Archives of Gynecology and Obstetrics

, Volume 271, Issue 4, pp 316–319

Small-cell carcinoma of the uterus and the vagina: experience with ten patients

Authors

    • Department of Obstetrics and GynecologyUniversity of Graz
  • C. Pasterk
    • Department of Obstetrics and Gynecology, Institute of PathologyUniversity of Vienna
  • O. Reich
    • Department of Obstetrics and GynecologyUniversity of Graz
  • A. Obermair
    • Department of Obstetrics and Gynecology, Institute of PathologyUniversity of Vienna
  • R. Winter
    • Department of Obstetrics and GynecologyUniversity of Graz
  • G. Breitenecker
    • Department of Obstetrics and Gynecology, Institute of PathologyUniversity of Vienna
Original Article

DOI: 10.1007/s00404-004-0630-1

Cite this article as:
Petru, E., Pasterk, C., Reich, O. et al. Arch Gynecol Obstet (2005) 271: 316. doi:10.1007/s00404-004-0630-1

Abstract

Background

Small cell carcinomas (small-CCs) of the uterine cervix are rare and highly malignant neoplasms. Patients tend to develop distant metastasis early and thus are potential candidates for systemic therapy. We reviewed the experience with small-CCs of the uterus and vagina at two Austrian University hospitals.

Material and methods

Ten patients (median age, 50 years; range, 18–92) with small-CC of the cervix (n=7), uterine corpus (n=2), and the vagina (n=1) were treated at the two centers between 1988 and 1998. Eight patients underwent radical surgery, 7 of whom also received chemotherapy. Two additional patients underwent primary radiotherapy.

Results

All Pap smears were suspicious for cervical malignancy. The median survival was 12 months (range, 6–86) and overall 5-year survival was 10%. Five of 8 surgically treated patients had lymph node involvement (62%). Of the 7 patients with small-CC of the cervix only one, who had FIGO stage IIB disease and positive pelvic nodes, survived long-term (86 months) with no evidence of disease. She had received six courses of dose-intensive platinum chemotherapy after radical surgery. All three patients with small-CC of the uterine corpus or vagina developed recurrence within the first year after diagnosis. Of the 7 patients who received chemotherapy, 5 developed progressive or recurrent disease in the paraaortic region (n=2), peritoneum (n=1), liver (n=1), or pelvis (n=1).

Conclusion

These results confirm the particularly unfavorable prognosis of patients with small-CC of the genital tract. The optimal treatment for these patients most probably including concurrent chemo-radiotherapy remains to be defined.

Keywords

Small cell carcinomaUterine cervixAdjuvant chemotherapyNeuroendocrine carcinoma

Introduction

Small cell carcinomas (small-CCs) of the uterine cervix are rare and aggressive neoplasms that have a poorer prognosis than corresponding squamous cell carcinomas [1]. Small-CCs tend to develop distant metastasis early and patients with these tumors are thus potential candidates for systemic therapy [29]. However, due to the rarity of these lesions, there are few reports in the literature on the outcome of adjuvant treatment strategies. The aim of the present study was to review the experience of two Austrian university centers with small-CCs of the uterus and vagina.

Material and methods

Using institutional databases, we identified a total of 10 patients with small-CC of the cervix (n=7), uterine corpus (n=2), and vagina (n=1) treated at the Departments of Obstetrics and Gynecology at the Universities of Graz (n=7) and Vienna (n=3) between 1988 and 1998. The median age was 50 years (range, 18–92). Patients with small-CC made up 2% of 497 patients overall treated for cervical cancer during the same time period at the two centers. Hospital records, histology and follow-up data were reviewed.

Histopathology

Histopathologic slides from all patients were reviewed and small-CC confirmed independently by two gynecologic pathologists (O.R. and G.B.). Histologically, the tumors were densely cellular and showed trabecular nesting or a sheet-like pattern. The nuclei were hyperchromatic. The cells had scant cytoplasm, round nuclei, an absence of nucleoli, and finely dispersed chromatin closely resembling the cells of oat cell carcinoma of the lung. Nuclear molding, single cell necrosis and high mitotic activity were seen in all tumors. No areas of glandular or squamous differentiation were identified. Additional immunohistochemistry was done for the purpose of this study. All ten tumors stained positively for neuron-specific enolase (MU058-UC, BioGenex, San Ramon, CA, USA) (Table 1). All tumors stained negatively for vimentin (MU074-UC, BioGenex), desmin (MU072-UC, BioGenex), and CD-45 (MU11-UC, BioGenex).
Table 1

Characteristics of ten patients with small cell carcinoma of the uterus, cervix or vagina. Patients #1–7 received adjuvant platinum-based chemotherapy, patient #8 underwent radical hysterectomy only, and patients #9 and #10 underwent primary radiotherapya. TAH total abdominal hysterectomy, BSO bilateral salpingo-oophorectomy, RAH radical abdominal hysterectomy, PLA pelvic lymphadenectomy, PALA paraaortic lymphadenectomy, PA sampling paraaortic sampling, LVSI lymphovascular space involvement, DOD dead of disease, AWD alive with disease, NED no evidence of disease

 

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5b

Patient 6

Patient 7

Patient 8

Patient 9

Patient 10

Neurone-specific enolase

+++

+++

++

++

+++

+++

++

+++

+++

+++

Chromo-granin

+

Negative

Negative

Negative

+

+

+

Negative

Negative

Negative

Tumor localization

Uterine corpus

Uterine cervix

Vagina

Uterine cervix

Uterine corpus

Uterine cervix

Uterine cervix

Uterine cervix

Uterine cervix

Uterine cervix

Age at diagnosis

55

44

50

24

63

23

18

50

78

92

Menopausal status

Peri-menopausal

Pre-menopausal

Post-menopausal

Premeno-pausal

Post-menopausal

Pre-menopausal

Pre-menopausal

Post-menopausal

Post-menopausal

Post-menopausal

FIGO stage

IIb

Ib1

IIb

IIb

IIb

IIb

IIb

Ib1

IIb

IIIb

Surgical treatment

TAH + BSO + PLA + PALA

RAH + PLA

Anterior exenteration, PLA

RAH + PLA

TAH + BSO + PLA + PA sampling

RAH + PLA

RAH + PLA + PALA

RAH + PLA

Biopsy

Biopsy

Lymph node status

Positive/positive

Negative

Positive

Positive

Positive/positive

Negative

Positivec/negative

Negative

LVSI

No

Yes

No

Yes

No

No

No

No

No

Yes

Adjuvant chemo-therapy

Carboplatin, epirubicin

Cisplatin, etoposide, epirubicin

Cisplatin, etoposide, epirubicin

Carboplatin, bleomycin

Cisplatin, Ifosfamide

Cisplatin, etoposide

Cisplatin, carboplatin

Primary radiotherapy

Teletherapy + brachytherapy

Teletherapy + brachytherapy

Site of progression/recurrence

Peritoneum

Liver

Paraaortic nodes

Pelvis

Paraaortic nodes

Lung, locoregional

Locoregional

Follow-up (months)

6

11

11

12

27

10

86

14

21

31

Disease-status

DOD

DOD

DOD

DOD

AWD

NED

NED

NED

DOD

DOD

aNone of the patients had residual disease after surgery. All tumors were classified as G3

bPatient #5 stained also positive for synaptophysin

cFour of 40 pelvic lymph nodes positive.

Results

All ten women presented with abnormal bleeding, vaginal discharge, or both. None of the patients had clinical signs of an endocrine abnormality. All Pap smears were suspicious for HSIL (high-grade squamous intraepithelial lesions) or invasive carcinoma [10]. Patient characteristics including therapeutic details are shown in Table 1. The median follow-up was 14 months.

The overall median survival was 12 months (range, 6–86) and the 5-year survival was 10%. Of the 7 patients with small-CC of the cervix (Table 1), only 1 (patient #7) survived long-term (86 months) with no evidence of disease (NED). This woman presented with FIGO stage IIB cervical cancer and positive pelvic lymph nodes, underwent radical abdominal hysterectomy, and received six courses of dose-intensive adjuvant cis/carboplatinum. The two patients with tumors of the uterine corpus (#1 and #5) developed recurrent disease at 6 and 7 months. The patient with small-CC of the vagina (#3) died of recurrent disease at 11 months.

Of the 7 patients who received chemotherapy, 5 developed progressive or recurrent disease in the paraaortic region (n=2), peritoneum (n=1), liver (n=1), or pelvis (n=1). Both patients who underwent primary radiotherapy developed recurrence within 17 months (one both locoregional and distant and the other locoregional) and died 21 and 31 months after diagnosis, respectively.

Discussion

Although 7 of the 10 patients with small-CC of the genital tract in the present series were diagnosed at an operable stage and received adjuvant chemotherapy, only 1 survived beyond 5 years. This is consistent with two previous series with no long-term survivors [4, 11]. In another series, only 1 of 8 patients was alive with no evidence of disease (NED) at 40 months after diagnosis [5]. In two other studies with a total of 42 patients, survival rates >5 years of 15% were observed [1, 12]. Two groups have reported 5-year survival rates of 36 and 47% in a total of 23 women who underwent radical surgery [13, 14]. Chan et al. [15] reported a median survival of 31 and 10 months in 34 women with stage I-IIA and IIB-IVB small-CC of the cervix.

We found positive pelvic/paraaortic lymph nodes in 5 of 8 surgically treated patients in our series (62%). This is consistent with three studies in which 44–57% of patients with small-CC had positive nodes [11, 16, 17].

Radiotherapy alone or as an adjunct to radical surgery has lead to disappointing survival results in the majority of studies [4, 11, 14, 18].

Morris et al. [19] described 7 patients with advanced disease treated with palliative chemotherapy with cisplatin, doxorubicin and etoposide. There was a complete response in 3, a partial response in 1, and disease stabilization in 2 patients. Four patients died of disease within 14 months and the other 3 were alive at 7, 18 and 21 months after diagnosis of recurrence or persistence.

The role of adjuvant chemotherapy in small-CC of the cervix is unclear. In one study, 13 patients with stage IA2 to IVB disease underwent neoadjuvant chemotherapy with vincristine, bleomycin and cisplatin [20]. Complete or partial responses were seen in 85% of these women. In two other small series, 6 of 8 patients who underwent neoadjuvant chemotherapy responded [2, 16].

Kim et al. [21] reported on a patient with stage IB small-CC of the cervix who underwent concomitant neoadjuvant chemo-radiotherapy followed by surgery and radiotherapy and survived 92 months after diagnosis.

Two studies with a total of 38 patients [6, 17] have looked at the use of adjuvant chemotherapy. Cisplatin and etoposide or vincristine, doxorubicin and cyclophosphamide (VAC) led to significantly improved survival compared to other cytotoxic regimens or adjuvant radiotherapy. Of 3 patients who underwent adjuvant chemotherapy with cisplatin, doxorubicin and etoposide, 2 were alive at 54 and 60 months and the other died of disease at 14 months [19]. In another study, 3 patients with small-CC of the cervix received adjuvant chemotherapy with cisplatin and etoposide. Two of these women were alive with NED at 17 and 61 months of follow-up and the third died at 30 months [22]. One patient who underwent adjuvant platinum-based chemotherapy was alive with NED at 47 months [2]. Delagoge et al. [4] reported tumor progression during initial treatment in 3 of 10 patients with small-CC of the cervix. Eight of these 10 women relapsed within 16 months and died of disease within 29 months [4]. Preoperative or postoperative platinum-etoposide chemotherapy with or without radiotherapy resulted in 1 complete response and 2 disease stabilizations among 6 patients [23].

Adjuvant chemo-radiotherapy was administered to two patients, both of whom were alive with NED at 28 and 47 months, respectively, [3]. Despite multiple lymph node metastases, one patient with small-CC of the cervix who was treated with adjuvant sequential chemo-radiotherapy survived for longer than 54 months [24]. Another report showed a tendency towards improved survival following adjuvant chemo-radiotherapy after radical surgery [25].

In a recent study, primary definitive concomitant chemo-radiotherapy using either cisplatin/etoposide or carboplatin/paclitaxel has lead to a 3-year survival rate of 60% in 31 patients [26]. Chemo-radiotherapy has been reported in another two patients. One survived beyond 5 years [27] whereas, the other developed early recurrence but was salvaged with secondary hysterectomy [23].

In our series, 5 of 7 recurrences developed at distant sites (Table 1). This pattern of recurrence is consistent with several other previous reports [5, 7, 26].

All tumors in our series stained positively for neuron-specific enolase and four of ten patients, including the long-term survivor, stained positively for chromogranin, a more specific marker for a neuroendocrine carcinoma. We saw no obvious difference between the clinical course of the disease in patients with tumors staining or those not staining positively for chromogranin.

In conclusion, our results confirm the particularly unfavorable prognosis of patients with small-CC of the genital tract. Larger studies on the use of concurrent chemo-radiotherapy either as definitive treatment [26] or as an adjunct to radical surgery are needed to define the optimal treatment of small-CC of the cervix.

Copyright information

© Springer-Verlag 2004