Review Article

Updates and management algorithm for

Int J Gynecol Cancer: first published as 10.1136/ijgc-2019-000504 on 1 July 2019. Downloaded from http://ijgc.bmj.com/ on August 20, 2020 by guest. Protected by copyright.
neuroendocrine tumors of the uterine cervix
Gloria Salvo,‍ ‍ 1
Antonio Gonzalez Martin,2 Naomi R Gonzales,1 Michael Frumovitz1

1
Department of Gynecologic Abstract most common (80%) followed by large-cell neuroen-
Oncology and Reproductive docrine carcinoma (12%), and other histologic types
Neuroendocrine carcinomas of the cervix account for less
Medicine, University of Texas
MD Anderson Cancer Center, than 2% of all invasive cervical cancers and are classified such as undifferentiated neuroendocrine tumors (8%).
Houston, Texas, USA as low-grade (carcinoid, atypical carcinoid tumor) or high- Unlike squamous and adenocarcinoma subtypes,
2
Department of Medical grade (known as small- and large-cell) neuroendocrine which spread primarily by local extension, high-grade
Oncology, Clinica Universidad carcinomas. There are increasing data showing that neuroendocrine tumors have a high rate of lymphatic
Navarra, Madrid, Spain cervical neuroendocrine carcinomas may be associated and hematogenous metastasis even when disease is
with the human papillomavirus (HPV), especially HPV18, clinically limited to the cervix. These tumors frequently
Correspondence to and most will stain positive for p16. Immunohistochemistry
have lymph vascular space involvement, strong asso-
Dr Gloria Salvo, Department markers such as synaptophysin and CD56 are the most
sensitive markers. Although there are no commonly
ciation with HPV18, and an increased risk of nodal
of Gynecologic Oncology
and Reproductive Medicine, associated mutations, PIK3CA, KRAS, and TP53 are the metastases at diagnosis, with 40% of clinical stage
University of Texas MD most frequently found mutations in neuroendocrine IB1 tumors diagnosed with positive pelvic nodes, in
Anderson Cancer Center, tumors. Neuroendocrine cervical carcinomas are comparison to 10%–15% node positivity seen in clin-
Houston, TX 77030, USA; ​ exceedingly aggressive tumors with a high tendency for ical stage IB1 squamous cell carcinoma.3 4 Patients
glorietasalvo@g​ mail.​com; ​
nodal involvement and distant metastases. Age, lymph with small-cell carcinoma are more likely to be diag-
GSalvo@​mdanderson.​org
node metastases, smoking, pure small-cell histology, and nosed at late stage.5 6 Extra-pelvic disease at the
tumor size are independent prognostic factors. Overall, time of diagnosis is also common, especially in the
Received 29 March 2019 the 5-year survival rate is 36% and the median overall lungs and liver, and is often associated with high risk
Revised 14 May 2019 survival ranges between 22 and 25 months. Treatment of relapse.7 8 The median overall survival for patients
Accepted 15 May 2019 options are often extrapolated from small-cell lung cancer
with small-cell neuroendocrine tumors is less than 2
and limited retrospective studies. The preferred treatment
is a multimodal approach of surgery, chemoradiation, and
years.5 6 9–11
systemic chemotherapy. The most common chemotherapy There is a total of 3,538 cases of neuroendocrine
regimen used as initial therapy is a combination of cervical cancers reported in 147 studies in the litera-
cisplatin and etoposide. In the setting of recurrent disease, ture to date and only nine studies included more than
a combination of topotecan, paclitaxel, and bevacizumab 50 patients.3 The lack of prospective studies limits
has demonstrated favorable outcomes. Multicenter tumor our ability to define concrete chemotherapy regimens,
registries, such as the Neuroendocrine Cervical Tumor and the primary treatment is a multimodal approach
Registry (NeCTuR), are an opportunity to evaluate patterns including surgery, radiation, and chemotherapy.12 13
of disease treatment and oncologic outcomes. At MD Anderson Cancer Center we have a registry
of neuroendocrine cervical carcinomas with patients
treated not only at our institution but also elsewhere.
All neuroendocrine cervical carcinomas are treated by
the same small group of physicians that also serve
as consultants for doctors from around the world. In
Background this review we aim to summarize the latest and most
Neuroendocrine tumors are a rare entity of the female relevant information regarding this disease and also
genital tract, with cervix being the most common provide our algorithms for diagnosis and treatment.
primary site.1 First described by Albores-Saavedra In addition, we will discuss key points to help physi-
in 1972, these tumors account for 1.4% of all inva- cians around the world provide better treatment for
sive cervical cancers and nearly 200 new cases are this uncommon disease.
© IGCS and ESGO 2019. No
diagnosed in the United States each year.2 3 The 2014
commercial re-use. See rights
and permissions. Published by World Health Organization (WHO) Classification2 cate-
BMJ. gorizes cervical neuroendocrine tumors as low-grade Etiology
To cite: Salvo G,
(previously referred to as carcinoid tumor and atypical The association between squamous cell carcinoma,
Gonzalez Martin A, carcinoid tumor) or high-grade neuroendocrine carci- adenocarcinoma, and adenosquamous carcinoma of
Gonzales NR, et al. Int J nomas (previously referred to as small-cell carcinoma the cervix with human papillomavirus (HPV) has been
Gynecol Cancer 2019;29:986– or large-cell neuroendocrine carcinoma) (Table 1). In well established and documented.14 15 For cervical
995. the cervix, small-cell neuroendocrine tumor is the neuroendocrine carcinomas, the link with HPV has not

986 Salvo G, et al. Int J Gynecol Cancer 2019;29:986–995. doi:10.1136/ijgc-2019-000504

 Review Article

Int J Gynecol Cancer: first published as 10.1136/ijgc-2019-000504 on 1 July 2019. Downloaded from http://ijgc.bmj.com/ on August 20, 2020 by guest. Protected by copyright.
Table 1  World Health Organization (WHO) neuroendocrine cervical carcinomas classification.
Uterine cervix Neuroendocrine tumors Low-grade neuroendocrine tumors
(carcinoid, atypical carcinoid tumor)
High-grade neuroendocrine tumors
(small-cell neuroendocrine carcinoma, large-cell neuroendocrine carcinoma)
Glandular tumor and precursors Adenocarcinoma admixed with neuroendocrine carcinoma

been as definitively established but emerging data suggest a likely the most specific marker to help confirm the diagnosis. Marker
association. Alejo et al16 explored HPV DNA detection and genotype positivity in small-cell neuroendocrine tumors ranges from 33%
distribution and their relation to histologic and immunohistochem- to 100%. In the latest systematic review published by Tempfer et
ical features in 49 cervical neuroendocrine tumors. The authors al,13 the most frequently observed immunohistochemistry markers
found that 86% of neuroendocrine tumors had HPV DNA. Single were synaptophysin (79%), neuron specific enolase (69%), chro-
infection (one HPV type) was reported in 98% of cases. HPV16 mogranin (66%), and CD56 (61%). Synaptophysin and CD56 are the
was found in 55% of neuroendocrine tumors, HPV18 in 41%, and most sensitive neuroendocrine markers, but CD56 lacks specificity.
4% of tumors were positive for other HPV types. HPV18 was four Chromogranin is the most specific neuroendocrine marker but
times (41%) more frequent in neuroendocrine tumors compared lacks sensitivity, with approximately 50% positivity for small-cell
with other histologies (10%) (p<0.001). The authors suggested neuroendocrine carcinoma.21
that the greater frequency of HPV18 in both neuroendocrine tumors In the study by Alejo et al,16 65% were positive for at least one
and adenocarcinomas is indicative of the greater affinity of HPV18 immunohistochemical marker (chromogranin, CD56, and/or synap-
for glandular and neuroendocrine cells compared with other HPV tophysin) with CD56 being the most frequently positive (62%)
types. They also found that neuroendocrine tumors were more followed by chromogranin (39%) and synaptophysin (26%). Simi-
frequently associated with concomitant glandular (rather than larly, other authors found CD56 to be the most sensitive marker of
squamous) lesions. Neuroendocrine carcinomas showed marked neuroendocrine differentiation (62%) followed by chromogranin A
lymphatic permeation, a feature that is particularly characteristic of (39%) and synaptophysin (26%).21 22 Chromogranin positivity may
HPV18-related tumors17 be very focal with punctuate cytoplasmic immunoreactivity, which
Almost all squamous cell carcinomas (97%) and half of adeno- is only visible on high-power magnification. Small-cell neuroen-
carcinomas show p16-positive staining.18 In the study by Alejo et docrine carcinoma may be only focally positive (often punctuate
al,16 the authors found that p16 staining was over-expressed in 86% cytoplasmic staining) or even negative with broad-spectrum cyto-
of cases. All carcinoid, atypical carcinoid, and large-cell neuroendo- keratins. As previously mentioned, most cervical high-grade neuro-
crine carcinomas were p16-positive, while 79% of small-cell carci- endocrine carcinomas are diffusely positive for p16 due to the
nomas showed p16-positive staining. Overall, concordant results presence of high-risk HPV.21
of p16 and HPV detection were observed in 89% of cases. In a Insulinoma-associated protein 1 (INSM1) may be more specific
study by Kuji et al,19 the authors evaluated 37 high-grade neuroen- for neuroendocrine tumors than chromogranin A or synaptophysin.23
docrine carcinomas and found that 72% had high-risk HPV infec- In a recent publication, 37 high-grade neuroendocrine cases were
tions (HPV16 in 14% and HPV18 in 86%). Castle et al20 published stained with neuroendocrine markers and INSM1. Chromogranin A
a metanalysis of 32 studies, including 403 small-cell and nine and synaptophysin were each expressed in 86% of cases. INSM1
studies including 45 large-cell neuroendocrine tumors. The authors was detected in 95% of cases. INSM1 seems to be a useful new
found that 85% of small-cell carcinomas were HPV-positive (HPV16 neuroendocrine marker and may be associated with the develop-
and/or HPV18: 78%). In a subanalysis of five studies, including 75 ment of high-grade neuroendocrine carcinomas.
patients with small-cell carcinoma, 93% were positive for p16 by Investigators at MD Anderson Cancer Center studied the immuno-
immunohistochemistry and 100% were HPV-positive. Large-cell histochemical expression and prognostic role in survival of HER-2/
neuroendocrine carcinomas were HPV-positive in 88% (HPV16 and/ neu, epidermal growth factor receptor (EGFR), vascular endothe-
or HPV18: 86%). lial growth factor (VEGF), cyclooxygenase-2 (COX-2), estrogen
The possible relationship between cervical neuroendocrine receptor, and progesterone receptor in small- and large-cell neuro-
carcinomas and HPV infection is a very important finding as these endocrine cervical carcinomas in 24 patients. Twenty-three cases
cancers may be prevented by prophylactic HPV vaccines. It also (96%) expressed VEGF, eight (33%) expressed EGFR, 10 (42%)
opens the possibility of administering immunotherapy or thera- expressed HER-2/neu, and seven (29%) expressed COX-2. No
peutic vaccines as a treatment for women with this disease. significant differences in the expression of these factors were found
between small- and large-cell tumors. Only HER-2/neu expression
was associated with survival, showing that patients with negative
Immunohistochemistry HER-2/neu expression tumors had significantly shorter survival
Immunohistochemistry stains are frequently used to help diagnose than those whose tumors were positive, 14.2 months versus 33
neuroendocrine tumors. The most frequently used neuroendocrine months, respectively (p=0.03).24
stains are chromogranin A, synaptophysin, CD56, and neuron-spe- Immunohistochemical expressions may be helpful when trying
cific enolase. For large-cell neuroendocrine carcinomas, in addition to determine the site of origin of metastatic small-cell carcinoma.
to morphology by hematoxylin and eosin stain, chromogranin A is Some studies have shown that 33%–84% of small-cell cervical

Salvo G, et al. Int J Gynecol Cancer 2019;29:986–995. doi:10.1136/ijgc-2019-000504 987

Review Article

carcinomas exhibit diffuse nuclear positivity for thyroid transcrip- suggest a low likelihood of response to PD-1/PD-L1 inhibitors in

Int J Gynecol Cancer: first published as 10.1136/ijgc-2019-000504 on 1 July 2019. Downloaded from http://ijgc.bmj.com/ on August 20, 2020 by guest. Protected by copyright.
tion factor-1 (TTF-1).21 25–27 Liu et al28 compared different expres- the recurrent setting.30
sion of neuroendocrine markers, TTF-1, p53, and Ki-67 in 23
cases of cervical small-cell and 56 cases of pulmonary small-cell
carcinomas using immunohistochemistry. The TTF-1 expression of Diagnosis, Staging, and Imaging
small-cell carcinoma of the lung showed significantly higher diffuse
Cervical neuroendocrine carcinomas are staged using the same
and strong positivity in tumor cell nuclei than the cervical coun-
International Federation of Gynecology and Obstetrics (FIGO)
terpart (p=0.003). Although both tumors had similar morphological
staging system used for other cervical histologies. The 2018 FIGO
features, they have different immunohistochemical panel. Both had
staging system allows for imaging and pathologic findings to modify
similar positivity for CD56 and chromogranin A, but the expression
tumor stage.31 This is a crucial change for cervical neuroendocrine
of the synaptophysin in cervical small-cell was significantly higher
carcinomas given the higher rate of nodal and distant metastasis at
than in small-cell lung cancer (p=0.007).
the time of diagnoses. The Society of Gynecologic Oncology (SGO)
Inmunohistochemistry is important at the time of diagnosis but guideline recommends that given the high rate of distant meta-
one should be aware that positive staining could be as low as 33% static disease in neuroendocrine tumors, imaging evaluation should
using standard markers and that stains may be only focally positive. include either a computed tomography (CT) or positron emission
New markers should be considered if the diagnosis is still unclear tomography (PET)/CT scan.32
as they shown higher positivity rates, as in the case of INMS-1 and For disease confined to the cervix both clinically and radiologi-
VEGF. cally, pelvic magnetic resonance imaging (MRI) is considered the
best imaging method for tumors greater than 10 mm to evaluate
tumor size and local extension of the disease.33 For women with
seemingly early-stage disease, we recommend obtaining a pelvic
Molecular and Immune Profile Testing MRI in order to determine if a patient is a candidate for surgical
Although small-cell cervical cancer is a rare tumor without a treatment. Another option is transrectal ultrasonography, although
unifying mutational event, identifying genetic alterations that are this is not commonly utilized at most centers. For other histo-
amenable to targeted therapy provides an opportunity to individ- logic subtypes of cervical cancer (squamous, adenocarcinoma, or
ualize therapy especially in relapses where the spectrum of treat- adenosquamous), when performed by expert radiologists, the accu-
ments is limited. While high-risk HPV may be involved at an early racy of transrectal ultrasound compared with MRI in detecting para-
stage of oncogenesis in many tumors, additional driving events metrial infiltration was 98.9% and 94.7% (p≤0.219), respectively. It
have been postulated to facilitate the progression of small-cell was considered superior to MRI in detecting small tumors (<1 cm3)
carcinomas. Identification of oncogenic drivers has allowed for (90.5% vs 81.1% (p≤0.049), respectively). Transrectal ultrasound
a better understanding of the natural history of neuroendocrine was also found to be superior to MRI when evaluating residual
tumors. In a recent systematic review, the most common mutations tumors after conization (93.7% vs 83.2%, respectively; p≤0.006).34
were in p53 (26%), KRAS (12%), PIK3CA (18%), and c-myc (53%) Our approach at MD Anderson Cancer Center is to conduct a
genes. Loss of heterozygosity was found in 30% of cases.13 thorough gynecologic examination, including a rectovaginal exam,
Frumovitz et al29 identified 44 patients with pure or mixed small- and a PET/CT scan for initial radiologic staging. For patients with
cell cervical cancer. All patients underwent mutational analysis disease seemingly limited to the cervix, we recommend either an
using next-generation sequencing of mutational hotspots in 50 MRI or ultrasound pre-operatively to evaluate local disease exten-
cancer-related genes. Thirty-five mutations were identified in 24 sion. For those patients dispositioned to primary radiation therapy, a
patients (55%). Most patients (63%) had one mutation, 29% had pelvic MRI is frequently performed for radiation planning.
two mutations, and 8% had three mutations. In all 44 patients, the We only perform brain imaging in the presence of lung or liver
most common mutations were in PIK3CA (n=8; 18%), KRAS (n=6, metastases or neurologic symptoms. We strongly encourage physi-
14%), and TP53 (n=5, 11%). No other mutation was found in >7% cians to stage patients using the FIGO 2018 system as it might
of specimens. Of the 24 patients who had a mutation, 21 (88%) had classify patients in a more 'real'/accurate stage according to tumor
at least one alteration for which there currently exists a class of size, nodal spread, and distant metastases. This allows more
biological agents targeting that mutation. Although in patients with tailored treatment and provides patients with a more definitive
small-cell cervical cancer no common mutation was found, almost discussion on prognosis when taking into account nodal status and
half had at least one actionable mutation for targeted therapy. This distant organ involvement (Figure 1).
is of great importance for patients with recurrent disease where
treatment options are limited. Mutational analysis may help to
select patients for phase I trials or even off-label therapies. Disease Prognosis
Our group at MD Anderson Cancer Center recently evaluated the Several studies have reported age,5 lymph node metastases,11 35–37
presence of PD-L1 receptors as well as mismatch repair proteins race,8 smoking,38 pure small-cell histology, LVSI,11 and tumor
(MLH1, MSH2, MSH6, and PMS2) in specimens of high-grade size35 36 38 as independent prognostic factors for neuroendocrine
neuroendocrine cervical cancer. In 23 samples tested for PD-L1 cervical carcinomas. However, stage was the most commonly cited
expression, 22 (96%) were negative for the receptor. In 25 spec- poor prognostic factor in a majority of studies.7 5 35–37 39 Overall, the
imens evaluated for microsatellite instability, all (100%) showed prognosis of women with neuroendocrine cervical cancer remains
intact expression of mismatch repair proteins. These findings poor despite multimodal treatment plans, with a 5-year survival

988 Salvo G, et al. Int J Gynecol Cancer 2019;29:986–995. doi:10.1136/ijgc-2019-000504

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Int J Gynecol Cancer: first published as 10.1136/ijgc-2019-000504 on 1 July 2019. Downloaded from http://ijgc.bmj.com/ on August 20, 2020 by guest. Protected by copyright.
Figure 1  High-grade neuroendocrine cervical carcinoma work-up. MRI, magnetic resonance imaging; PET/CT, positron
emission tomography/computed tomography. *FIGO 2018 stage.

rate of 36% and a median overall survival between 22 and 25 Ishikawa et al11 of 93 patients with stage I-II high-grade neuroen-
months.5 When considering early (I-II) versus advanced stage (III- docrine carcinoma of the cervix showed a median overall survival
IV), the 5-year overall survival rates are 31%–51% and 0%–7%, of 111 months and a disease-free survival of 47 months. There
respectively7 38 40 (Table 2). was significant variability as to how patients were treated, but the
majority of patients (88; 95%) underwent radical surgery, and five
(5%) had definitive radiotherapy. Of the patients receiving surgery,
Primary Treatment 37 (40%) underwent radical surgery and pelvic lymphadenectomy
Early-Stage Disease with post-operative chemotherapy, 14 (15%) received only surgery,
In a recently published systematic review that included 3,538 and 25 (27%) received adjuvant radiation or chemoradiation
neuroendocrine patients, the most common primary treatment was therapy after surgery with or without neoadjuvant chemotherapy
radical surgery combined with chemotherapy, either as neoadjuvant before surgery. The hazard ratio (HR) for death for patients who did
or adjuvant (40/48 studies).13 There was no standard chemotherapy not undergo surgery as part of their primary treatment was 4.74
regimen but platinum and etoposide was the most commonly used (95% CI 1.01 to 15.9). Patients who underwent radical surgery had
treatment (24/40 studies). Radiotherapy-based treatment schemes a better overall survival than those who received definitive radio-
were also commonly utilized in the upfront setting for early-stage therapy (p=0.043). The authors found that most clinicians favored
disease (15/48 studies). radical surgery followed by adjuvant chemotherapy with an etopo-
Both the SGO32 and the Gynecologic Cancer Intergroup (GCIG)41 side–platinum or irinotecan–platinum regimen as the optimal treat-
recommend multimodal therapy for all stages of neuroendocrine ment of choice for stages I-II high-grade neuroendocrine cervical
tumors of the cervix, and the majority of patients receive some
carcinoma. They also concluded that even in early-stage disease,
combination of surgery, radiation, and chemotherapy. For early-
both local recurrence and distant metastasis occurred frequently,
stage disease (tumors ≤4 cm) and negative nodes on imaging,
and therefore a more effective treatment strategy is required.
radical hysterectomy and pelvic lymphadenectomy followed
Wang et al42 reviewed 146 patients with stage I-II disease. Of
by chemotherapy with platinum and etoposide is the primary
these, 116 (79%) underwent surgery as part of their primary treat-
management recommended with consideration for additional
radiotherapy.32 ment (primary surgery with/without adjuvant therapy, neoadjuvant
chemotherapy plus radical hysterectomy, or peri-operative chemo-
Surgery therapy plus radical hysterectomy). The remaining 30 patients did
There are no prospective studies comparing surgery with chemo- not undergo surgery but rather had radiation therapy with or without
radiation therapy for early-stage, resectable tumors. A study from chemotherapy. The authors found there was a trend of worse

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Table 2  Oncologic outcomes of patients with high-grade neuroendocrine cervical carcinoma
DFS 5-year 5-year
Author Year N Type Stage (months) OS (months) DFS (%) OS (%)
Chan38 2003 34 Multicenter I-IIA 31 32
IIB-IVB 10 0
Weed44 2003 15 Single institution All stages 13
45
Viswanathan 2004 21 Single institution IB1-IIIB 41 29
Chen5 2008 288 SEER All stages 36
52
Lee 2008 68 Multicenter IB1 55
IB2-IIA 54 32
All stages 47
Zivanovic77 2009 17 Single institution All stages 21 22
IA1-IB2 31
IIB-IV 6
Cohen10 2010 188 SEER + 52 patients I-IIA 37
from four hospitals IIB-IVA 10
IVB 0
Wang42 2012 179 Multicenter All stages 16 25 (CSS) 43*; 63†
IIB-IVB
Yin64 2015 23 Single institution I-IIIB 40
41
Stecklein 2016 32 Single institution All stages 20 27
Lee69 2016 61 Multicenter All stages 64 36
Xie65 2017 48 Single institution All stages 30 31
11
Ishikawa11 2018 93 Multicenter IA-IIB 47 111 49 55
Tempfer13 2018 3538 Meta-analysis All stages 16 40 34
*Primary treatment containing etoposide and platinum for at least five cycles.
†Concurrent chemoradiation with etoposide and platinum for at least five cycles.
CSS, Cancer Surveillance System; DFS, disease-free survival; OS, overall survial; SEER, Surveillance, Epidemiology, and End Results
Program.

failure-free survival (41% vs 61%, p=0.086) and cancer-specific survival rate was 83% for patients who received chemotherapy and
survival (48% vs 62%, p=0.122) for those women who had radical 0% for patients who did not receive chemotherapy as part of their
surgery compared with those who did not undergo surgery. initial treatment (p=0.03). The estimated 3-year overall survival
From our study of patients with stage I-IIA clinically node-neg- rate was 83% for patients who received chemotherapy and 20%
ative disease, those who received definitive chemoradiation had for patients who did not receive chemotherapy as part of their
significantly better median event-free survival than those who initial treatment (p=0.36). Ishikawa et al11 found that there was an
underwent surgery (median not reached vs 18 months, p=0.04).38 improved disease-free survival in 41 patients who received adju-
Based on the conflicting results from multiple retrospective studies, vant chemotherapy with etoposide-platinum or irinotecan-platinum
the role of surgery for early-stage neuroendocrine tumors seems (HR 0.27, 95% CI 0.10 to 0.69). Also, adjuvant chemotherapy after
unclear, but certainly surgery alone without adjuvant chemotherapy surgery reduced extra-pelvic recurrences with an OR of 0.37 (95%
and/or radiation is not appropriate for any patient with high-grade CI 0.13 to 0.99, p=0.047). A trend toward improved overall survival
neuroendocrine carcinomas of the cervix. was also observed when adjuvant chemotherapy was given, but
Chemotherapy was not statistically significant (HR 0.39, 95% CI 0.15 to 1.01). Lee
Unlike the role of surgery for patients with neuroendocrine tumors, et al43 reported on a trend in favor of post-operative chemotherapy,
the role of chemotherapy is well established. There is no standard and concluded that primary radical surgery followed by adjuvant
chemotherapy regimen, but due to its pathologic appearances chemotherapy is the preferred treatment modality for patients with
and clinical behaviors similar to small-cell lung cancer, almost all early-stage disease.
patients with small-cell cervical cancer receive platinum and etopo- Regarding the number of cycles of adjuvant chemotherapy, Pei
side as part of their primary therapy.13 For early-stage disease, et al44 retrospectively evaluated 92 patients with stage I-II small-
SGO and GCIG guidelines recommend that patients with complete cell carcinomas and found that adjuvant chemotherapy with
surgical resection undergo adjuvant chemotherapy.32 41 Zivanovic cisplatin and etoposide for at least five cycles was associated with
et al7 reported on 11 patients with early-stage disease (stage improved 5-year recurrence-free survival compared with other
IA2-IB2). Of the 11 patients, seven recurred with 86% of patients treatments (68% vs 21%, p<0.001). On multivariate analysis, nodal
having distant recurrence. The 3-year distant recurrence-free disease (p<0.003), parametrial extension (p<0.03), and cycles of

990 Salvo G, et al. Int J Gynecol Cancer 2019;29:986–995. doi:10.1136/ijgc-2019-000504

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etoposide-cisplatin (cisplatin-etoposide <5 cycles: p<0.001 and no chemoradiation with concurrent cisplatin and etoposide. Chemo-

Int J Gynecol Cancer: first published as 10.1136/ijgc-2019-000504 on 1 July 2019. Downloaded from http://ijgc.bmj.com/ on August 20, 2020 by guest. Protected by copyright.
chemotherapy: p<0.004) were independent prognostic factors for therapy regimen consists of cisplatin 60 mg/m2 on day 1 and
disease recurrence. etoposide 100 mg/m2 on days 1–3 every 21 days. We decrease the
dose of etoposide from 120 to 100 because of the potential toxicity
Pelvic Radiation with concurrent radiation. Patients receive two cycles as concur-
A retrospective study including 68 patients with stage IB1-IIA rent chemotherapy, and two to four additional cycles after radia-
disease reported by Lee et al43 suggested that radical hysterec- tion is completed. Ideally, we aim for patients to be able to receive
tomy followed by adjuvant chemotherapy might be sufficient, as a total of six cycles. In order to decrease the treatment morbidity
the patients who received chemoradiation did not seem to have a associated with post-operative radiotherapy, we only perform SLN
better outcome. In a Japanese multicenter study, the risk of pelvic mapping and not a full lymphadenectomy when bilateral mapping
recurrences after surgery were lower if patients received post-op- is achieved (Figure 2).
erative radiation (16%) versus patients who did not undergo radi-
ation (25%) but the difference did not reach significance (OR 0.61,
95% CI 0.16 to 2.01).11 Data from MD Anderson Cancer Center Prophylactic Cranial Radiation
showed that the most common sites for first recurrence are outside As treatment for small-cell cervical cancer is derived from the liter-
the pelvis: 38% in the lungs, 34% in the liver, and 25% presenting ature on small-cell lung cancer where prophylactic brain irradiation
as carcinomatosis.38 Brain recurrence was seen in 25% of patients, is commonly used for occult metastases, the use of this approach in
and always in the setting of concurrent lung or liver metastases. If cervical small-cell tumors has been explored. Weed at al reported
patients received radiation therapy, only 21% had in-field recur- in 2003 that 25% (2/8) of patients with apparent early-stage small-
rences. cell cervical cancer developed brain metastases and therefore
There seems to be agreement for early-stage disease that chemo- they proposed prophylactic cranial radiation.45 However, neither
therapy is a key component of treatment, but there are conflicting routine brain CT nor cranial radiation are recommended by the SGO
data on the role of combined surgery and chemoradiation. guidelines on initial evaluation of asymptomatic patients for small-
Protocol at MD Anderson Cancer Center for early-stage disease cell tumors. In their 14-year retrospective experience Hoskins et
(tumors ≤4 cm) and negative nodes on pre-operative imaging is al found no cranial metastases.35 Data from MD Anderson Cancer
open radical hysterectomy and sentinel lymph node (SLN) biopsies. Center showed that brain metastases were mostly found (7/8
Post-operatively, our treatment recommendations include adjuvant patients, 86%) when other organ metastases were found.46 47

Figure 2  High-grade neuroendocrine cervical carcinoma primary treatment algorithm.*FIGO 2018 stage **If possible six
cycles of chemotherapy, with a minimum of four cycles total. PLND, pelvic lymph node dissection; SLN mapping, sentinel
lymph node mapping.

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As part of our primary treatment plan, we do not perform prophy- disease extent. The 3-year disease-free survival rate was 55% and

Int J Gynecol Cancer: first published as 10.1136/ijgc-2019-000504 on 1 July 2019. Downloaded from http://ijgc.bmj.com/ on August 20, 2020 by guest. Protected by copyright.
lactic whole-brain radiation for asymptomatic patients. recurrences were unlikely after 3 years.39
An abstract presented at55 by Bajaj et al56 reported on 73 patients
Fertility-Sparing Surgery with small-cell cervical carcinoma stage IB2-IVA treated with
With a median age at diagnosis for cervical neuroendocrine tumors chemoradiation at seven centers in the United States. The median
of 37 (range 24–77) years, fertility preservation may be a concern follow-up time was 19 months with 66% of patients having had
both for patients and physicians.46 The two primary issues in this a recurrence. Median time to recurrence was 10 months. Recur-
patient population are ovarian function (both hormonal and repro- rence was associated with current smoking (HR 3.32, p<0.01), total
ductive function) and uterine preservation. As it pertains to the equi-effective dose (EQD2) <50 Gy vs 71–80 Gy (HR 3.3, p=0.07),
question of ovarian preservation and maintaining ovarian function and no brachytherapy (HR 1.5, p=0.25). Brain recurrences were
in patients with locally advanced disease, one may consider ovarian seen in 15% of patients. A decreased hazard of brain recurrence was
transposition. However, even when doing so, after external beam associated with brachytherapy (HR 0.05, p<0.01), total equi-effec-
pelvic radiation and/or brachytherapy, ovarian preservation is only tive dose (EQD2) >75 Gy (HR 0.11, p=0.04), and cisplatin and etopo-
maintained in 65% of patients.48 In addition, particularly in patients side versus cisplatin alone (HR 0.35, p=0.23). Overall survival for
with neuroendocrine tumors, there are theoretical concerns all patients was 48%, favoring concurrent chemoradiation followed
regarding residual microscopic disease in the ovary. by adjuvant chemotherapy versus concurrent chemoradiation only
(HR 0.49, p=0.10). The number of cycles (cisplatin-etoposide) was
There are no data to support the consideration of fertility pres-
associated with improved overall survival (HR 0.45, p=0.01) and
ervation, such as simple conization or radical trachelectomy, in
decreased recurrence (HR 0.67, p=0.07). Patients receiving cispla-
patients with early-stage disease. Although fertility-preserving
tin-etoposide had improved overall survival (59% vs 44%) and a
surgeries have been reported in women with early-stage small-
lower recurrence rate (65% vs 74%) compared with those receiving
cell cervical cancer,49–51 uterine preservation fertility-sparing treat-
cisplatin only. Robin et al57 identified 100 patients in the National
ment is not recommended by the National Comprehensive Cancer
Cancer Data Base (NCDB) with locally advanced non-metastatic
Network (NCCN) guidelines for cervical neuroendocrine tumors.52
neuroendocrine cervical cancer that were treated with definitive
Given that most patients are likely to undergo post-operative radia-
chemoradiation between 2004 and 2012. In multivariate analysis,
tion therapy it would be unusual to consider fertility-sparing surgery.
the addition of brachytherapy, compared with external beam radio-
Our approach at MD Anderson Cancer Center is to delay starting
therapy alone, was associated with an improved median survival
treatment for 2 to 3 weeks in order to allow for ovarian stimula-
of 49 vs 22 months (HR 0.48, 95% CI 0.25 to 0.88). There was no
tion and egg retrieval. However, ovarian transposition at the time
difference in overall survival for patients treated with neoadjuvant
of radical surgery when the plan is for post-operative radiation
chemotherapy versus patients who received chemotherapy started
or prior to definitive chemoradiation for locally advanced disease
concurrently with radiation (HR 0.85, 95% CI 0.48 to 1.50).
seems reasonable if the ovaries appear grossly normal intra-oper-
For women with stage IB3-IVA (FIGO 2018) disease or non-sur-
atively. For young women (<50 years old) who are ultimately made
gical candidates, our recommendation at MD Anderson Cancer
menopausal by surgical and/or radiation therapies, we recommend
Center is chemoradiation with cisplatin and etoposide followed by
starting hormone replacement therapy. We strongly recommend
additional chemotherapy with cisplatin and etoposide for a total of
against any uterine-preserving surgeries such as simple conization,
four to six cycles (two cycles with radiation and two to four cycles
simple trachelectomy, or radical trachelectomy.
after radiation completed) with a goal of six total cycles. For women
with stage IVB disease, palliative chemotherapy with cisplatin and
Locally Advanced Disease etoposide is recommended (Figure 2).
The SGO guideline recommendation for locally advanced disease
or non-surgical candidates is a combination of chemotherapy (plat-
inum and etoposide) and radiation.32 The most commonly used
regimen of cisplatin and etoposide is usually given with cisplatin at Recurrent Disease
60 to 80 mg/m2 on day 1 and etoposide at 80 to 120 mg/m2 on days First Recurrence
1 to 3 every 21 to 28 days.53–55 Carboplatin may be substituted for For patients with recurrent disease, there is limited consensus
cisplatin. Other regimens such as paclitaxel and cisplatin, paclitaxel on the optimal treatment approach with no standard treatment
and carboplatin, and the combination of vincristine, cisplatin, and protocols, and both the SGO and GCIG recommend individualized
bleomycin have also been reported. treatment.32 41 Often the standard choices include single-agent
Hoskins et al35 first reported that cisplatin and etoposide could topotecan, irinotecan, paclitaxel, or docetaxel as these regimens
be safely administered concurrently with radiation, with additional are commonly used to treat recurrent small-cell lung cancer. Our
cisplatin and etoposide given after completing radiation (chemora- experience at MD Anderson Cancer Center showed that these
diation followed by chemotherapy). A combined modality approach single-agent regimens had very low activity in patients with recur-
of chemoradiation followed by chemotherapy showed that for rent neuroendocrine cervical cancer.
stage IB-IVB, concurrent chemoradiation with ≥5 cycles of cispla- Our regimen of choice for patients with recurrent or progres-
tin-etoposide was associated with improved 5-year disease-free sive disease who have already been treated with a platinum
survival (63% vs 13%, p=0.025) and overall survival (75% vs 17%, and etoposide combination is a triplet regimen including topo-
p=0.016).42 Distant disease recurrence was the most common type tecan, paclitaxel, and bevacizumab given in the same manner
of recurrence (28%) and clinical outcome correlated with initial as in Gynecologic Oncology Group (GOG) 240, a phase III study

992 Salvo G, et al. Int J Gynecol Cancer 2019;29:986–995. doi:10.1136/ijgc-2019-000504

 Review Article

in patients with recurrent cervical cancer (squamous cell carci- m2 on days 1–3), paclitaxel (175 mg/m2 on day 1), and bevaci-

Int J Gynecol Cancer: first published as 10.1136/ijgc-2019-000504 on 1 July 2019. Downloaded from http://ijgc.bmj.com/ on August 20, 2020 by guest. Protected by copyright.
noma, adenocarcinoma, and adenosquamous carcinoma).58 The zumab (15 mg/kg on day 1 on a 21-day cycle) (the 'Texas Cock-
rationale for this schema is that first this regimen is tolerable in tail'). As part of our strategy for treating patients with recurrent
women who have previously undergone definitive chemoradiation. disease, we order molecular testing, PD-L1, and mismatch repair
In addition, as single-agent paclitaxel or topotecan are active and proteins (MLH1, MSH2, MSH6, and PMS2) testing at the time of first
frequently used in recurrent small-cell lung cancer, the combina- recurrence. We use our own institutional platform or other outside
tion would presumably be equally as active, and potentially more providers that offer similar mutational analyses (eg, Foundation
active than the single-agent regimens. Third, small-cell cervical Medicine or Caris). As most patients with recurrence will eventually
cancers express the vascular epithelial growth factor receptor have progressive disease, this testing allows us to triage patients to
over 95% of the time supporting the addition of bevacizumab as a targeted therapy either on-protocol or off-label (Figure 3).
an active agent.24 Finally, all three drugs have been approved by
the US Food and Drug Administration for the treatment of recur- Multiple Recurrences
rent cervical cancer, thus reimbursement is usually not a concern. Immune checkpoint inhibitors and targeted therapies may be bene-
Our results with the three-drug combination were published in the ficial when patients have suffered multiple recurrences; however,
largest series of chemotherapy treatments for women with recur- the literature is limited in this setting with only three case reports
rent neuroendocrine cervical carcinoma.59 Thirteen patients who published to date. Paraghamian et al used nivolumab in a patient
received topotecan, paclitaxel, and bevacizumab were compared with recurrent, metastatic, programmed cell death ligand-1
with 21 patients receiving other regimens, mostly platinum-based (PD-L1)-negative small-cell neuroendocrine cervical carcinoma,
regimens with or without taxane. The triplet regimen was associ- who experienced a complete response.60 Sharabi et al61 reported a
ated with a significant improvement in outcome. Median progres- patient with metastatic, chemotherapy-refractory neuroendocrine
sion-free survival was 8 months versus 4 months for the triplet carcinoma with bowel obstruction due to a large tumor burden.
regimen and other regimens, respectively (HR 0.21, 95% CI 0.09 Liquid biopsy demonstrated a high number of tumor mutations. The
to 0.54). Median overall survival was 9.7 months for the triplet patient was treated with radiotherapy combined with nivolumab
regimen and 9.4 months for patients receiving other regimens (HR and experienced a near-complete systemic resolution of disease
0.53, 95% CI 0.23 to 1.22). For the triplet regimen, 62% of patients for at least 10 months. Our experience with checkpoint inhibi-
received treatment for >6 months and 31% for >12 months versus tors, however, has been disappointing with no responders (article
19% and 10% of those who received other regimens, respectively. in preparation). As mentioned above, high-grade neuroendocrine
For first recurrence, patients at MD Anderson Cancer Center are cervical tumors are almost always PD-L1-negative and microsatel-
typically treated with the three-drug regimen topotecan (0.75 mg/ lite-stable so checkpoint inhibitors should be used with caution.30

Figure 3  High-grade neuroendocrine cervical carcinoma management algorithm for first recurrence. MRI, magnetic resonance
imaging; MSI, mismatch repair proteins (MLH1, MSH2, MSH6, PMS2); PET/CT, positron emission tomography/computed
tomography.

Salvo G, et al. Int J Gynecol Cancer 2019;29:986–995. doi:10.1136/ijgc-2019-000504 993

Review Article

Lyons et al62 used the mitogen-activated protein kinase 1 (MEK)-in- References

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Competing interests  None declared. 24. Tangjitgamol S, Ramirez PT, Sun CC, et al. Expression of HER-2/neu,
Patient consent for publication  Not required. epidermal growth factor receptor, vascular endothelial growth factor,
cyclooxygenase-2, estrogen receptor, and progesterone receptor
Provenance and peer review  Commissioned; internally peer reviewed. in small cell and large cell neuroendocrine carcinoma of the uterine

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 Review Article

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