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  • Research article
  • Open Access
  • Open Peer Review

Neuroendocrine carcinoma of the cervix: a systematic review of the literature

  • 1Email author,
  • 2,
  • 1,
  • 1,
  • 3,
  • 4 and
  • 1
BMC Cancer201818:530

https://doi.org/10.1186/s12885-018-4447-x

  • Received: 28 January 2018
  • Accepted: 26 April 2018
  • Published:
Open Peer Review reports

Abstract

Background

Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for this type of malignancy based on controlled trials.

Methods

We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials describing the management and outcome of women with NECC.

Results

Three thousand five hundred thirty-eight cases of NECC in 112 studies were identified. The pooled proportion of NECC among women with cervical cancer was 2303/163470 (1.41%). Small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early and late stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively. Tumors expressed synaptophysin (424/538 cases; 79%), neuron-specific enolase (196/285 cases; 69%), chromogranin (323/486 cases; 66%), and CD56 (162/267; 61%). The most common primary treatment was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy, described in 42/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies). Overall, the prognosis of women with NECC was poor with a mean recurrence-free survival of 16 months and a mean overall survival of 40 months. Immune checkpoint inhibitors and targeted agents were reported as being active in three case reports.

Conclusion

NECC is a rare variant of cervical cancer with a poor prognosis. Multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early stage disease while chemotherapy with cisplatin and etoposide or topotecan, paclitaxel, and bevacizumab is appropriate for women with locally advanced or recurrent NECC. Immune checkpoint inhibitors may be beneficial, but controlled evidence for their efficacy is lacking.

Keywords

  • Neuroendocrine
  • Cervical cancer
  • Small cell cancer
  • Large cell cancer
  • Chemotherapy
  • Radical surgery

Background

Neuroendocrine neoplasias (NENs) are aggressive malignancies derived from neuroendocrine cells. The term neuroendocrine refers to the fact that the tumor cells originate from the embryonic neuroectoderm and display an immunohistochemical profile consistent with endocrine glandular cells [1]. They may or may not secrete peptide hormones. In humans, NENs are typically located in the gastrointestinal tract, the pancreas, and the lungs and are subdivided in well-differentiated NENs and poorly differentiated NENs [2]. Well-differentiated NENs include neuroendocrine tumors (NET) G1 (also known as typical carcinoid), NET G2 (also known as atypical carcinoid), and NET G3. Poorly differentiated neuroendocrine carcinomas (NECs) include small cell NEC and large cell NEC (Table 1).
Table 1

Grading of neuroendocrine neoplasias of the cervix

Classification/Grade

Mitotic Indexa

Ki-67 Indexb

Well-differentiated NEN

 NET G1

<  2/10

≤ 2

 NET G2

2–20

3–20

 NET G3c

>  20

>  20

Poorly differentiated NEN

 NEC G3

>  20

>  20

  Small cell carcinoma

  

  Large cell carcinoma

  

According to Kim et al. [2]. NEN neuroendocrine neoplasia, NET neuroendocrine tumor, NEC neuroendocrine carcinoma

aMitotic index: based on the evaluation of mitoses in 50 high-power fields (HPF; 0.2 mm2 each) in areas of higher density; expressed as mitoses per 10 high-power fields (mitoses/2 mm2)

bKi-67 proliferation index: based on the evaluation of ≥500 tumor cells in areas of higher nuclear labeling (so-called hotspots)

cNET G3 is defined as NET with Ki-67 proliferation index/mitotic index > 20 and without morphological features of small cell NEC or large cell NEC

Rarely, NENs may also occur in other organs such as the female genital tract [3]. Neuroendocrine carcinoma of the cervix (NECC) is an aggressive histological variant of cervical cancer accounting for about 1–1.5% of all cervical cancers [1, 4]. Small cell NEC is the most common type of NECC, whereas well-differentiated NETs, especially NET G1 (typical carcinoid) and NET G2 (atypical carcinoid), are very rare at this location [5]. Grading of NECC is similar to NEN of other locations like lung or the digestive system (Table 1). Due to the rarity of this malignancy, the management of NECC is difficult and associated with uncertainty. An interdisciplinary approach is necessary, because most studies investigating the treatment of neuroendocrine tumors have been performed in patients with tumors in organs other than the cervix, mostly the lung and pancreas [4, 6]. Specifically, neuroendocrine tumors mainly occur in the lungs, and thus treatment schedules for neuroendocrine tumors originating in other organs are similar to those used in small cell lung cancer. The biology of NECC is different from squamous cell carcinoma or adenocarcinoma of the cervix regarding a number of characteristics. For example, NECC is more likely to invade the lymph-vascular space and to spread to the regional lymph node basin at the time of diagnosis. Also, local and distant relapses occur more often in NECC, and the 5-year overall survival is significantly poorer with around 30% compared to > 65% for squamous cell carcinoma and adenocarcinoma of the cervix [1, 4]. Thus, the aggressive nature of NECC resembles that of small cell lung cancer which, at the time of initial diagnosis, is rarely localized and mostly locally advanced or metastasized.

Positive immunohistochemical staining for neuroendocrine markers like synaptophysin (SYN), chromogranin (CHG), CD56 (N-CAM), and neuron-specific enolase (NSE) is diagnostic for NECC. For establishing the diagnosis, positive staining of at least two neuroendocrine markers is recommended. SYN and CD56 are the most sensitive markers. In some cases of small cell NECC, however, expression of neuroendocrine markers may be negative. Differential diagnosis of NECC includes metastasis of extracervical NEC (e.g. lung or gastro-entero-pancreatic NEC) and extracervical NEC with local wide tumor spread (e.g. urinary bladder, rectum, or Merkel cell carcinoma of the skin). NECC must be distinguished from lymphomas, poorly-differentiated squamous cell carcinomas, and sarcomas or melanomas with morphological small cell-like features. Furthermore, large cell NECC may be positive for p63, a marker strongly expressed in squamous cell carcinomas. In this case, however, positive immunohistochemical staining for neuroendocrine markers excludes the diagnosis of squamous cell carcinoma. While isolated neuroendocrine cells may occur in squamous cell carcinomas and adenocarcinomas, these tumors should not be interpreted as NECs if they lack the morphological features of NECs.

NSE is not only expressed on the surface of NECC tumor cells, but is also present in the serum of the majority of patients and may thus be used as a serum tumor marker for NECC. For example, in a series of six patients with small cell NECC and 13 patients with squamous cell cervical carcinoma, elevated serum levels of NSE were noted in four of six patients with NECC, but in none of the patients with squamous cell carcinoma [7]. Similar to squamous cell cervical carcinoma, high-risk HPV DNA has been detected in the majority of small cell and large cell NECC [8]. In a recent meta-analysis, Castle et al. [9] analyzed HPV infection data in 403 cases of small cell and 45 cases of large cell NECC. They found that 85 and 88% of cases were HPV positive, respectively. The predominant subtypes were HPV18 and HPV16. The authors conclude that HPV infection is the underlying cause for most cases of NECC and that most if not all cases could thus be prevented by prophylactic HPV vaccination.

No treatment schemes for NECC based on prospective clinical trials are currently available due to the rarity of this malignancy. Many authors have therefore used multimodality approaches, mainly derived from the therapy of cervical cancer in general as well as from neuroendocrine tumors of the lung in particular. In 2011, the Society of Gynecologic Oncology (SGO) published a clinical document on the management of women with NECC [10]. They also recommend a multimodality therapeutic strategy. Regarding chemotherapy, the SGO recommends etoposide/platinum-based chemotherapies for NECC but not for well differentiated carcinoid tumors, which should be managed similar to gastroenteropancreatic NETs. The Gynecologic Cancer InterGroup (GCIG), in 2014, also published a consensus review on the treatment of small cell NECC [11]. They recommend radical surgery for early stage disease, either primarily or after neoadjuvant chemotherapy. For patients with advanced stage disease, the GCIG recommends chemoradiation or systemic chemotherapy consisting of etoposide and cisplatin. In line with the SCG and GCIG recommendations, treatment schemes for patients with NECC in the literature usually consist of radical hysterectomy followed by adjuvant chemotherapy for early stage disease. For locally advanced and metastatic disease, definitive concurrent chemoradiation, neoadjuvant chemotherapy followed by surgery, or chemotherapy alone have been described [1, 4]. Various chemotherapy regimens have been reported in women with NECC and they usually differ from those typically used in squamous cell carcinoma and adenocarcinoma of the cervix. For example, Yin et al. used a combination of cisplatin and etoposide in 23 cases of NECC [12]. Other chemotherapy regimens described in the literature are cisplatin/irinotecan [13], carboplatin/paclitaxel [14], and cisplatin/vincristine/bleomycin [15].

To highlight the clinical characteristics, management, and prognosis of women with NECC, we report the results of a systematic review of the literature with cohort studies, case series, and case reports of women with NECC. We discuss the most common therapies and respective outcomes of this malignancy.

Methods

We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials using the search terms (“neurosecretory systems”[MeSH Terms] OR (“neurosecretory”[All Fields] AND “systems”[All Fields]) OR “neurosecretory systems”[All Fields] OR “neuroendocrine”[All Fields]) AND (“uterine cervical neoplasms”[MeSH Terms] OR (“uterine”[All Fields] AND “cervical”[All Fields] AND “neoplasms”[All Fields]) OR “uterine cervical neoplasms”[All Fields] OR (“cervical”[All Fields] AND “cancer”[All Fields]) OR “cervical cancer”[All Fields]) AND (“therapy”[Subheading] OR “therapy”[All Fields] OR “treatment”[All Fields] OR “therapeutics”[MeSH Terms] OR “therapeutics”[All Fields]). After screening all abstracts of the publications identified by the initial search, studies and case reports reporting on women with NECC were included in the analysis. Suitability of studies was defined for the purpose of this review as reporting on the clinical or biological characteristics, treatment, or clinical outcomes of patients with large cell NECC, small cell NECC, cervical carcinoid tumor, or atypical cervical carcinoid tumor with or without concomitant features of differentiation [16]. In the next step, studies not reporting individual data of women with NECC, duplicate publications, and studies reporting on women with neuroendocrine tumors metastatic to the cervix were excluded. All remaining studies were then retrieved in full and a cross reference search was performed and additional suitable studies reporting on women with NECC as defined above were added to the analysis. Data were extracted, summarized, and analyzed using summary descriptive statistics. Data are given as means or medians where appropriate. No comparative statistics were used.

Results

A systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials was performed on 21–10-2017 and identified 453 citations. After screening all abstracts, 124 citations were included in the analysis [1, 7, 8, 1214, 17134]. Two studies not reporting individual data of women with NECC, double publications, and a study reporting on women with neuroendocrine tumors metastatic to the cervix were excluded [1, 12, 119]. The 121 selected studies were then retrieved in full and a cross reference search was performed which identified 26 additional studies reporting on women with NECC as defined above [15, 135159]. Figure 1 shows a flow diagram of the literature search.
Fig. 1
Fig. 1

Flow diagram of the literature search algorithm

We included 147 studies in the final analysis. Table 2 shows study and patient characteristics of 112 studies with individual patient data suitable for pooled analysis. Among these 112 studies, we found 17 retrospective cohort studies, 49 retrospective cases series, and 46 case reports. No prospective studies or interventional trials were identified. Only 8 studies reported on ≥50 patients with NECC describing 130 [59], 100 [100], 68 [71], 64 [129], 61 [142], 57 [134], and 50 [96] cases, respectively. One registry study included 1896 patients without reporting individual patient data [145]. In summary, 3538 cases of NECC have been reported in the literature. Seventeen studies described the total number of cervical cancer patients, among which NECC cases were identified, thus allowing for a calculation of the incidence of NECC among cervical cancer cases. The respective incidences given in these studies were 6/73 (8.22%) [75], 130/2108 (6.17%) [59], 14/389 (3.60%) [108], 10/365 (2.74%) [122], 12/452 (2.65%) [76], 14/649 (2.16%) [103], 44/2835 (1.55%) [109], 1896/127332 (1.49%) [145], 9/677 (1.33%) [56], 31/2385 (1.30%) [48], 25/2201 (1.14%) [120], 11/1370 (0.80%) [117], 64/9474 (0.68%) [129], 14/2074 (0.68%) [150], 6/972 (0.62%) [101], 10/2096 (0.48%) [62], and 7/8018 (0.09%) [123] for a pooled rate of 2303/163470 (1.41%) cases.
Table 2

Clinical characteristics of women with neuroendocrine carcinoma of the cervix

Author [Ref]

Year

Study type

# of Cases

Incidence (%)

Early Stage/Advanced stage

Small cell/large cell/other

Immunohistochemical profile (n)

Molecular characteristics (n)

Baggar [135]

2017

CR

1

1/0

1/0/0

CHG (1), CD56 (1)

Cho [34]

2017

CS

16

12/4

16/0/0

SYN (16), CHG (12), ERBB4 (16)

ATRX (4/5), ERBB4 (4/5)

Damian [41]

2017

CR

1

1/0

1/0/0

Kuji [67]

2017

CS

37

30/7

29/8/0

SYN (32), CHG (32)

Paraghamian [149]

2017

CR

1

1/0

1/0/0

Wu [128]

2017

CR

1

1/0

1/0/0

SYN (1), CHG (1)

Xie [158]

2017

CS

48

40/8

31/1/16

SYN (45), NSE (25), CD56 (13)

Cavalcanti [29]

2016

CR

1

1/0/0

p53 (1), MST1R (1), MYCN Ampl. (1), U2AF1 (1), GATA3 (1)

Duan [45]

2016

CS

26

22/4

25/0/1

SYN (24), NSE (19), CD56 (13)

Frumovitz [47]

2016

COS

44

26/18

38/0/6

p53 (5), PIK3CA (8), KRAS (6)

Ganesan [48]

2016

CS

31

31/2385 (1.30%)

31/0/0

Lee [142]

2016

COS

61

41/20

41/7/13

SYN (33/43), CHG (30/43), CD56 (30/43)

Margolis [145]

2016

COS

1896

1896/127332 (1.49%)

582/1157

Rajkumar [151]

2016

CR

1

1/0

0/1/0

SYN (1), CHG (1), CD56 (1), p16 (1)

Robin [100]

2016

COS

100

Stecklein [153]

2016

COS

40

33/7

26/8/6

SYN (36), CHG (26), CD56 (14)

Majhi [79]

2015

CR

1

1/0

SYN (1), CHG (1), NSE (1)

Nagao [86]

2015

CS

23

18/5

11/12/0

Sheth [152]

2015

CR

1

1/0

1/0/0

SYN (1), CHG (1), CD56 (1)

Singh [105]

2015

CR

1

1/0

1/0/0

SYN (1), CHG (1)

Sodsanrat [109]

2015

CS

44

44/2835 (1.55%)

Wang [156]

2015

CR

1

1/0

1/0/0

SYN (1), CHG (1), CD56 (1)

Wang [157]

2015

CS

32

32/0

22/0/10

Yin [12]

2015

CS

23

18/5

23/0/0

Yuan [132]

2015

CS

38

38/0

38/0/0

Bellefqih [136]

2014

CS

6

Dongol [139]

2014

CS

4

3/1

4/0/0

SYN (4), NSE (4)

Lyons [144]

2014

CR

1

1/0

1/0/0

KRAS (1)

Omori [148]

2014

CR

1

0/1

0/1/0

SYN (1), CHG (1), CD56 (1), p16 (1), p53 (1)

Yin [129]

2014

COS

64

64/9474 (0.68%)

47/17

64/0/0

Yousef [131]

2014

CR

1

0/1

1/0/0

SYN (1)

Zaid [134]

2014

CS

57

49/8

49/8/0

Intaraphet [59]

2013

COS

130

130/2108 (6.17%)

82/48

130/0/0

Kim [63]

2013

CR

1

1/0

1/0/0

CHG (1), NSE (1)

Kuroda [69]

2013

CR

1

1/0

0/1/0

SYN (1), CD56 (1), p16 (1)

Li [76]

2013

CS

12

12/452 (2.65%)

8/4

6/6/0

SYN (11), CHG (10), CD56 (11), AE1/3 (12), p16 (11)

McCann [146]

2013

COS

26

14/12

21/2/2

Murakami [147]

2013

CR

1

0/1

0/1/0

SYN (1), CHG (1), NSE (1)

Rekhi [96]

2013

COS

50

26/14/10

SYN (22/37), CHG (27/37), NSE (7/8), CD56 (8/8)

Sitthinumsawan [108]

2013

COS

14

14/389 (3.60%)

9/5

8/3/3

SYN (11), CHG (9), NSE (12), CD56 (11)

Wang [125]

2013

CS

13

13/0/0

SYN (13), CHG (9)

Hara [54]

2012

CR

1

1/0

0/0/1

SYN (1), CHG (1), CD56 (1)

Lin [78]

2012

CS

5

4/1

Peng [150]

2012

CS

14

14/2074 (0.68%)

11/3

9/0/5

Siriaunkgul [106]

2012

CS

26

21/5

21/3/2

Sisti [107]

2012

CR

1

1/0

1/0/0

SYN (1), CHG (1), NSE (1)

Tanimoto [154]

2012

CR

1

0/1

0/1/0

Teefey [114]

2012

CR

1

1/0

1/0/0

SYN (1), CHG (1), CD56 (1), p16 (1)

Hao [53]

2011

CR

1

1/0

0/1/0

CHG (1), CD56 (1), p16 (1)

Komiyama [66]

2011

CR

1

1/0

0/0/1

SYN (1), CHG (1), NSE (1)

Nasu [13]

2011

CR

1

1/0

1/0/0

McCluggage [84]

2010

CS

21

13/8/0

SYN (19), CHG (11), CD56 (19), AE1/3 (17), p16 (21), PGP9.5 (9)

Niwa [88]

2010

CR

1

1/0

0/1/0

Rashed [95]

2010

CR

1

1/0

1/0/0

CHG (1)

Bifulco [27]

2009

CR

1

0/1

0/1/0

SYN (1), NSE (1)

Kajiwara [61]

2009

CS

7

2/5

3/2/2

SYN (7), CHG (6)

Lee [74]

2009

CR

1

1/0

1/0/0

NSE (1), CD56 (1)

Li [77]

2009

CR

1

0/1

0/1/0

Wang [123]

2009

CS

7

7/8018 (0.09%)

7/0

0/7/0

Zivanovic [159]

2009

COS

17

11/6

17/0/0

Albores-Saavedra [21]

2008

CS

2

2/0

0/2/0

SYN (2), CHG (2), CD56 (2)

Chung [36]

2008

CR

1

1/0

1/0/0

SYN (1), CHG (1), CD56 (1)

Lee [71]

2008

CS

68

68/0

Alphandery [22]

2007

CR

1

0/1

1/0/0

SYN (1), CHG (1), CD56 (1), c-Kit (1)

Kasamatsu [62]

2007

CS

10

10/2096 (0.48%)

9/1

Ko [64]

2007

CR

1

1/0

0/1/0

SYN (1), CHG (1), NSE (1)

Tangjitgamol [113]

2007

CR

1

0/1

0/1/0

Cetiner [30]

2006

CR

1

1/0

0/1/0

CHG (1), NSE (1)

Horn [56]

2006

CS

9

9/677 (1.33%)

9/0/0

SYN (7), CHG (7), NSE (7), CD56 (8), p16 (9), p53 (2)

Ohwada [89]

2006

CR

1

1/0

0/1/0

SYN (1), CHG (1), p16 (1)

Wang [124]

2006

CS

31

25/4/2

Baykal [26]

2005

CR

1

1/0

0/0/1

CHG (1), NSE (1)

Chatterjee [32]

2005

CR

1

1/0

1/0/0

NSE (1)

Tangjitgamol [112]

2005

CS

24

16/8

18/6/0

Tsunoda [117]

2005

CS

11

11/1370 (0.80%)

7/4

11/0/0

SYN (8), CHG (7), NSE (9), CD56 (6)

Dikmen [43]

2004

CR

1

1/0

0/1/0

SYN (1), CHG (1), NSE (1)

Ishida [60]

2004

CS

10

5/5/0

p53 (1)

Trinh [116]

2004

CR

1

1/0

1/0/0

Viswanathan [121]

2004

COS

21

17/4

21/0/0

SYN (19), CHG (16), CD56 (15)

Wang [8]

2004

CS

22

18/4

22/0/0

SYN (16), CHG (16), NSE (15), p16 (20), Rb loss (18)

Hoskins [14]

2003

CS

34

17/17

34/0/0

Sato [101]

2003

CS

6

6/972 (0.62%)

6/0

0/6/0

SYN (6), CHG (6)

Conner [39]

2002

CS

23

18/0/5

SYN (13), CHG (10), p53 (10)

Grayson [51]

2002

CS

12

0/12/0

SYN (11)

Marshall [83]

2002

CR

1

0/1

SYN (1)

Ribeiro-Silva [99]

2002

CR

1

1/0

0/0/1

CHG (1)

Balega [25]

2001

CR

1

1/0

SYN (1), CHG (1)

Bermúdez [15]

2001

COS

20

14/6

12/6/2

SYN (8/18), CHG (9/18), NSE (15/18)

Boruta [137]

2001

CS

11

11/0

9/1/1

Lenczewski [75]

2001

CS

6

6/73 (8.22%)

6/0/0

Rhemtula [97]

2001

CS

5

2/3

0/5/0

SYN (5), MNF116 (5)

Straughn [110]

2001

CS

16

15/1

15/0/0

SYN (8/13), CHG (8), NSE (12)

p53 (8), c-myc (8/15), PCNA (5/15)

Collinet [38]

2000

CS

5

2/3

5/0/0

Delaloge [42]

2000

COS

10

7/3

10/0/0

Herrington [55]

1999

CS

25

25/0/0

Rb (2)

Koch [65]

1999

CR

1

1/0

1/0/0

SYN (1), CHG (1)

McGarry [85]

1999

CR

1

1/0

1/0/0

SYN (1), CHG (1), NSE (1)

Wistuba [127]

1999

CS

15

2/8/5

p53 (7), KRAS (0), LOH (7)

Yun [133]

1999

CR

1

1/0

0/1/0

SYN (1), CHG (1)

Mannion [80]

1998

CS

38

25/5/8

LOH (9)

Wang [155]

1998

CS

7

7/0

7/0/0

CHG (4), NSE (7)

Gilks [50]

1997

CS

12

12/0

0/12/0

SYN (6), CHG (12), NSE (4)

Toki [115]

1996

CR

1

1/0

1/0/0

CHG (1), NSE (1), SER (1)

Abulafia [19]

1995

CS

3

3/0

3/0/0

 

Abeler [18]

1994

COS

26

16/10

26/0/0

SYN (7), CHG (5), NSE (19)

Chen [7]

1994

CS

6

6/0/0

NSE (6)

Lewandowski [143]

1993

CS

4

2/2

4/0/0

CHG (1), NSE (2)

Gersell [49]

1988

COS

15

10/5

15/0/0

SYN (10), CHG (11), NSE (11)

Sheets [103]

1988

COS

14

14/649 (2.16%)

14/0

14/0/0

van Nagell [120]

1988

CS

25

25/2201 (1.14%)

25/0/0

CHG (8), NSE (8)

Walker [122]

1988

CS

14

10/365 (2.74%)

8/6

12/0/2

Turner [118]

1986

CR

1

1/0

1/0/0

Pooled Analysis

3538

2303/163470 (1.41%)

1479 (50.7%)/ 1436 (49.3%)

1123 (80.0%)/ 176 (12.5%)/ 105 (7.5%)

SYN (424/538; 79%), CHG (323/486; 66%), NSE (196/285; 69%), CD56 (162/267; 61%), AE1/3 (29/33; 88%), c-Kit (1/1; 100%), ERBB4 (16/16; 100%), MNF116 (5/5; 100%), p16 (67/70; 96%), p53 (13/33; 39%), PGP9.5 (9/21; 43%), Rb (2/25; 8%), Rb loss (18/22; 82%), SER (1/1; 100%)

ATRX (4/5; 80%), ERBB4 (4/5; 80%), p53 (22/86; 26%), MST1R (1/1; 100%), MYCN Ampl. (1/1; 100%), U2AF1 (1/1; 100%), GATA3 (1/1; 100%), PIK3CA (8/44; 18%), KRAS (7/60; 12%), c-myc (8/15; 53%), PCNA (5/15; 33%), LOH (16/53; 30%)

Abbreviations: Study types: COS cohort study, CR case report, CS case series. Immunohistochemical profile: CD56 = N-CAM; CHG chromogranin, MNF116 pan-cytokeratin antibody, NSE neuron-specific enolase, Rb retinoblastoma protein, SER Serotonin, SYN synaptophysin. Molecular characteristics, LOH loss of heterozygosity; Ampl amplified

The most common histological subtype of NECC was small cell NECC. Specifically, small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early (International Federation of Gynecology and Obstetrics [FIGO] stages I to IIA) and late (FIGO stages IIB to IV) stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively.

The immunohistochemical profiles of NECC demonstrated expression of SYN (424/538 cases; 79%), NSE (196/285 cases; 69%), CHG (323/486 cases; 66%), and CD56 (162/267; 61%) as the most typical markers of NECC. Only a fraction of the published studies analyzed molecular tumor profiles. Among them, the mutations most often identified were in the p53 (22/86; 26%), KRAS (7/60; 12%), PIK3CA (8/44; 18%), and c-myc (8/15; 53%) genes, respectively. Loss of heterozygosity (LOH) was found to be present in 16/53 (30%) cases. Additional file 1: Figure S1 demonstrates immunohistochemical stainings of a small cell NECC with positive staining for CD56 (N-CAM) and the proliferation marker Ki-67.

Treatment modalities and outcomes are shown in Table 3. The most common primary treatment modality of NECC was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy. Specifically, radical surgery and adjuvant chemotherapy were described in 21/48 studies. Neoadjuvant chemotherapy followed by radical surgery with or without adjuvant therapies (radiotherapy, radiochemotherapy, or chemotherapy) were described in 12/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy with cisplatin, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There was no retrospective or prospective comparison of the efficacy of surgery-based, chemotherapy-based, and radiotherapy-based treatment schemes within comparable disease stages in the published studies. After recurrence of NECC, chemotherapy was used in most studies (7/10 studies), followed by radiotherapy (3/10 studies), and surgery (2/10 studies).
Table 3

Treatment modalities and outcomes of women with neuroendocrine carcinoma of the cervix

Author

Year

N

Treatment modalities (Initial)

Treatment modalities (Recurrence)

Chemotherapy regimens adjuvant/Neo-Adjuvant

Chemotherapy regimens recurrence/primary advanced

RXT (n)/Gray

Recurrence-free survival duration (m)

Overall survival duration (m)

2- or 3-Year Overall survival rate (%)

5-Year overall survival rate (%)

Paraghamian [149]

2017

1

S + CHXT

CHXT, RXT, NIV

EP

PACTOP

1

7

Wu [128]

2017

1

NACT+S + CHXT

IfoEP

78

78

Xie [158]

2017

48

NACT+S + CHXT, S + RXT, S + CHXT

EP, CPAC, BEP

30

57

31

Lee [142]

2016

61

S + CHXT, RXCT, S + RXCT, CHXT

EP, CPAC, FUP

64

36

Rajkumar [151]

2016

1

S + CHXT

EP

18

18

Robin [100]

2016

100

RCXT, NACT+RCXT

48

  

Stecklein [153]

2016

40

S, S + RXT, RXT + CHXT, RCXT

9

30

27

Nagao [86]

2015

23

S + CHXT, S + RCXT, RXT

CPAC, IP

64

Singh [105]

2015

1

S + CHXT

EP

26

26

Wang [156]

2015

1

NACT+RXCT

EP, N

−/25

6

6

Yin [12]

2015

23

NACT+S + CHXT, NACT+S + RXT + CHXT

EP

69 (3), 54 (20)

55

39

Dongol [139]

2014

4

NACT+S + CHXT

EP, VPB

10

Lyons [144]

2014

1

NACT+S + RXCT

MEK-Inh

EP

TRAM

1/45

4

12

Omori [148]

2014

1

NACT+S + CHXT

IP

21

21

Kim [63]

2013

1

S + RCXT

CHXT, S

CPAC, EP

1/50

4

12

McCann [146]

2013

26

S, NACT+S, S + RXT

CHXT

EP

EPA

34

49

71

Murakami [147]

2013

1

CHXT

IP

3

5

Lin [78]

2012

5

RXT, RXCT, S + RXCT

CHXT

FUP, EPD

6

22

Peng [150]

2012

14

S + RXT + CHXT, S + CHXT

EP, FUP, EP + CPAC

6

32

40

25

Teefey [114]

2012

1

NACT+S

EP

24

24

Komiyama [66]

2011

1

S + CHXT

CHXT, RXT

EPPAC

IP

11

19

Nasu [13]

2011

1

NACT+S + CHXT

CHXT

IP

AMR, EP

0

27

Bifulco [27]

2009

1

S + RXT + CHXT

CPAC

12

12

Li [77]

2009

1

RXCT

EP

1/63

21

21

Wang [123]

2009

7

S, S + CHXT, S + RXT

EP, EPEpi, P, PE

32

28

Zivanovic [159]

2009

17

S + CHXT, RXCT

EP

−/14

21

30

Lee [71]

2008

68

S, NACT+S + RXCT, NACT+S + RXT

EP, CPAC, VPB, IPPAC

54

64.6

46.6

Kasamatsu [62]

2007

10

S, S + RXT, S + CHXT

EP, PDC

2/45–50

8

29

43

Ko [64]

2007

1

S + RCXT+CHXT

P

1/53

24

24

Tangjitgamol [113]

2007

1

S + CHXT

CHXT

CPAC

CPAC, EP

19

27

Baykal [26]

2005

1

S + CHXT+RCXT

EP

1/50

21

21

Tangjitgamol [112]

2005

24

S, S + CHXT, S + RXT, RCXT, RXT, CHXT

21

Tsunoda [117]

2005

11

S + CHXT, S + RXT, RCXT

EP, PPep

3/50; 2/80

27

27

Trinh [116]

2004

1

S + CHXT+RCXT

52

52

Viswanathan [121]

2004

21

S, RXT, RCXT, S + CHXT, NACT+RXT

EP, EPD

41

29

Hoskins [14]

2003

34

CHXT+RCXT

EP, CPAC

60

Sato [101]

2003

6

S + RXT + CHXT

36

33

Bermúdez [15]

2001

20

S + RXT, NACT+S, CHXT

VBP

−/50

39

60

39

Boruta [137]

2001

11

S + CHXT

VAC, EP

24

38

Collinet [38]

2000

5

S + CHXT, S + RXT, RXT

 

EP, EDC

3/55–105

15

17

Delaloge [42]

2000

3

S + RXT, S + CHXT, S + RXCT

PVep

16

33

20

McGarry [85]

1999

1

NACT+RXT

S

EP

−/83

0

18

Abulafia [19]

1995

3

S + CHXT, S + CHXT+RXT

RXT

EVP-16

30

36

Lewandowski [143]

1993

4

S + CHXT, CHXT+RXT, NACT+S + RXT, NACT+CHXT

EPD

2/45

25

Gersell [49]

1988

15

S, RXT, S + RXT, RXT + CHXT

*

18

33

Sheets [103]

1988

14

S, S + RXT

8/45–60

19

15

Walker [122]

1988

14

RXT, S, CHXT, S + CHXT, RXT + CHXT

VDaCy

14

14

Turner [118]

1986

1

S + CHXT+RXT

VACyMVP

1/45

2

4

Pooled Analysis

  

S + CHXT (21/48); NACT+S ± Other (12/48); RXT/RCXT or RXT + CHXT (15/43)

CHXT (7/10); RXT (3/10); S (2/10)

EP (24/40); EP + Other (6/40); CPAC (7/40); IP (4/40); FUP (3/40)

EP ± Other (5/8)

16 Months

40 Months

50%

34%

Abbreviations: NACT Neoadjuvant Chemotherapy, S Surgery, RCXT Radio-Chemotherapy, E Etoposide, P Cisplatin/Carboplatin, CHXT Chemotherapy, I Irinotecan, AMR Amrubicin, PAC Paclitaxel, Ifo Ifosfamide, ICI Immune-Checkpoint-Inhibitor, FU 5-Fluorouracil, Epi Epirubicin, D Doxorubicin, C Cyclophosphamide, Pep Peplomycin, Vep Vepesid, * Various combinations including Cisplatin, Cytoxan, Methotrexate, Procarbazin, and VP-16¸ VDaCy, Vincristin, Daunorubicin, Cytoxan, VACMVP Vincristin, Adriamycin, Cyclophosphamide, Methotrexate, VP-16, V Vincristine/Vinblastin, TOP Topotecan, NIV Nivolumab, N Nedaplatin, MEKInh MEK-Inhibitor, TRAM Trametinib, A Adriamycin

There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies), similar to the treatment routinely used for small cell lung cancer. EP combined with other substances such as bleomycin, cyclophosphamide, or doxorubicin was reported in another 6/40 studies, making EP alone or in combination by far the most commonly used cytotoxic regimen. Other commonly used cytotoxic regimens in the primary therapy setting (neoadjuvant or adjuvant) were cisplatin/carboplatin and paclitaxel (7/40 studies) and cisplatin combined with irinotecan (4/40 studies). Other regimes such as 5-fluorouracil/cisplatin, vincristine/cisplatin/bleomycin, vincristine/adriamycin/cisplatin, and irinotecan/cisplatin/paclitaxel were only rarely used. In women with recurrent NECC, EP alone or in combination with other cytotoxic drugs was also the most commonly used cytotoxic regimen (5/8 studies). Overall, the prognosis of women with NECC was poor. The recurrence-free survival was short with a mean duration of 16 months and the mean overall survival duration of women with NECC was 40 months. In a pooled analysis of all studies reporting absolute survival rates, the 2-year- and 5-year overall survival rates were 50 and 34%, respectively.

Targeted therapies and immune-checkpoint inhibitors were only described in three studies [102, 144, 149]. Paraghamian et al. used nivolumab in a patient with recurrent, metastatic, programmed cell death 1 ligand 1 (PD-L1)-negative small cell NECC, who experienced a complete response [149]. Sharabi et al. report a patient with metastatic, chemotherapy-refractory NECC with bowel obstruction due to a large tumor burden [102]. Liquid biopsy demonstrated a high number of tumor mutations. She was treated with radiotherapy combined with nivolumab and experienced a near-complete systemic resolution of disease for at least 10 months. Lastly. Lyons et al. used the mitogen-activated protein kinase 1 (MEK)-inhibitor trametinib in a woman with recurrent small cell NECC and a Kirsten rat sarcoma gene (KRAS)-mutated tumor [144]. This patient also experienced a complete response.

The largest cohort of women with NECC was published by Margolis et al. [145]. Using the National Cancer Database (NCDB), the authors identified 1896 patients with NECC. These patients were younger, more often white, and diagnosed with metastatic disease at presentation compared to women with squamous cell cervical cancer. In a multivariable analysis, NECC patients of all tumor stages had a significantly higher risk of death compared to women with squamous cell cervical cancer. Three other large cohorts analyzed data sets of 188 [37], 130 [59], and 100 [100] cases, respectively. Cohen et al. summarized the characteristics and treatment results of 188 patients most of whom had early stage disease (n = 135 with FIGO stages I-IIA) [37]. The 5-year disease-specific survival in FIGO stages I-IIA, IIB-IVA, and IVB disease were 36.8, 9.8, and 0%, respectively. In this patient cohort, adjuvant chemotherapy or chemoradiation was associated with a significantly improved survival in all patients. Consequently, use of chemotherapy or chemoradiation was an independent prognostic factor for improved survival. Robin et al. used the National Cancer Data Base to identify 100 women with locally advanced NECC treated with definitive chemoradiotherapy [100]. There was a substantial improvement in overall survival when brachytherapy was administered in addition to external beam radiotherapy resulting in an improved median survival of 48.6 vs. 21.6 months. Intaraphet et al. looked at 130 patients with small cell NECC and identified older age and locoregional lymph node involvement as the most important prognostic factors among surgically treated patients [59].

The largest series of women analyzing the treatment efficacy of chemotherapy among women with recurrent NECC was published by Frumovitz et al. [140]. They compared 13 patients who received the combination of topotecan, paclitaxel, and bevacizumab (TPB) with 21 patients receiving other regimens, mostly a platinum-based regimen with or without a taxane. TPB was associated with a significantly improved outcome. For example, the median progression-free survival was 7.8 months for TPB and 4.0 months for non-TPB regimens and the median overall survival was 9.7 months for TPB and 9.4 months for the non-TPB regimens. Eight women (62%) who received TPB versus four (19%) who received non-TPB regimens were on treatment for > 6 months, and four patients (31%) in the TPB group versus two (10%) in the non-TPB group were on treatment for > 12 months.

The bulk of studies identified in this systematic review were small case series (43.8%) and case reports (41.1%). As expected, the heterogeneity among these studies with low numbers of NECC patients was considerable. However, as shown in Table 3, most patients were treated with radical surgery and adjuvant or neoadjuvant chemotherapy, whereas chemotherapy alone or radio/chemo/therapy alone were rarely used. Long-term survivors among these women were almost exclusively found in cases with early stage disease at initial presentation, complete tumor resection, and chemotherapy with or without radiotherapy.

Discussion

NECC is an aggressive histological variant of cervical cancer accounting for 1.4% of all cervical cancers. The management of NECC is difficult and is associated with uncertainty. Therefore, we performed a systematic review of the literature and identified data of 3538 NECC cases from 112 studies. We found that NECC is a rare variant of cervical cancer with small cell NECC being the most common histological subtype. This tumor carries a poor prognosis with a mean overall survival of 40 months and a 5-year overall survival rate of 34%. Multimodality treatment with radical surgery and adjuvant or neoadjuvant chemotherapy with etoposide and cisplatin is the mainstay of treatment for early stage disease while combined radiochemotherapy and chemotherapy are appropriate for women with locally advanced or recurrent NECC. A large number of chemotherapy regimens have been described in the treatment of patients with NECC but cisplatin/carboplatin and etoposide alone or in combination with other substances have been described in more than two thirds of the published studies. Novel therapeutics such as immune checkpoint inhibitors and targeted therapies may be beneficial, but evidence for their efficacy is lacking.

Although there is no standard of care regarding the choice of chemotherapy for women with NECC, we found that cisplatin/carboplatin and etoposide was the most commonly used regimen in the primary treatment and may thus be regarded as an informal standard. Of note, this combination was described in 30/40 studies. The exact dosage and therapy duration of this scheme, however, varied considerably in the published studies. For example, Baykal et al. used cisplatin 80 mg/m2 on day 1 together with etoposide 120 mg/m2 on days 1, 2, and 3 in a 21 day cycle [26]. Intaraphet et al. used cisplatin 75 mg/m2 and etoposide 100 mg/m2 every 3 weeks [59]. Hoskins et al. used etoposide (40 mg/m2/d) and cisplatin (25 mg/m2/d) over 5 consecutive days starting on days 1, 15, 29, and 43 and combined this scheme with locoregional irradiation started on day 15 [14].

In women with recurrent NECC, cisplatin/etoposide alone or in combination with other cytotoxic drugs was also the most commonly used cytotoxic regimen described in 5/8 studies. Of note, women with recurrent disease who had already been treated with cisplatin/carboplatin and etoposide in the primary setting might benefit from a triplet regimen consisting of topotecan, paclitaxel, and bevacizumab. In the largest series of women with recurrent NECC, Frumovitz et al. found that the combination of topotecan, paclitaxel, and bevacizumab was superior to platinum-based regimens with or without a taxane [140]. Thus, in women who already had received cisplatin/carboplatin and etoposide in the primary treatment, topotecan, paclitaxel, and bevacizumab might be an appropriate choice.

Women with NECC have a poor prognosis irrespective of the treatments used. Even with aggressive treatment schemes involving radical surgery, chemotherapy and radiotherapy, the mean 5-year overall survival rate was only 34% in our pooled analysis of the published data. Therefore, new treatment concepts are warranted for this subgroup of cervical cancer patients. Targeted therapies and immune-checkpoint inhibitors might be such new treatment options for NECC. In two case reports, nivolumab led to durable remissions in patients with recurrent disease as did the MEK-inhibitor trametinib in a woman with recurrent small cell NECC and a KRAS-mutated tumor [102, 144, 149]. Clearly, this is not a broad evidence base. On the other hand, NECC is a very rare disease and in view of a reasonable alternative, these novel agents might be used in women with recurrent NECC and progression after conventional chemotherapy regimens such as cisplatin/etoposide or topotecan, paclitaxel, and bevacizumab. When comparing these regimens to those usually used for small cell lung cancer, platinum compounds, etoposide, topotecan and anthracyclines are familiar substances whereas paclitaxel or bevacizumab are rarely used in small cell lung cancer.

Conclusions

We found that NECC is a rare form of cervical cancer with a poor prognosis. Due to the small number of cases and the retrospective nature of this analysis, conclusions are limited, but multimodality treatment with radical surgery and adjuvant or neoadjuvant chemotherapy with etoposide and cisplatin is the mainstay of treatment for early stage disease while combined radiochemotherapy and chemotherapy are appropriate for women with locally advanced or recurrent NECC. In light of the poor prognosis of women with NECC despite aggressive treatment, novel therapeutics such as immune checkpoint inhibitors and targeted agents should be incorporated into the management even without controlled evidence.

Abbreviations

CHG: 

Chromogranin

EP: 

Cisplatin/carboplatin and etoposide

FIGO: 

International federation of gynecology and obstetrics

GCIG: 

Gynecologic Cancer InterGroup

KRAS: 

Kirsten rat sarcoma gene

LOH: 

Loss of heterozygosity

MEK-1: 

Mitogen-activated protein kinase 1

NCDB: 

National Cancer Database

NEC: 

Neuroendocrine carcinoma

NECC: 

Neuroendocrine carcinoma of the cervix

NEN: 

Neuroendocrine neoplasia

NET: 

Neuroendocrine tumor

NSE: 

Neuron-specific enolase

PD-L1: 

Programmed cell death 1 ligand 1

SGO: 

Society of Gynecologic Oncology

SYN: 

Synaptophysin

TPB: 

Topotecan, paclitaxel, and bevacizumab

Declarations

Acknowledgements

We acknowledge support by the DFG Open Access Publication Funds of the Ruhr-Universität Bochum.

Availability of data and materials

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Authors’ contributions

CBT and GAR collected the data. GAR analyzed the data. CBT, ZH, AD, and BS wrote the manuscript. PK, IT, and GAR critically contributed to the manuscript text. IT provided the data shown in Additional file 1: Figure S1. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Obstetrics and Gynecology, Ruhr-Universität Bochum, Bochum, Germany
(2)
Department of Pathology, Ruhr-Universität Bochum, Bochum, Germany
(3)
Department of Hematology and Oncology, Ruhr-Universität Bochum, Bochum, Germany
(4)
Department of Obstetrics and Gynecology, St. Elisabeth Hospital, Bochum, Germany

References

  1. Gadducci A, Carinelli S, Aletti G. Neuroendrocrine tumors of the uterine cervix: a therapeutic challenge for gynecologic oncologists. Gynecol Oncol. 2017;144:637–46. https://doi.org/10.1016/j.ygyno.2016.12.003.PubMedView ArticleGoogle Scholar
  2. Kim JY, Hong SM, Ro JY. Recent updates on grading and classification of neuroendocrine tumors. Ann Diagn Pathol. 2017;29:11–6.Google Scholar
  3. Guadagno E, de RG, de Del Basso Caro M. Neuroendocrine tumours in rare sites: differences in nomenclature and diagnostics-a rare and ubiquitous histotype. J Clin Pathol. 2016;69:563–74. https://doi.org/10.1136/jclinpath-2015-203551.PubMedView ArticleGoogle Scholar
  4. Burzawa J, Gonzales N, Frumovitz M. Challenges in the diagnosis and management of cervical neuroendocrine carcinoma. Expert Rev Anticancer Ther. 2015;15:805–10. https://doi.org/10.1586/14737140.2015.1047767.PubMedView ArticleGoogle Scholar
  5. Lax SF, Horn LC, Löning T. Categorization of uterine cervix tumors: What's new in the 2014 WHO classification. Pathologe. 2016;37(6):573–84.Google Scholar
  6. Grande E, Capdevila J, Castellano D, Teulé A, Durán I, Fuster J, et al. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish task force Group for Neuroendocrine Tumors (GETNE). Ann Oncol. 2015;26:1987–93. https://doi.org/10.1093/annonc/mdv252.PubMedView ArticleGoogle Scholar
  7. Chen CA, Wu CC, Juang GT, Wang JF, Chen TM, Hsieh CY. Serum neuron-specific enolase levels in patients with small cell carcinoma of the uterine cervix. J Formos Med Assoc. 1994;93:81–3.PubMedGoogle Scholar
  8. Wang HL, Lu DW. Detection of human papillomavirus DNA and expression of p16, Rb, and p53 proteins in small cell carcinomas of the uterine cervix. Am J Surg Pathol. 2004;28:901–8.PubMedView ArticleGoogle Scholar
  9. Castle PE, Pierz A, Stoler MH. A systematic review and meta-analysis on the attribution of human papillomavirus (HPV) in neuroendocrine cancers of the cervix. Gynecol Oncol. 2018;148:422–9. https://doi.org/10.1016/j.ygyno.2017.12.001.PubMedView ArticleGoogle Scholar
  10. Gardner GJ, Reidy-Lagunes D, Gehrig PA. Neuroendocrine tumors of the gynecologic tract: a Society of Gynecologic Oncology (SGO) clinical document. Gynecol Oncol. 2011;122:190–8. https://doi.org/10.1016/j.ygyno.2011.04.011.PubMedView ArticleGoogle Scholar
  11. Satoh T, Takei Y, Treilleux I, Devouassoux-Shisheboran M, Ledermann J, Viswanathan AN, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for small cell carcinoma of the cervix. Int J Gynecol Cancer. 2014;24:S102–8. https://doi.org/10.1097/IGC.0000000000000262.PubMedView ArticleGoogle Scholar
  12. Yin ZM, Yu AJ, Wu MJ, Fang J, Liu LF, Zhu JQ, Yu H. Effects and toxicity of neoadjuvant chemotherapy preoperative followed by adjuvant chemoradiation in small cell neurdendocrine cervical carcinoma. Eur J Gynaecol Oncol. 2015;36:326–9.PubMedGoogle Scholar
  13. Nasu K, Hirakawa T, Okamoto M, Nishida M, Kiyoshima C, Matsumoto H, et al. Advanced small cell carcinoma of the uterine cervix treated by neoadjuvant chemotherapy with irinotecan and cisplatin followed by radical surgery. Rare Tumors. 2011;3:e6. https://doi.org/10.4081/rt.2011.e6.PubMedPubMed CentralView ArticleGoogle Scholar
  14. Hoskins PJ, Swenerton KD, Pike JA, Lim P, Aquino-Parsons C, Wong F, Lee N. Small-cell carcinoma of the cervix: fourteen years of experience at a single institution using a combined-modality regimen of involved-field irradiation and platinum-based combination chemotherapy. J Clin Oncol. 2003;21:3495–501. https://doi.org/10.1200/JCO.2003.01.501.PubMedView ArticleGoogle Scholar
  15. Bermúdez A, Vighi S, García A, Sardi J. Neuroendocrine cervical carcinoma: a diagnostic and therapeutic challenge. Gynecol Oncol. 2001;82:32–9. https://doi.org/10.1006/gyno.2001.6201.PubMedView ArticleGoogle Scholar
  16. Albores-Saavedra J, Gersell D, Gilks CB, Henson DE, Lindberg G, Santiago H, 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 Lab Med. 1997;121:34–9.PubMedGoogle Scholar
  17. Abdallah R, Bush SH, Chon HS, Apte SM, Wenham RM, Shahzad MMK. Therapeutic dilemma: prognostic factors and outcome for neuroendocrine tumors of the cervix. Int J Gynecol Cancer. 2016;26:553–60. https://doi.org/10.1097/IGC.0000000000000631.PubMedView ArticleGoogle Scholar
  18. Abeler VM, Holm R, Nesland JM, Kjørstad KE. Small cell carcinoma of the cervix. A clinicopathologic study of 26 patients. Cancer. 1994;73:672–7.PubMedView ArticleGoogle Scholar
  19. Abulafia O, Sherer DM. Adjuvant chemotherapy in stage IB neuroendocrine small cell carcinoma of the cervix. Acta Obstet Gynecol Scand. 1995;74:740–4.PubMedView ArticleGoogle Scholar
  20. Agarwal S, Schmeler KM, Ramirez PT, Sun CC, Nick A, Dos Reis R, et al. Outcomes of patients undergoing radical hysterectomy for cervical cancer of high-risk histological subtypes. Int J Gynecol Cancer. 2011;21:123–7. https://doi.org/10.1097/IGC.0b013e3181ffccc1.PubMedPubMed CentralView ArticleGoogle Scholar
  21. Albores-Saavedra J, Martinez-Benitez B, Luevano E. Small cell carcinomas and large cell neuroendocrine carcinomas of the endometrium and cervix: polypoid tumors and those arising in polyps may have a favorable prognosis. Int J Gynecol Pathol. 2008;27:333–9. https://doi.org/10.1097/PGP.0b013e31815de006.PubMedView ArticleGoogle Scholar
  22. Alphandery C, Dagrada G, Frattini M, Perrone F, Pilotti S. Neuroendocrine small cell carcinoma of the cervix associated with endocervical adenocarcinoma: a case report. Acta Cytol. 2007;51:589–93.PubMedView ArticleGoogle Scholar
  23. Ambros RA, Park JS, Shah KV, Kurman RJ. Evaluation of histologic, morphometric, and immunohistochemical criteria in the differential diagnosis of small cell carcinomas of the cervix with particular reference to human papillomavirus types 16 and 18. Mod Pathol. 1991;4:586–93.PubMedGoogle Scholar
  24. Asensio N, Luis A, Costa I, Oliveira J, Vaz F. Meningeal carcinomatosis and uterine carcinoma: three different clinical settings and review of the literature. Int J Gynecol Cancer. 2009;19:168–72. https://doi.org/10.1111/IGC.0b013e31819a1e1a.PubMedView ArticleGoogle Scholar
  25. Balega J, Ulbright TM, Look KY. Coexistence of metastatic neuroendocrine carcinoma of the uterine cervix with human immunodeficiency virus infection. Int J Gynecol Cancer. 2001;11:334–7.PubMedView ArticleGoogle Scholar
  26. Baykal C, Al A, Tulunay G, Bulbul D, Güler G, Ozer S, Küçükali T. High-grade neuroendocrine carcinoma of the cervix. A case report. Gynecol Obstet Investig. 2005;59:207–11. https://doi.org/10.1159/000084259. View ArticleGoogle Scholar
  27. Bifulco G, Mandato VD, Giampaolino P, Piccoli R, Insabato L, de Rosa N, Nappi C. Small cell neuroendocrine cervical carcinoma with 1-year follow-up: case report and review. Anticancer Res. 2009;29:477–84.PubMedGoogle Scholar
  28. Brown KR, Leitao MM. Cisplatin-induced syndrome of inappropriate antidiuretic hormone (SIADH) in a patient with neuroendocrine tumor of the cervix: a case report and review of the literature. Eur J Gynaecol Oncol. 2010;31:107–8.PubMedGoogle Scholar
  29. Cavalcanti MS, Schultheis AM, Ho C, Wang L, DeLair DF, Weigelt B, et al. Mixed mesonephric adenocarcinoma and high-grade neuroendocrine carcinoma of the uterine cervix: case description of a previously unreported entity with insights into its molecular pathogenesis. Int J Gynecol Pathol. 2017;36:76–89. https://doi.org/10.1097/PGP.0000000000000306.PubMedPubMed CentralView ArticleGoogle Scholar
  30. Cetiner H, Kir G, Akoz I, Gurbuz A, Karateke A. Large-cell neuroendocrine carcinoma of the cervix associated with cervical-type invasive adenocarcinoma: a report of case and discussion of histogenesis. Int J Gynecol Cancer. 2006;16:438–42. https://doi.org/10.1111/j.1525-1438.2006.00194.x.PubMedView ArticleGoogle Scholar
  31. Chan JK, Loizzi V, Burger RA, Rutgers J, Monk BJ. Prognostic factors in neuroendocrine small cell cervical carcinoma: A multivariate analysis. Cancer. 2003;97:568–74. https://doi.org/10.1002/cncr.11086.PubMedView ArticleGoogle Scholar
  32. Chatterjee S, Chakravorty S, Kapoor P, Chattopadhyay D. Small cell neuroendocrine carcinoma of cervix--a case report. Indian J Pathol Microbiol. 2005;48:410–2.PubMedGoogle Scholar
  33. Chavez-Blanco A, Taja-Chayeb L, Cetina L, Chanona-Vilchis G, Trejo-Becerril C, Perez-Cardenas E, et al. Neuroendocrine marker expression in cervical carcinomas of non-small cell type. Int J Gynecol Pathol. 2002;21:368–74.PubMedView ArticleGoogle Scholar
  34. Cho SY, Choi M, Ban H-J, Lee CH, Park S, Kim H, et al. Cervical small cell neuroendocrine tumor mutation profiles via whole exome sequencing. Oncotarget. 2017;8:8095–104. https://doi.org/10.18632/oncotarget.14098.PubMedView ArticleGoogle Scholar
  35. Chun K-C, Kim D-Y, Kim J-H, Kim Y-M, Kim Y-T, Nam J-H. Neoadjuvant chemotherapy with paclitaxel plus platinum followed by radical surgery in early cervical cancer during pregnancy: three case reports. Jpn J Clin Oncol. 2010;40:694–8. https://doi.org/10.1093/jjco/hyq039.PubMedView ArticleGoogle Scholar
  36. Chung W-K, Yang J-H, Chang S-E, Lee M-W, Choi J-H, Moon K-C, Koh J-K. A case of cutaneous metastasis of small-cell neuroendocrine carcinoma of the uterine cervix. Am J Dermatopathol. 2008;30:636–8. https://doi.org/10.1097/DAD.0b013e31817e6f27.PubMedView ArticleGoogle Scholar
  37. Cohen JG, Kapp DS, Shin JY, Urban R, Sherman AE, L-m C, et al. Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients. Am J Obstet Gynecol. 2010;203:347.e1–6. https://doi.org/10.1016/j.ajog.2010.04.019.View ArticleGoogle Scholar
  38. Collinet P, Lanvin D, Declerck D, Chevalier-Place A, Leblanc E, Querleu D. Neuroendocrine tumors of the uterine cervix. Clinicopathologic study of five patients. Eur J Obstet Gynecol Reprod Biol. 2000;91:51–7.PubMedView ArticleGoogle Scholar
  39. Conner MG, Richter H, Moran CA, Hameed A, Albores-Saavedra J. Small cell carcinoma of the cervix: a clinicopathologic and immunohistochemical study of 23 cases. Ann Diagn Pathol. 2002;6:345–8. https://doi.org/10.1053/adpa.2002.36661.PubMedView ArticleGoogle Scholar
  40. Cui S, Lespinasse P, Cracchiolo B, Sama J, Kreitzer MS, Heller DS. Large cell neuroendocrine carcinoma of the cervix associated with adenocarcinoma in situ: evidence of a common origin. Int J Gynecol Pathol. 2001;20:311–2.PubMedView ArticleGoogle Scholar
  41. Damian A, Lago G, Rossi S, Alonso O, Engler H. Early detection of bone metastasis in small cell neuroendocrine carcinoma of the cervix by 68Ga-DOTATATE PET/CT imaging. Clin Nucl Med. 2017;42:216–7. https://doi.org/10.1097/RLU.0000000000001498.PubMedView ArticleGoogle Scholar
  42. Delaloge S, Pautier P, Kerbrat P, Castaigne D, Haie-Meder C, Duvillard P, et al. Neuroendocrine small cell carcinoma of the uterine cervix: what disease? What treatment? Report of ten cases and a review of the literature. Clin Oncol (R Coll Radiol). 2000;12:357–62.View ArticleGoogle Scholar
  43. Dikmen Y, Kazandi M, Zekioglu O, Ozsaran A, Terek MC, Erhan Y. Large cell neuroendocrine carcinoma of the uterine cervix: a report of a case and review of the literature. Arch Gynecol Obstet. 2004;270:185–8. https://doi.org/10.1007/s00404-003-0482-0.PubMedView ArticleGoogle Scholar
  44. Donati P, Paolino G, Donati M, Panetta C. Adenocarcinoma of the cervix associated with a neuroendocrine small cell carcinoma of the cervix in the spectrum of Muir-Torre syndrome. Eur J Gynaecol Oncol. 2015;36:213–5.PubMedGoogle Scholar
  45. Duan X, Ban X, Zhang X, Hu H, Li G, Wang D, et al. MR imaging features and staging of neuroendocrine carcinomas of the uterine cervix with pathological correlations. Eur Radiol. 2016;26:4293–302. https://doi.org/10.1007/s00330-016-4327-1.PubMedView ArticleGoogle Scholar
  46. Emmett M, Gildea C, Nordin A, Hirschowitz L, Poole J. Variations in treatment of cervical Cancer according to tumor morphology-population-based cohort analysis of English National Cancer Registration Data. Int J Gynecol Cancer. 2017;27:138–46. https://doi.org/10.1097/IGC.0000000000000859.PubMedView ArticleGoogle Scholar
  47. Frumovitz M, Burzawa JK, Byers LA, Lyons YA, Ramalingam P, Coleman RL, Brown J. Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer. Gynecol Oncol. 2016;141:588–91. https://doi.org/10.1016/j.ygyno.2016.04.001.PubMedPubMed CentralView ArticleGoogle Scholar
  48. Ganesan R, Hirschowitz L, Dawson P, Askew S, Pearmain P, Jones PW, et al. Neuroendocrine carcinoma of the cervix: review of a series of cases and correlation with outcome. Int J Surg Pathol. 2016;24(6):490. https://doi.org/10.1177/1066896916643385.PubMedView ArticleGoogle Scholar
  49. Gersell DJ, Mazoujian G, Mutch DG, Rudloff MA. Small-cell undifferentiated carcinoma of the cervix. A clinicopathologic, ultrastructural, and immunocytochemical study of 15 cases. Am J Surg Pathol. 1988;12:684–98.PubMedView ArticleGoogle Scholar
  50. Gilks CB, Young RH, Gersell DJ, Clement PB. Large cell neuroendocrine corrected carcinoma of the uterine cervix: a clinicopathologic study of 12 cases. Am J Surg Pathol. 1997;21:905–14.PubMedView ArticleGoogle Scholar
  51. Grayson W, Rhemtula HA, Taylor LF, Allard U, Tiltman AJ. Detection of human papillomavirus in large cell neuroendocrine carcinoma of the uterine cervix: a study of 12 cases. J Clin Pathol. 2002;55:108–14.PubMedPubMed CentralView ArticleGoogle Scholar
  52. Gressner O, Sauerbruch T. Secondary small cell neuroendocrine carcinoma of the cervix after radiotherapy for cervical squamous cell carcinoma. Int J Gynaecol Obstet. 2007;99:138. https://doi.org/10.1016/j.ijgo.2007.05.027.PubMedView ArticleGoogle Scholar
  53. Hao H, Itoyama M, Tsubamoto H, Tsujimoto M, Hirota S. Large cell neuroendocrine carcinoma of the cervix associated with intestinal variant invasive mucinous adenocarcinoma. Pathol Int. 2011;61:55–7. https://doi.org/10.1111/j.1440-1827.2010.02606.x.PubMedView ArticleGoogle Scholar
  54. Hara H, Ishii E, Hondo T, Nakagawa M, Teramoto K, Oyama T. Cytological features of atypical carcinoid combined with adenocarcinoma of the uterine cervix. Diagn Cytopathol. 2012;40(8):724. https://doi.org/10.1002/dc.21657.PubMedView ArticleGoogle Scholar
  55. Herrington CS, Graham D, Southern SA, Bramdev A, Chetty R. Loss of retinoblastoma protein expression is frequent in small cell neuroendocrine carcinoma of the cervix and is unrelated to HPV type. Hum Pathol. 1999;30:906–10.PubMedView ArticleGoogle Scholar
  56. Horn L-C, Hentschel B, Bilek K, Richter CE, Einenkel J, Leo C. Mixed small cell carcinomas of the uterine cervix: prognostic impact of focal neuroendocrine differentiation but not of Ki-67 labeling index. Ann Diagn Pathol. 2006;10(3):140. https://doi.org/10.1016/j.anndiagpath.2005.07.019.PubMedView ArticleGoogle Scholar
  57. Horn L-C, Lindner K, Szepankiewicz G, Edelmann J, Hentschel B, Tannapfel A, et al. p16, p14, p53, and cyclin D1 expression and HPV analysis in small cell carcinomas of the uterine cervix. Int J Gynecol Pathol. 2006;25:182–6. https://doi.org/10.1097/01.pgp.0000185406.85685.df.PubMedView ArticleGoogle Scholar
  58. Hsieh T-C, Wu Y-C, Sun S-S, Yang C-F, Yen K-Y, Liang J-A, Kao C-H. Rare breast and adrenal gland metastases from small-cell neuroendocrine carcinoma of uterine cervix. Clin Nucl Med. 2012;37(3):280. https://doi.org/10.1097/RLU.0b013e31823ea6c4.PubMedView ArticleGoogle Scholar
  59. Intaraphet S, Kasatpibal N, Siriaunkgul S, Sogaard M, Patumanond J, Khunamornpong S, et al. Prognostic impact of histology in patients with cervical squamous cell carcinoma, adenocarcinoma and small cell neuroendocrine carcinoma. Asian Pac J Cancer Prev. 2013;14:5355–60.PubMedView ArticleGoogle Scholar
  60. Ishida GM, Kato N, Hayasaka T, Saito M, Kobayashi H, Katayama Y, et al. Small cell neuroendocrine carcinomas of the uterine cervix: a histological, immunohistochemical, and molecular genetic study. Int J Gynecol Pathol. 2004;23:366–72.PubMedView ArticleGoogle Scholar
  61. Kajiwara H, Hirabayashi K, Miyazawa M, Nakamura N, Hirasawa T, Muramatsu T, et al. Immunohistochemical expression of somatostatin type 2A receptor in neuroendocrine carcinoma of uterine cervix. Arch Gynecol Obstet. 2009;279:521–5. https://doi.org/10.1007/s00404-008-0760-y.PubMedView ArticleGoogle Scholar
  62. Kasamatsu T, Sasajima Y, Onda T, Sawada M, Kato T, Tanikawa M. Surgical treatment for neuroendocrine carcinoma of the uterine cervix. Int J Gynaecol Obstet. 2007;99:225–8. https://doi.org/10.1016/j.ijgo.2007.06.051.PubMedView ArticleGoogle Scholar
  63. Kim DY, Yun HJ, Lee YS, Lee HN, Kim CJ. Small cell neuroendocrine carcinoma of the uterine cervix presenting with syndrome of inappropriate antidiuretic hormone secretion. Obstet Gynecol Sci. 2013;56:420–5. https://doi.org/10.5468/ogs.2013.56.6.420.PubMedPubMed CentralView ArticleGoogle Scholar
  64. Ko M-L, Jeng C-J, Huang S-H, Shen J, Chen S-C, Tzeng C-R. Large cell neuroendocrine carcinoma of the uterine cervix associated with adenocarcinoma. Taiwan J Obstet Gynecol. 2007;46:68–70. https://doi.org/10.1016/S1028-4559(08)60111-4.PubMedView ArticleGoogle Scholar
  65. Koch CA, Azumi N, Furlong MA, Jha RC, Kehoe TE, Trowbridge CH, et al. Carcinoid syndrome caused by an atypical carcinoid of the uterine cervix. J Clin Endocrinol Metab. 1999;84:4209–13. https://doi.org/10.1210/jcem.84.11.6126.PubMedView ArticleGoogle Scholar
  66. Komiyama S, Nishio E, Torii Y, Kawamura K, Oe S, Kato R, et al. A case of primary uterine cervical neuroendocrine tumor with meningeal carcinomatosis confirmed by diagnostic imaging and autopsy. Int J Clin Oncol. 2011;16:581–6. https://doi.org/10.1007/s10147-010-0155-5.PubMedView ArticleGoogle Scholar
  67. Kuji S, Watanabe R, Sato Y, Iwata T, Hirashima Y, Takekuma M, et al. A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: analysis of 37 cases. Gynecol Oncol. 2017;144:384–90. https://doi.org/10.1016/j.ygyno.2016.11.020.PubMedView ArticleGoogle Scholar
  68. Kumar S, Nair S, Alexander M. Carcinomatous meningitis occurring prior to a diagnosis of large cell neuroendocrine carcinoma of the uterine cervix. J Postgrad Med. 2004;50:311–2.PubMedGoogle Scholar
  69. Kuroda N, Wada Y, Inoue K, Ohara M, Mizuno K, Toi M, et al. Smear cytology findings of large cell neuroendocrine carcinoma of the uterine cervix. Diagn Cytopathol. 2013;41:636–9. https://doi.org/10.1002/dc.21834.PubMedView ArticleGoogle Scholar
  70. Lan-Fang L, Hai-Yan S, Zuo-Ming Y, Jian-Qing Z, Ya-Qing C. Small cell neuroendocrine carcinoma of the cervix: analysis of the prognosis and role of radiation therapy for 43 cases. Eur J Gynaecol Oncol. 2012;33:68–73.PubMedGoogle Scholar
  71. Lee J-M, Lee K-B, Nam J-H, Ryu S-Y, Bae D-S, Park J-T, et al. Prognostic factors in FIGO stage IB-IIA small cell neuroendocrine carcinoma of the uterine cervix treated surgically: results of a multi-center retrospective Korean study. Ann Oncol. 2008;19:321–6. https://doi.org/10.1093/annonc/mdm465.PubMedView ArticleGoogle Scholar
  72. Lee SW, Nam J-H, Kim D-Y, Kim J-H, Kim K-R, Kim Y-M, Kim Y-T. Unfavorable prognosis of small cell neuroendocrine carcinoma of the uterine cervix: a retrospective matched case-control study. Int J Gynecol Cancer. 2010;20:411–6. https://doi.org/10.1111/IGC.0b013e3181ce427b.PubMedView ArticleGoogle Scholar
  73. Lee S-W, Lim K-T, Bae DS, Park SY, Kim YT, Kim K-R, Nam J-H. A multicenter study of the importance of systemic chemotherapy for patients with small-cell neuroendocrine carcinoma of the uterine cervix. Gynecol Obstet Investig. 2015;79:172–8. https://doi.org/10.1159/000367920. View ArticleGoogle Scholar
  74. Lee W-J, Lee D-W, Lee M-W, Choi J-H, Moon K-C, Koh J-K. Multiple cutaneous metastases of neuroendocrine carcinoma derived from the uterine cervix. J Eur Acad Dermatol Venereol. 2009;23:494–6. https://doi.org/10.1111/j.1468-3083.2008.02955.x.PubMedView ArticleGoogle Scholar
  75. Lenczewski A, Terlikowski S, Sulkowska M, Famulski W, Kisielewski W, Kulikowski M. Small cell carcinoma of the uterine cervix--an uncommon variant of cervical cancer with neuroendocrine features. Folia Histochem Cytobiol. 2001;39(Suppl 2):89–90.PubMedGoogle Scholar
  76. Li S, Zhu H. Twelve cases of neuroendocrine carcinomas of the uterine cervix: cytology, histopathology and discussion of their histogenesis. Acta Cytol. 2013;57:54–60. https://doi.org/10.1159/000342516.PubMedView ArticleGoogle Scholar
  77. Li WWH, Yau TN, Leung CWL, Pong WM, Chan MYM. Large-cell neuroendocrine carcinoma of the uterine cervix complicating pregnancy. Hong Kong Med J. 2009;15:69–72.PubMedGoogle Scholar
  78. Lin Y, Lin WY, Liang JA, Lu YY, Wang HY, Tsai SC, Kao CH. Opportunities for 2-(18)F fluoro-2-deoxy-D-glucose PET/CT in cervical-vaginal neuroendocrine carcinoma: Case series and literature review. Korean J Radiol. 2012;13:760–70. https://doi.org/10.3348/kjr.2012.13.6.760.PubMedPubMed CentralView ArticleGoogle Scholar
  79. Majhi U, Murhekar K, Sundersingh S, Srinivasan V. Basaloid squamous cell carcinoma of cervix showing neuroendocrine differentiation. J Cancer Res Ther. 2015;11:492–3. https://doi.org/10.4103/0973-1482.146114.PubMedView ArticleGoogle Scholar
  80. Mannion C, Park WS, Man YG, Zhuang Z, Albores-Saavedra J, Tavassoli FA. Endocrine tumors of the cervix: morphologic assessment, expression of human papillomavirus, and evaluation for loss of heterozygosity on 1p,3p, 11q, and 17p. Cancer. 1998;83:1391–400.PubMedView ArticleGoogle Scholar
  81. Markopoulos MC, Lagadas AA, Alexandrou P, Giannakopoulos KC, Polyzos A. Prolonged disease free survival with aggressive adjuvant chemotherapy in a case of large cell neuroendocrine carcinoma of the uterine cervix. J BUON. 2009;14:322–3.PubMedGoogle Scholar
  82. Marongiu A, Salvati M, D'Elia A, Arcella A, Giangaspero F, Esposito V. Single brain metastases from cervical carcinoma: report of two cases and critical review of the literature. Neurol Sci. 2012;33:937–40. https://doi.org/10.1007/s10072-011-0861-4.PubMedView ArticleGoogle Scholar
  83. Marshall L-J, Sutton CD, White SA, Mackay H, Dennison AR. Syndrome X induced by carcinoid syndrome secondary to a cervical neuroendocrine primary tumour. ANZ J Surg. 2002;72:372–4.PubMedView ArticleGoogle Scholar
  84. McCluggage WG, Kennedy K, Busam KJ. An immunohistochemical study of cervical neuroendocrine carcinomas: neoplasms that are commonly TTF1 positive and which may express CK20 and P63. Am J Surg Pathol. 2010;34:525–32. https://doi.org/10.1097/PAS.0b013e3181d1d457.PubMedView ArticleGoogle Scholar
  85. McGarry RC, Smith C, Seemayer TA. Treatment resistant small cell carcinoma of the cervix. Oncology. 1999;57:293–6. https://doi.org/10.1159/000012063.PubMedView ArticleGoogle Scholar
  86. Nagao S, Miwa M, Maeda N, Kogiku A, Yamamoto K, Morimoto A, et al. Clinical features of neuroendocrine carcinoma of the uterine cervix: a single-institution retrospective review. Int J Gynecol Cancer. 2015;25:1300–5. https://doi.org/10.1097/IGC.0000000000000495.PubMedView ArticleGoogle Scholar
  87. Nakata SI, Yamamoto K, Kobayashi Y, Maeda K, Tsuda H, Deguchi M, et al. Excellent results of radiotherapy for neuroendocrine carcinoma of the uterine cervix. Oncol Rep. 2001;8:777–9.PubMedGoogle Scholar
  88. Niwa K, Nonaka-Shibata M, Satoh E, Hirose Y. Cervical large cell neuroendocrine carcinoma with cytologic presentation: a case report. Acta Cytol. 2010;54:977–80.PubMedGoogle Scholar
  89. Ohwada M, Wada T, Saga Y, Tsunoda S, Jobo T, Kuramoto H, et al. C-kit overexpression in neuroendocrine small cell carcinoma of the uterine cervix. Eur J Gynaecol Oncol. 2006;27:53–5.PubMedGoogle Scholar
  90. Perrin L, Bell J, Ward B. Small cell carcinoma of the cervix of neuroendocrine origin causing obstructed labour. Aust N Z J Obstet Gynaecol. 1996;36:85–7.PubMedView ArticleGoogle Scholar
  91. Powell JL, McKinney CD. Large cell neuroendocrine tumor of the cervix and human papillomavirus 16: a case report. J Low Genit Tract Dis. 2008;12:242–4. https://doi.org/10.1097/LGT.0b013e3181641b4f.PubMedView ArticleGoogle Scholar
  92. Puig F, Rodrigo C, Muñoz G, Lanzón R. Small cell neuroendocrine carcinoma of the cervix: report of two cases. Eur J Gynaecol Oncol. 2009;30:321–2.PubMedGoogle Scholar
  93. Pyeon SY, Park JY, Ulak R, Seol HJ, Lee JM. Isolated brain metastasis from uterine cervical cancer: a case report and review of literature. Eur J Gynaecol Oncol. 2015;36:602–4.PubMedGoogle Scholar
  94. Ramalingam P, Malpica A, Deavers MT. Mixed endocervical adenocarcinoma and high-grade neuroendocrine carcinoma of the cervix with ovarian metastasis of the former component: a report of 2 cases. Int J Gynecol Pathol. 2012;31:490–6. https://doi.org/10.1097/PGP.0b013e31824735a5.PubMedView ArticleGoogle Scholar
  95. Rashed MM, Bekele A. Neuroendocrine differentiation in a case of cervical cancer. Pan Afr Med J. 2010;6:4.PubMedGoogle Scholar
  96. Rekhi B, Patil B, Deodhar KK, Maheshwari A, A Kerkar R, Gupta S, et al. Spectrum of neuroendocrine carcinomas of the uterine cervix, including histopathologic features, terminology, immunohistochemical profile, and clinical outcomes in a series of 50 cases from a single institution in India. Ann Diagn Pathol. 2013;17:1–9. https://doi.org/10.1016/j.anndiagpath.2012.01.009.PubMedView ArticleGoogle Scholar
  97. Rhemtula H, Grayson W, van Iddekinge B, Tiltman A. Large-cell neuroendocrine carcinoma of the uterine cervix--a clinicopathological study of five cases. S Afr Med J. 2001;91:525–8.PubMedGoogle Scholar
  98. Rhiem K, Possover M, Gossmann A, Drebber K, Mallmann P, Ulrich U. “Occult” neuroendocrine component and rare metastatic pattern in cervical cancer: report of a case and brief review of the literature. Eur J Gynaecol Oncol. 2007;28:139–41.PubMedGoogle Scholar
  99. Ribeiro-Silva A, Novello-Vilar A, Cunha-Mercante AM, de Angelo Andrade LAL. Malignant mixed Mullerian tumor of the uterine cervix with neuroendocrine differentiation. Int J Gynecol Cancer. 2002;12:223–7.PubMedView ArticleGoogle Scholar
  100. Robin TP, Amini A, Schefter TE, Behbakht K, Fisher CM. Brachytherapy should not be omitted when treating locally advanced neuroendocrine cervical cancer with definitive chemoradiation therapy. Brachytherapy. 2016;15:845–50. https://doi.org/10.1016/j.brachy.2016.08.007.PubMedView ArticleGoogle Scholar
  101. Sato Y, Shimamoto T, Amada S, Asada Y, Hayashi T. Large cell neuroendocrine carcinoma of the uterine cervix: a clinicopathological study of six cases. Int J Gynecol Pathol. 2003;22:226–30. https://doi.org/10.1097/01.PGP.0000071046.12278.D1.PubMedView ArticleGoogle Scholar
  102. Sharabi A, Kim SS, Kato S, Sanders PD, Patel SP, Sanghvi P, et al. Exceptional response to Nivolumab and stereotactic body radiation therapy (SBRT) in neuroendocrine cervical carcinoma with high tumor mutational burden: management considerations from the center for personalized Cancer therapy at UC san Diego Moores Cancer center. Oncologist. 2017;22:631–7. https://doi.org/10.1634/theoncologist.2016-0517.PubMedPubMed CentralView ArticleGoogle Scholar
  103. Sheets EE, Berman ML, Hrountas CK, Liao SY, DiSaia PJ. Surgically treated, early-stage neuroendocrine small-cell cervical carcinoma. Obstet Gynecol. 1988;71:10–4.PubMedGoogle Scholar
  104. Silva-Meléndez PE, Escobar PF, Héctor S, Gutiérrez S, Rodríguez M. Small cell carcinoma of the uterine cervix: a case report and literature review. Bol Asoc Med P R. 2015;107:55–7.PubMedGoogle Scholar
  105. Singh S, Redline R, Resnick KE. Fertility-sparing management of a stage IB1 small cell neuroendocrine cervical carcinoma with radical abdominal trachelectomy and adjuvant chemotherapy. Gynecol Oncol Rep. 2015;13:5–7. https://doi.org/10.1016/j.gore.2015.04.004.PubMedPubMed CentralView ArticleGoogle Scholar
  106. Siriaunkgul S, Utaipat U, Suwiwat S, Settakorn J, Sukpan K, Srisomboon J, Khunamornpong S. Prognostic value of HPV18 DNA viral load in patients with early-stage neuroendocrine carcinoma of the uterine cervix. Asian Pac J Cancer Prev. 2012;13:3281–5.PubMedView ArticleGoogle Scholar
  107. Sisti G, Buccoliero AM, Novelli L, Sansovini M, Severi S, Pieralli A, et al. A case of metachronous double primary neuroendocrine cancer in pancreas/ileum and uterine cervix. Ups J Med Sci. 2012;117:453–6. https://doi.org/10.3109/03009734.2012.707254.PubMedPubMed CentralView ArticleGoogle Scholar
  108. Sitthinamsuwan P, Angkathunyakul N, Chuangsuwanich T, Inthasorn P. Neuroendocrine carcinomas of the uterine cervix: a clinicopathological study. J Med Assoc Thail. 2013;96:83–90.Google Scholar
  109. Sodsanrat K, Saeaib N, Liabsuetrakul T. Comparison of clinical manifestations and survival outcomes between neuroendocrine tumor and squamous cell carcinoma of the uterine cervix: results from a tertiary Center in Southern Thailand. J Med Assoc Thail. 2015;98:725–33.Google Scholar
  110. Straughn JM, Richter HE, Conner MG, Meleth S, Barnes MN. Predictors of outcome in small cell carcinoma of the cervix--a case series. Gynecol Oncol. 2001;83:216–20. https://doi.org/10.1006/gyno.2001.6385.PubMedView ArticleGoogle Scholar
  111. Strinić T, Tomić S, Pejković L, Eterović D, Forko JI, Karelović DA. Cure from the small cell neuroendocrine carcinoma of the uterine cervix following conventional surgery. Zentralbl Gynakol. 2000;122:387–9.PubMedGoogle Scholar
  112. Tangjitgamol S, Ramirez PT, Sun CC, See HT, Jhingran A, Kavanagh JJ, Deavers MT. Expression of HER-2/neu, epidermal growth factor receptor, vascular endothelial growth factor, cyclooxygenase-2, estrogen receptor, and progesterone receptor in small cell and large cell neuroendocrine carcinoma of the uterine cervix: a clinicopathologic and prognostic study. Int J Gynecol Cancer. 2005;15:646–56. https://doi.org/10.1111/j.1525-1438.2005.00121.x.PubMedView ArticleGoogle Scholar
  113. Tangjitgamol S, Manusirivithaya S, Choomchuay N, Leelahakorn S, Thawaramara T, Pataradool K, Suekwatana P. Paclitaxel and carboplatin for large cell neuroendocrine carcinoma of the uterine cervix. J Obstet Gynaecol Res. 2007;33:218–24. https://doi.org/10.1111/j.1447-0756.2007.00509.x.PubMedView ArticleGoogle Scholar
  114. Teefey P, Orr B, Vogt M, Roberts W. Neuroendocrine carcinoma of the cervix during pregnancy: a case report. Gynecol Oncol Case Rep. 2012;2:73–4. https://doi.org/10.1016/j.gynor.2012.03.003.PubMedPubMed CentralView ArticleGoogle Scholar
  115. Toki T, Katayama Y, Motoyama T. Small-cell neuroendocrine carcinoma of the uterine cervix associated with micro-invasive squamous cell carcinoma and adenocarcinoma in situ. Pathol Int. 1996;46:520–5.PubMedView ArticleGoogle Scholar
  116. Trinh XB, Bogers JJ, van Marck EA, Tjalma WAA. Treatment policy of neuroendocrine small cell cancer of the cervix. Eur J Gynaecol Oncol. 2004;25:40–4.PubMedGoogle Scholar
  117. Tsunoda S, Jobo T, Arai M, Imai M, Kanai T, Tamura T, et al. Small-cell carcinoma of the uterine cervix: a clinicopathologic study of 11 cases. Int J Gynecol Cancer. 2005;15:295–300. https://doi.org/10.1111/j.1525-1438.2005.15219.x.PubMedView ArticleGoogle Scholar
  118. Turner WA, Gallup DG, Talledo OE, Otken LB, Guthrie TH. Neuroendocrine carcinoma of the uterine cervix complicated by pregnancy: case report and review of the literature. Obstet Gynecol. 1986;67:80S–3S.PubMedView ArticleGoogle Scholar
  119. van Nagell JR, Donaldson ES, Wood EG, Maruyama Y, Utley J. Small cell cancer of the uterine cervix. Cancer. 1977;40:2243–9.PubMedView ArticleGoogle Scholar
  120. van Nagell JR, Powell DE, Gallion HH, Elliott DG, Donaldson ES, Carpenter AE, et al. Small cell carcinoma of the uterine cervix. Cancer. 1988;62:1586–93.PubMedView ArticleGoogle Scholar
  121. Viswanathan AN, Deavers MT, Jhingran A, Ramirez PT, Levenback C, Eifel PJ. Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence. Gynecol Oncol. 2004;93:27–33. https://doi.org/10.1016/j.ygyno.2003.12.027.PubMedView ArticleGoogle Scholar
  122. Walker AN, Mills SE, Taylor PT. Cervical neuroendocrine carcinoma: a clinical and light microscopic study of 14 cases. Int J Gynecol Pathol. 1988;7:64–74.PubMedView ArticleGoogle Scholar
  123. Wang K-L, Wang T-Y, Huang Y-C, Lai JC-Y, Chang T-C, Yen M-S. Human papillomavirus type and clinical manifestation in seven cases of large-cell neuroendocrine cervical carcinoma. J Formos Med Assoc. 2009;108:428–32. https://doi.org/10.1016/S0929-6646(09)60088-7.PubMedView ArticleGoogle Scholar
  124. Wang K-L, Yang Y-C, Wang T-Y, Chen J-R, Chen T-C, Chen H-S, et al. Neuroendocrine carcinoma of the uterine cervix: a clinicopathologic retrospective study of 31 cases with prognostic implications. J Chemother. 2006;18:209–16. https://doi.org/10.1179/joc.2006.18.2.209.PubMedView ArticleGoogle Scholar
  125. Wang Y, Mei K, Xiang MF, Li JM, Xie RM. Clinicopathological characteristics and outcome of patients with small cell neuroendocrine carcinoma of the uterine cervix: case series and literature review. Eur J Gynaecol Oncol. 2013;34:307–10.PubMedGoogle Scholar
  126. Weed JC, Graff AT, Shoup B, Tawfik O. Small cell undifferentiated (neuroendocrine) carcinoma of the uterine cervix. J Am Coll Surg. 2003;197:44–51. https://doi.org/10.1016/S1072-7515(03)00120-0.PubMedView ArticleGoogle Scholar
  127. Wistuba II, Thomas B, Behrens C, Onuki N, Lindberg G, Albores-Saavedra J, Gazdar AF. Molecular abnormalities associated with endocrine tumors of the uterine cervix. Gynecol Oncol. 1999;72:3–9. https://doi.org/10.1006/gyno.1998.5248.PubMedView ArticleGoogle Scholar
  128. Wu P-Y, Cheng Y-M, New GH, Chou C-Y, Chiang C-T, Tsai H-W, Huang Y-F. Case report: term birth after fertility-sparing treatments for stage IB1 small cell neuroendocrine carcinoma of the cervix. BMC Womens Health. 2017;17:56. https://doi.org/10.1186/s12905-017-0404-0.PubMedPubMed CentralView ArticleGoogle Scholar
  129. Yin ZM, Yu AJ, Wu MJ, Zhu JQ, Zhang X, Chen JH, et al. Prognostic factors and treatment comparison in small cell neuroendocrine cervical carcinoma. Eur J Gynaecol Oncol. 2014;35:259–63.PubMedGoogle Scholar
  130. Yoshida Y, Sato K, Katayama K, Yamaguchi A, Imamura Y, Kotsuji F. Atypical metastatic carcinoid of the uterine cervix and review of the literature. J Obstet Gynaecol Res. 2011;37:636–40. https://doi.org/10.1111/j.1447-0756.2010.01402.x.PubMedView ArticleGoogle Scholar
  131. Yousef I, Siyam F, Layfield L, Freter C, Sowers JR. Cervical neuroendocrine tumor in a young female with lynch syndrome. Neuro Endocrinol Lett. 2014;35:89–94.PubMedPubMed CentralGoogle Scholar
  132. Yuan L, Jiang H, Lu Y, Guo S-W, Liu X. Prognostic factors of surgically treated early-stage small cell neuroendocrine carcinoma of the cervix. Int J Gynecol Cancer. 2015;25:1315–21. https://doi.org/10.1097/IGC.0000000000000496.PubMedView ArticleGoogle Scholar
  133. Yun K, Cho NP, Glassford GN. Large cell neuroendocrine carcinoma of the uterine cervix: a report of a case with coexisting cervical intraepithelial neoplasia and human papillomavirus 16. Pathology. 1999;31:158–61.PubMedView ArticleGoogle Scholar
  134. Zaid T, Burzawa J, Basen-Engquist K, Bodurka DC, Ramondetta LM, Brown J, Frumovitz M. Use of social media to conduct a cross-sectional epidemiologic and quality of life survey of patients with neuroendocrine carcinoma of the cervix: a feasibility study. Gynecol Oncol. 2014;132:149–53. https://doi.org/10.1016/j.ygyno.2013.10.015.PubMedView ArticleGoogle Scholar
  135. Baggar S, Ouahbi H, Azegrar M, El M'rabet FZ, Arifi S, Mellas N. Carcinome neuroendocrine du col utérin: À propos d’un cas avec revue de la littérature. Pan Afr Med J. 2017;27:82. https://doi.org/10.11604/pamj.2017.27.82.10902.PubMedPubMed CentralView ArticleGoogle Scholar
  136. Bellefqih S, Khalil J, Mezouri I, Kebdani T, Benjaafar N. Carcinome neuroendocrine à petites cellules du col utérin: À propos de six cas et revue de la littérature. Cancer Radiother. 2014;18:201–7. https://doi.org/10.1016/j.canrad.2014.01.003.PubMedView ArticleGoogle Scholar
  137. Boruta DM, Schorge JO, Duska LA, Crum CP, Castrillon DH, Sheets EE. Multimodality therapy in early-stage neuroendocrine carcinoma of the uterine cervix. Gynecol Oncol. 2001;81:82–7. https://doi.org/10.1006/gyno.2000.6118.PubMedView ArticleGoogle Scholar
  138. Chang TC, Lai CH, Tseng CJ, Hsueh S, Huang KG, Chou HH. Prognostic factors in surgically treated small cell cervical carcinoma followed by adjuvant chemotherapy. Cancer. 1998;83:712–8.PubMedView ArticleGoogle Scholar
  139. Dongol S, Tai Y, Shao Y, Jiang J, Kong B. A retrospective clinicopathological analysis of small-cell carcinoma of the uterine cervix. Mol Clin Oncol. 2014;2:71–5. https://doi.org/10.3892/mco.2013.193.PubMedView ArticleGoogle Scholar
  140. Frumovitz M, Munsell MF, Burzawa JK, Byers LA, Ramalingam P, Brown J, Coleman RL. Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix. Gynecol Oncol. 2017;144:46–50. https://doi.org/10.1016/j.ygyno.2016.10.040.PubMedView ArticleGoogle Scholar
  141. Futagami M, Yokoyama Y, Mizunuma H. Presentation of a patient with pT2bN1M0 small cell carcinoma of the uterine cervix who obtained long-term survival with maintenance chemotherapy, and literature-based discussion. Eur J Gynaecol Oncol. 2011;32:99–102.PubMedGoogle Scholar
  142. Lee DY, Chong C, Lee M, Kim JW, Park NH, Song YS, Park SY. Prognostic factors in neuroendocrine cervical carcinoma. Obstet Gynecol Sci. 2016;59:116–22. https://doi.org/10.5468/ogs.2016.59.2.116.PubMedPubMed CentralView ArticleGoogle Scholar
  143. Lewandowski GS, Copeland LJ. A potential role for intensive chemotherapy in the treatment of small cell neuroendocrine tumors of the cervix. Gynecol Oncol. 1993;48:127–31. https://doi.org/10.1006/gyno.1993.1021.PubMedView ArticleGoogle Scholar
  144. Lyons YA, Frumovitz M, Soliman PT. Response to MEK inhibitor in small cell neuroendocrine carcinoma of the cervix with a KRAS mutation. Gynecol Oncol Rep. 2014;10:28–9. https://doi.org/10.1016/j.gore.2014.09.003.PubMedPubMed CentralView ArticleGoogle Scholar
  145. Margolis B, Tergas AI, Chen L, Hou JY, Burke WM, Hu JC, et al. Natural history and outcome of neuroendocrine carcinoma of the cervix. Gynecol Oncol. 2016;141:247–54. https://doi.org/10.1016/j.ygyno.2016.02.008.PubMedPubMed CentralView ArticleGoogle Scholar
  146. McCann GA, Boutsicaris CE, Preston MM, Backes FJ, Eisenhauer EL, Fowler JM, et al. Neuroendocrine carcinoma of the uterine cervix: the role of multimodality therapy in early-stage disease. Gynecol Oncol. 2013;129:135–9. https://doi.org/10.1016/j.ygyno.2013.01.014.PubMedView ArticleGoogle Scholar
  147. Murakami R, Kou I, Date K, Nakayama H. Advanced composite of large cell neuroendocrine carcinoma and squamous cell carcinoma: a case report of uterine cervical cancer in a virgin woman. Case Rep Obstet Gynecol. 2013;2013:921384. https://doi.org/10.1155/2013/921384.PubMedPubMed CentralView ArticleGoogle Scholar
  148. Omori M, Hashi A, Kondo T, Tagaya H, Hirata S. Successful neoadjuvant chemotherapy for large cell neuroendocrine carcinoma of the cervix: a case report. Gynecol Oncol Case Rep. 2014;8:4–6. https://doi.org/10.1016/j.gynor.2013.12.001.PubMedView ArticleGoogle Scholar
  149. Paraghamian SE, Longoria TC, Eskander RN. Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report. Gynecol Oncol Res Pract. 2017;4:3. https://doi.org/10.1186/s40661-017-0038-9.PubMedPubMed CentralView ArticleGoogle Scholar
  150. Peng P, Ming W, Jiaxin Y, Keng S. Neuroendocrine tumor of the uterine cervix: a clinicopathologic study of 14 cases. Arch Gynecol Obstet. 2012;286:1247–53. https://doi.org/10.1007/s00404-012-2407-2.PubMedView ArticleGoogle Scholar
  151. Rajkumar S, Iyer R, Culora G, Lane G. Fertility sparing management of large cell neuroendocrine tumour of cervix: a case report & review of literature. Gynecol Oncol Rep. 2016;18:15–7. https://doi.org/10.1016/j.gore.2016.10.002.PubMedPubMed CentralView ArticleGoogle Scholar
  152. Sheth S, Shende D, Arneja S. Small cell neuroendocrine carcinoma of cervix and leiomyoma between the vagina and rectum. J Obstet Gynaecol. 2015;35:314–5. https://doi.org/10.3109/01443615.2014.940295.PubMedView ArticleGoogle Scholar
  153. Stecklein SR, Jhingran A, Burzawa J, Ramalingam P, Klopp AH, Eifel PJ, Frumovitz M. Patterns of recurrence and survival in neuroendocrine cervical cancer. Gynecol Oncol. 2016;143:552–7. https://doi.org/10.1016/j.ygyno.2016.09.011.PubMedView ArticlePubMed CentralGoogle Scholar
  154. Tanimoto H, Hamasaki A, Akimoto Y, Honda H, Takao Y, Okamoto K, et al. A case of large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix successfully treated by postoperative CPT-11+CDDP chemotherapy after non-curative surgery. Gan To Kagaku Ryoho. 2012;39:1439–41.PubMedGoogle Scholar
  155. Wang PH, Liu YC, Lai CR, Chao HT, Yuan CC, Small YKJ. Cell carcinoma of the cervix: analysis of clinical and pathological findings. Eur J Gynaecol Oncol. 1998;19:189–92.PubMedGoogle Scholar
  156. Wang Q, Liu Y-H, Xie L, Hu W-J, Liu B-R. Small cell carcinoma of the uterine cervix in pregnancy: a case report and review of the literature. Oncol Lett. 2015;9:91–5. https://doi.org/10.3892/ol.2014.2668.PubMedView ArticleGoogle Scholar
  157. Wang Z, Wu L, Yao H, Sun Y, Li X, Li B, et al. Clinical analysis of 32 cases with neuroendocrine carcinoma of the uterine cervix in early-stage disease. Zhonghua Fu Chan Ke Za Zhi. 2015;50:198–203.PubMedGoogle Scholar
  158. Xie S, Song L, Yang F, Tang C, Yang S, He J, Pan X. Enhanced efficacy of adjuvant chemotherapy and radiotherapy in selected cases of surgically resected neuroendocrine carcinoma of the uterine cervix: a retrospective cohort study. Medicine (Baltimore). 2017;96:e6361. https://doi.org/10.1097/MD.0000000000006361.View ArticleGoogle Scholar
  159. Zivanovic O, Leitao MM, Park KJ, Zhao H, Diaz JP, Konner J, 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(3):590. https://doi.org/10.1016/j.ygyno.2008.11.010.PubMedView ArticleGoogle Scholar

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