No | 39 (79.6) | 33.2% | .41 |
| Yes | 10 (20.4) | 25.7% | |
a After surgery (includes patients with stage I-IIA disease only).
For primary treatment, 55.3% underwent surgery, 16.0% had chemoradiation, 12.8% radiation, 3.2% chemotherapy alone, and 12.8% had other or no treatment. Of patients with stage I-IIA disease, 68.1% underwent surgery, 8.9% had radiation therapy, 8.9% underwent chemoradiation, 1.5% had chemotherapy only, and 12.6% had other or no treatment. Of those with stage IIB-IVA disease, 26.7% had surgery, 35.6% underwent chemoradiation, 24.4% had radiation therapy, 6.7% underwent chemotherapy alone, and 6.6% had other or no treatment. Of those with stage IVB disease, 25% underwent chemoradiation, 12.5% had surgery, 12.5% were treated with chemotherapy, 12.5% received radiation alone, and 37.5% had unknown treatment. Of all women who had surgery, 84.6% underwent a radical and 11.5% had a simple hysterectomy. Pelvic lymph node dissections were performed in 54% of patients and 36.2% had a paraaortic lymph node dissection. Of these patients, 49.5% had lymph node metastasis. Of those with information on lymphovascular space invasion (LVI), 69.4% had LVI; 71.2% of patients with stage I-IIA disease had tumors with LVI. Of the 81 patients who received chemotherapy, 51.9% had cisplatin combined with etoposide, 25.9% had other cisplatin combinations, and 7.4% had cisplatin alone, and 14.8% had other chemotherapy. Of those patients with known recurrence information, 10 patients had local recurrence, 61 had distant recurrence, and 5 patients had both local and distant recurrence.
The overall 5-year disease survival for patients with stage I-IIA and IIB-IV was 36.8%, and 8.9%, respectively ( P < .001) ( Figure 1 ). Chemotherapy (as primary, adjuvant, or with concurrent radiation) was associated with improved survival in stage IIB-IVA disease compared with those who did not receive chemotherapy (3-year survival: 17.8% vs 12.0%; P = .043) ( Figure 2 ). However, in the 135 patients with stage I-IIA disease, those who had any chemotherapy vs no chemotherapy had 5-year survivals of 47.3% and 38.7%, respectively ( P = .908). Those who had radiation therapy vs no radiation had a 5-year survival of 26.9% vs 36.4%, respectively ( P = .115). Patients with tumors <2 cm had a 5-year survival of 67.4% vs 34.4% in those with larger tumors ( P = .057). The 5-year survival for stage I-IIA patients who received a radical hysterectomy was 38.2% compared with 23.8% for those who did not undergo radical hysterectomy ( P < .001) ( Figure 3 ). In multivariate analysis, early-stage disease (I-IIA), use of any chemotherapy, and radical hysterectomy were independent prognostic factors for improved survival ( Table 3 ).
