Management of adenocarcinoma and neuroendocrine carcinoma of the cervix

INTRODUCTION — Squamous cell carcinomas (SCCs) account for approximately 80 percent of cervical cancers, adenocarcinomas 15 percent, and adenosquamous carcinomas 3 to 5 percent (show table 1). In addition, neuroendocrine or small cell carcinomas can originate in the cervix in women, but are infrequent.
In general, the management of adenocarcinoma or adenosquamous carcinoma of the cervix is similar to that of patients with squamous cell cancers [1,2]. When adjusted for stage, many [3-5] but not all [6-9], series support the prognostic equivalence of glandular versus squamous cell histology. The worse outcome in some series is attributed to a higher rate of distant metastases [6,10,11].
Unique issues pertaining to adenocarcinoma and neuroendocrine or small cell cervical cancer will be reviewed here. Management issues that are similar for both squamous and nonsquamous invasive cervical cancers are discussed in depth separately. (See "Management of invasive cervical cancer: Early stage disease (FIGO IA, IB1, nonbulky IIA) and special circumstances" and see "Management of invasive cervical cancer: IB2, bulky IIA, and locally advanced disease"). Clinical manifestations, epidemiology, staging and diagnosis of cervical cancer are also presented elsewhere. (See "Epidemiology, clinical features, and diagnosis of invasive cervical cancer" and see "Staging of cervical cancer").
ADENOCARCINOMA
Microinvasive disease — There is substantial controversy regarding the definition and optimal management for microinvasive adenocarcinoma [12,13]. Conization, radical trachelectomy, simple hysterectomy, and radical hysterectomy have all been proposed. In one literature review, none of 48 women with stage IA1 disease (show table 2) who underwent simple hysterectomy or therapeutic conization developed recurrent disease, with up to 320 months follow-up [14]. The authors suggested that simple hysterectomy without lymphadenectomy may be adequate treatment for stage IA1 adenocarcinoma of the cervix; others concur [12,15].
The management dilemma in young women who desire to preserve fertility is complicated by the multifocal nature of glandular lesions and the poor predictive value of conization margins for residual disease. Furthermore, cervical cytology smears and endocervical curettage are poor surveillance tools for following patients after conservative management of adenocarcinoma in situ or microinvasive adenocarcinoma.
The value of careful review of the pathology slides with the pathologist cannot be overemphasized. Review is important for determining whether the patient is a candidate for conservative therapy with conization alone versus radical trachelectomy or, when hysterectomy is planned, to determine the appropriate route and type of procedure.
Because of controversy regarding the definition of microinvasive disease, firm treatment recommendations for individual patients cannot be made without knowledge of the exact pathologic findings. In general, if the disease is minimal (labeled carcinoma in situ by some pathologists, microinvasive disease by others) and there are wide negative margins on cold knife conization, then a simple hysterectomy may be a reasonable option. We tend to perform a modified radical hysterectomy whenever there is a question of more than minimal disease; the added surgical morbidity of this approach is minimal when performed by experienced gynecologic oncologists.
Invasive disease — Women with invasive cervical adenocarcinoma are treated identically to those with SCC. The trials demonstrating benefit from concomitant chemoradiotherapy compared to radiation therapy alone all included women with not only SCC but also adenocarcinoma or adenosquamous histology [16-19].
Neoadjuvant chemotherapy — Neoadjuvant (preoperative) chemotherapy may be beneficial in women with adenocarcinoma. In one report, a median of three courses of cisplatin (50 mg/m2 on day one), etoposide (100 mg/m2 on days one, three, and five), and mitomycin (10 mg/m2 on day one) were administered to 16 patients with stage IB1 to IVB cervical adenocarcinoma [20]. At the time of radical hysterectomy, which was performed in 12 patients with stage I or II disease, moderate to marked pathologic changes were noted in the three clinical complete responders. Similar data have been reported by others [21,22]. Further study of this approach is needed.
Advanced disease — Active single agents for advanced cervical adenocarcinoma include cisplatin, ifosfamide [23], paclitaxel [24], gallium nitrate [25], leucovorin-modulated 5-FU [26], and oral etoposide [27].
Few studies have systematically examined combination therapy: In one report, the combination of mitomycin, cisplatin, and etoposide was administered to 31 women with advanced or recurrent cervical adenocarcinoma; the response rate was 27 percent, and was long-lasting in three [28]. In a second series, 19 women with locally advanced, recurrent, or metastatic cervical adenocarcinoma received epirubicin (70 mg/m2), paclitaxel (175 mg/m2 over three hours), and cisplatin (50 mg/m2), each repeated every three weeks [29]. In the women with locally advanced disease, the overall clinical and pathologic response rates were 64 and 62 percent. Comparable response rates (54 and 44 percent, respectively) and median survival durations (19 and 12 months, respectively) were shown among women with advanced or recurrent nonsquamous cell (n = 58) and squamous cell cervical cancers (n = 142) using a variety of cisplatin-based chemotherapy regimens (cisplatin plus ifosfamide or paclitaxel or both, or MVAC [methotrexate, vinblastine, doxorubicin, and cisplatin]) [5]. Cisplatin/topotecan is also an active regimen for cervical adenocarcinomas and adenosquamous cancers [30].
Surgical resection may be useful in carefully selected patients with isolated pulmonary metastases. (See "Surgical resection of pulmonary metastases").
NEUROENDOCRINE CANCER — Small cell and large cell neuroendocrine cervical cancers are rare, but aggressive neoplasms that are considered an extrapulmonary variant of pulmonary small cell cancer. (See "Pathobiology and staging of small cell carcinoma of the lung"). The cervix should always be considered as the site of origin in a woman with a neuroendocrine or small cell carcinoma of unknown primary site. (See "Neuroendocrine carcinoma of unknown primary site" and see "Extrapulmonary small cell cancer").
Most published series contain few patients. Survival is poor with hysterectomy alone, but there is no consensus as to optimal management [31-33]. Most patients are treated with a multimodality approach, using chemotherapy regimens that are typically used for small cell lung cancer [34-41]. (See "First-line chemotherapy for small cell lung cancer"). Results from two of the largest reports are illustrative: In a series of 23 women, adjuvant chemotherapy with either PVB (cisplatin, vinblastine, and bleomycin) or VAC/PE (vincristine, doxorubicin, cyclophosphamide, alternating with cisplatin and etoposide) was administered after radical hysterectomy [40]. At a median follow-up of 41 months, 10 of 14 patients receiving VAC/PE were alive as compared to only three of nine receiving PVB. A report from Taiwan included 2 cases of atypical carcinoid, four large cell neuroendocrine cancers, and 25 cases of small cell neuroendocrine carcinoma [41]. Two- and five-year survival rates were 55 and 32 percent, respectively, and did not differ according to chemotherapy regimen, lymph node involvement, type of surgery, histology, or FIGO stage in this small, heterogeneous trial.
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