Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence

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Abstract

Objective. To analyze the sites of relapse and overall survival in women with neuroendocrine marker-positive small cell carcinoma of the cervix.

Methods. The records of all women who had their initial treatment for cervical cancer at The University of Texas M.D. Anderson Cancer Center between 1980 and 2000 were reviewed. Fifty-one patients had stages I–III cancers that were originally described as “small cell” or “neuroendocrine.” Histological material was available for reexamination in 45 cases; of these, 21 were found to have small cell neuroendocrine carcinoma (SCNEC) as indicated by positive staining for chromogranin, synaptophysin, or CD56. Local treatment consisted of a radical hysterectomy in six patients and radiation therapy in 15. Thirteen patients received chemotherapy as part of their initial treatment. The median follow-up for surviving patients was 83 months (range, 25–209 months).

Results. Fourteen (66%) of the 21 patients had a relapse. The median time to first relapse from the initiation of treatment was 8.4 months (range, 3.6–28 months). Most patients developed hematogenous distant metastases before their death. Only 2 of 15 patients who were treated with radiation therapy had a recurrence within the radiation fields. However, five patients had a recurrence above the radiation fields in the paraaortic lymph nodes, and two patients had a recurrence distal to the pelvic fields in the vagina. No patient had brain metastases as the sole site of first recurrence. However, two patients developed brain metastases concurrently with lung metastases. The overall survival rate was 29% at 5 years; none of the patients who had disease more extensive than stage IB1 or clinical evidence of lymph node metastases survived their disease.

Conclusions. Patients with small cell neuroendocrine cervical cancer have a poor prognosis. Their course is frequently characterized by the development of widespread hematogenous metastases; locoregional recurrence outside irradiated fields is also frequent. Brain metastases were seen only in patients who also had lung metastases, suggesting that prophylactic cranial irradiation would be of little benefit.

Introduction

Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare malignancy, representing less than 5% of all cases of cervical cancer. It is characterized by frequent and early nodal and distant metastases, resulting in a relatively poor prognosis. Histologically, SCNEC is indistinguishable from small cell carcinoma in other sites. Characteristic features include small (less than two to three times the diameter of a small resting lymphocyte or 14–21 μm) cells with hyperchromatic nuclei and scant cytoplasm. Nucleoli are inconspicuous or absent. Frequent mitoses as well as necrosis are commonly identified. Small cell carcinoma is diagnosed on hematoxylin–eosin staining alone and is independent of the extent of neuroendocrine differentiation [1]. However, neuroendocrine markers are commonly used to assist in classification. Up to 80% of hematoxylin- and eosin-diagnosed small cell carcinomas also stain positive with neuroendocrine markers [2].

Most clinicians favor the use of chemotherapy to treat SCNEC because of the strong evidence supporting concurrent chemoradiation in other types of cervical cancer and high incidence of distant metastases in the SCNEC subgroup. However, the regimen, timing, and duration of chemotherapy remain controversial. Although patients with locoregionally advanced disease are usually treated with radiation therapy, the optimal locoregional treatment for women with early-stage cancers has not been determined. On the basis of similarities between SCNEC and small cell lung cancer, it has been suggested that prophylactic cranial irradiation may be indicated; however, its role has not been clearly defined [3].

We performed a retrospective review to learn more about patterns of relapse, treatment effectiveness, and overall survival in women with neuroendocrine marker-positive small cell carcinoma of the cervix.

Section snippets

Methods

A database of patients treated for carcinoma of the uterine cervix at The University of Texas M.D. Anderson Cancer Center was searched to identify patients whose tumors were described in the original pathology reports as “small cell” or “neuroendocrine” cervical carcinoma. Patients who had hematogenous distant metastases at diagnosis were excluded. Fifty-one patients met these criteria.

For this study, a gynecologic pathologist (M.D.) reexamined all the available biopsy and hysterectomy

Patient characteristics

The median patient age was 46 years (range, 26–78 years) (Table 1). Race was recorded as white in 14 patients, African American in 2, Hispanic in 3, and Asian in 2. Five patients reported a history of tobacco use. The mean hemoglobin concentration at diagnosis was 12 g/dl.

Fifteen patients had stage I disease, and six had stage II or III disease. None of the six patients treated with radical hysterectomy had evidence of lymph node involvement. However, 6 of the 15 patients treated with radiation

Discussion

For this study, we restricted our analysis to patients with neuroendocrine marker-positive small cell carcinoma. A key component of our review was that all pathologic material was rereviewed by one pathologist using modern classification methods and staining techniques. Our approach is important because confusion about definitions of disease has made it difficult to interpret the results of previous reports on small cell carcinomas of the cervix. Albores-Saavedra et al. [4] published the first

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