J Huazhong Univ Sci TechnolMed Sci

DOI 10.1007/s11596-010-0554-x
30(5):626-630,2010
J Huazhong Univ Sci TechnolMed Sci 30(5):2010

626

Clinicopathological Features and Prognosis of Small Cell Carcinoma of

the Cervix*
Jie LIU ( )1, Yuan LI ( )2, Shuang LI ( )3 , Dan WANG ( )3, Ting HU ( )3, Yuhan MENG ()3,
Ding MA ( )3, Hongbing CAI ()4, Zehua WANG ()5, Chengliang XIONG ()1,
Huiping ZHANG ()1#
1
Reproductive Medicine Center, Research Institute for Family Planning of Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China
2
Grade 2006, Tongji Medical College, Huazhong University of Science and Technology, 430030, China
3
Tumor Molecular Biology Center, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, 430030, China
4
Department of Obstetrics and Gynecology of Zhongnan Hospital, Wuhan University, 430060 Wuhan, China
5
Department of Obstetrics and Gynecology, Xiehe Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2010

Summary: Small cell carcinoma of cervix (SCCC) is a rare disease with highly aggressive behaviour
and is pathologically hard to diagnose. In this study, the clinicopathological features, diagnosis,
treatment and prognosis of the condition were examined. Clinical records and follow-up data of 7
cases of SCCC were retrospectively studied. Our results showed that five non-recurrent cases initially
presented irregular vaginal bleeding or increased apocenosis of varying degrees. Pathological examination revealed that the stroma was diffusely infiltrated with small monomorphous cells ranging from
round to oval shape. Three cases were immunohistochemically confirmed. One case was accompanied with squamous cell cancer. Of the 7 cases, one case was classified as stageb1, two stageb2,
one stage a, one stage b, and one stage b. On the basis of their stages of condition, one subject
with stage III b underwent chemotherapy, and one with stage Ib2 received extensive hysterectomy
plus pelvic lymphadenectomy, while the other 5 cases were treated by extensive hysterectomy and
pelvic lymphadenectomy in combination with pre- and/or post-operative adjuvant chemotherapy and
radiotherapy. Of the 7 patients, 4 had relapse-free survival of 14, 14, 16 and 28 months respectively.
It is concluded that SCCC is an aggressive tumor with propensity for early pelvis lymph node metastases. Early-stage patients should be treated by extensive hysterectomy and pelvic lymphadenectomy
in combination with pre- and/or post-operative adjuvant chemotherapy and radiotherapy.
Key words: cervix; small cell carcinoma; clinicopathological features; prognosis

Small cell carcinoma of cervix (SCCC) is a rare and

unique neuroendocrine tumor primarily located in the
cervix, representing approximately 1%6% of all cervical cancers[1, 2]. It is one of the most aggressive gynecological malignancies. On the basis of retrospective
analysis of clinical data of 7 patients with SCCC, this
paper examined the clinicopathological features, prognostic factors and treatment of SCCC to help better understand this special gynecologic neoplasm.

1 MATERIALS AND METHODS

1.1 General Data
From July 2003 to October 2007, 7 patients diagJie LIU, E-mail: liujie.8383@yahoo.com.cn
#
Corresponding author: E-mail: zhpmed @yahoo.com.cn
*
This project was supported by a grant from the Program of
Scientific Innovation of Huazhong University of Science and
Technology (No. HF-05-035-07-540).

nosed as having small cell carcinoma of the uterus and

treated at Tongji Hospital, Tongji Medical College of
Huazhong University of Science and Technology,
Zhongnan Hospital of Wuhan University and Xiehe
Hospital of Tongji Medical College under Huazhong
University of Science and Technology (All institutions
are located in Wuhan, China). All biopsies were
re-examined and confirmed by a single pathologist. Patients were aged 2456 y with an average age of 39 y, of
which one patient had no childbearing history. In accordance with staging method of International Federation of
Gynecology and Obstetrics (FIGO) in 1994, one case
was categorized as SCCC stage b1, 2 were classified
as stage b2, 2 stage a and 1 was at stage b and 1
stage b.
Of the 7 cases, 2 presented with irregular vaginal
bleeding (28.6%), 1 case with vaginal discharge (14.3%),
2 with both contact bleeding and vaginal discharge
(28.6%). The other 2 cases had cervical cancer recurrence after receiving surgery and chemotherapy (28.6%).
The results of cervical biopsy under colposcopy revealed

627

J Huazhong Univ Sci TechnolMed Sci 30(5):2010

no evidence of systemic endocrine disorders in the series.

The cervical examination revealed erosion in 1 case, 2
nodular change in 2, and local cauliflower-like change in
1. In 4 of the 5 cases of primary tumors, their lesions
measured 4 cm in diameter and <4 cm in 1. One recurrent case presented with no secondary foci, and the other

Case

Age
(year)

38

36

24

42

28

49

56

6 non-recurrent cases showed mucosal thickening at the

right side of vaginal residue and anterior vaginal wall,
with a cord-like nodule measuring about 522 cm, adjacent to the right ilium (table 1). In the 7 SCCC patients,
follow-up data was available in 4, with their follow-up
time lasting for 1428 months, ended on Dec. 31, 2008.

Table 1 Clinical and pathological data of 7 cases of small cell carcinoma of the cervix
Clinical
Gross apClinical
Immunohistosymptoms
Pathology
Treatment
pearance
stage
chemistry
and signs
Extensive uterus
Irregular
Cauliflower
resection with
bleeding for
-like,
b2
SCCC

pelvic lymone month

3 cm4 cm
phadenectomy
Vaginal
SCCC
Chemotherapy
Nodular,
discharge
with
+ surgery
diameter 7
b
Syn (+) NSE (+)
for over 4
squamous
+ chemotherapy
cm
months
carcinoma
+ radiotherapy
Brittle and
Irregular
Undiffereasily bleedbleeding for
entiated

Chemotherapy
b
ing,, diameter
6 months
SCCC
5 cm
Vaginal
Off-white
discharge,
nodular,
as well as
Surgery
1.5 cm1.0
b1
SCCC
Syn (+) NSE (-)
+ chemotherapy
bloody leucm
corrhea for
3 months
Increasing
Cauliflower
and bloody
Chemotherapy
-like,
Syn (+) CD56
vaginal
+ surgery
b2
SCCC
diameter 4
(+)
+ chemotherapy
discharge
cm
for 1 month
Surgery
After a

a
SCCC

+ chemotherapy
stage che+ radiotherapy
motherapy
Over 2 y
after SCCC
Cord-like
chemothernodular, 5
Surgery
cm2 cm2
apy, with

a
SCCC
+ chemotherapy
dysuria for
cm, touched
over 9
at right ilium
months,

1.2 Pathological Features

1.2.1 Gross Observation The cervix size of the SCCC
patients was normal or increased to 56 cm in diameter.
The tumor was located in the cervical canal, showing
cauliflower-like, nodular or erosion-like change, with
moderately rigid texture. The cross-section of the tumor
looked pale, grossly similar to the appearance of common cervical cancer.
1.2.2 Microscopy Under low magnification microscope,
the tumor distribution assumed island-like, flake-like,
cord-like or diffuse pattern. Under high power microscope, the tumor generally showed uniform small round,
oval or fusi-form cells of small size, with scant cytoplasm and hyperchromatic nuclei, fine and rich chromatin and inconspicuous nucleoli. The nuclei were strongly
stained and rich in fine chromatin, with blurred nucleoli.
More cells were at mitotic phase. The cancer cells were

Survival
time
(month)
16, tumor-free
survival

14, tumor-free
survival

28, tumor-free
survival

14, tumor-free
survival

arranged densely in flake, diffusely infiltrating the

stroma (lymphatic lumen) (fig. 1). In case 1, the cells of
the cervix showed extensive necrosis commonly seen in
small cell cancer, without parametrial infiltration or pelvic lymph node metastases. In case 2, the cancer cells
infiltrated into the deep stroma, with the whole parametrial muscular layer being infiltrated, without vascular invasion, and metastastic foci was found outside
the right ilium. In case 4, the carcinoid tumor of the cervix invaded into middle 1/3 of the muscular layer of cervical wall, with cancer cells infiltrating into the deep
stroma. In case 5, the cancer cells infiltrated into the superficial layer of the stroma, without parametrial infiltration, and the small cell carcinoma invaded into the inner
1/3 of cervical wall, with vascular invasion and one metastastic focus was found at left obturator lymph node. In
case 6, there were metastases in two pelvic lymph nodes.

628
In case 7, the poorly differentiated SCCC infiltrated into
the deep layer of stroma, without parametrial infiltration,
with the whole muscular layer infiltrated, without vascu-

J Huazhong Univ Sci TechnolMed Sci 30(5):2010

lar invasion and pelvic lymph node metastases. One case

was complicated with squamous cell carcinoma.

Fig. 1 Microscopic features of small cell carcinoma of the cervix

A: Tumor cells were arranged in trabecular pattern, with oval oncocytes, scanty cytoplasm, hyperchromatic nuclei, inconspicuous nucleoli and numerous mitotic figures (HE200); B: Ditto (HE400); C: Cancer embolus formed in tumor lymphatic vessel due to cancerous invasion, with monomorphous round cancer cells diffusely infiltrating into lymphatic lumen
(HE400); D: Tumor cells with CD56 (+) (S-P400); E: tumor cells with CgA (+) (S-P400); Tumor cells with PCK (+)
(S-P400); G: Tumor cells with Syn (+) (S-P400); H: Tumor cells with NSE () (S-P400)

1.2.3 Immunohistochemistry The immunohistochemical examination (S-P staining) was employed for the
specimens from three cases of our series. The relevant
markers for neuroendocrine cell included neuron-specific
enolase (NSE), chromogranin A (CgA), synaptophysin
(Syn) and neural cell adhesion molecule (CD56) and the
markers of epithelium, for example: cytokeratin (PCK),
epithelial membrane antigen (EMA) were detected. In
case 2, the markers and the results were as follows: Syn
(+), NSE (+) and EMA (+). In case 4, the markers and
the results included: CD56 (+), CgA (+), PCK (+), Syn
(+) and NSE () (fig. 1). And in case 5, the markers and
the results were: CgA (+), Syn (+), CD56 (+) and PCK
(+).
1.3 Treatment and Prognosis
In our series, 6 patients were surgically treated by
extensive uterus resection plus pelvic lymphadenectomy.
The operation was not performed in one subject with
undifferentiated small cell cancer at b stage, and only
Cape Billiton (TP) chemotherapy was given, and the data
about her survival were lost. The surgical procedures
were performed for 3 patients at b stage, with one undergoing no adjuvant radiation or chemotherapy,
whereas the other two undergoing the EIP [VP-16 (etoposide) + IPO (ifosfamide)+DDP (cisplatin)] or [CPT-11
(Yilin Aitken) +DDP (cisplatin)] chemotherapeutic protocols. During follow-up study, their tumor-free survival
was 16, 14 and 28 months respectively. One patient at
b stage and one recurrent patient at a stage received
local pelvic radiotherapy and systemic chemotherapy,
with chemotherapeutic protocol of PF (DDP+5-Fu
(5-fluorouracil) or PFM [DDP+MMC (mitomycin)+5-Fu], and the survival data were lost. The other
patient at a stage recurred in two years after postoperative chemotherapy, and then underwent PFM
(DDP+MMC+5-Fu) chemotherapy and had a tumor-free
survival of 14 months in follow-up investigation.

3 DISCUSSION
SCCC is a rare gynecological neoplasm with unique
biological behaviors, accounting for approximately
1%6% of all cervical malignancies[1]. Though the incidence is low, it progresses rapidly, is of aggressive nature, with high possibility of recurrence, tends to have
poor prognosis compared with other cervical malignancies[3, 4].
The clinical manifestations and predilection site of
SCCC are similar to squamous carcinoma, but it lacks a
typical precursor lesion, i.e., cervical intraepithelial neoplasia (CIN)[5]. Common symptoms of the cancer include
irregular vaginal bleeding, exudation discharge and pain
at late stage. It is highly aggressive in terms of biological
behaviors. In this study, five patients with primary SCCC
had irregular vaginal bleeding or apocenosis. Although
previous studies demonstrated that, in some SCCC cases,
there was secretion of intracellular hormone, only few
patients had neuroendocrine symptoms, most of them
being Cushing Syndrome caused by the elevated serum
adrenocorticotropin (ATCH)[6]. In our series, no patients
had the syndrome. In addition, compared with common
types of cervical cancer, no obvious differences were
found in age, weight, pregnancy times, race, social and
economic status, tumor size, growth pattern, depth of
stroma infiltration or clinical stage among SCCC patients
[7, 8]
. Atypical SCCC tends to be confused with cellular
squamous cell carcinoma, embryonal rhabdomyosarcoma,
endometrial stromal sarcoma, non-Hodgkin lymphoma,
etc. Therefore, to better understand the features of SCCC
will help us to achieve early diagnosis and treatment.
In terms of biological behaviors, SCCC cells tend to
secrete a variety of hormones, such as 5-HT and adrenocorticotropic hormones, diffusely infiltrate the stroma,
without involving cervical surface epithelia, and usually
yield negative findings on cervical cytological examination. Moreover, CIN is rarely found adjacent to SCCC,

J Huazhong Univ Sci TechnolMed Sci 30(5):2010

as only few tumors are engaged in exophytic or polypoid

growth[9]. Furthermore, the propensity for early lymphatic and vascular invasion as well as distant organ metastases is significantly higher in SCCC than in common
types of cervical cancer. The distant organ metastases
occur mostly in lung, liver, brain, bone, kidney, breast,
pancreas and other organs[10]. In 7 SCCC patients in our
series, 4 had metastases to pelvic lymph node and 2 did
not. The result was unknown in 1 case. The size of local
cervical SCCC lesions is significantly associated with
presence of metastasis to pelvic lymph node and recurrence[7]. Usually, at the time when definite diagnosis of
SCCC is made, the condition is at a late stage, and, its
prognosis is poor as compared with other cervical malignancies. Generally speaking, SCCC is highly aggressive with regard to its biological behaviors. A previous
study showed that the undifferentiated carcinoma of
SCCC was closely related to HPV18 infection[1113].
Herrington et al[14] believed that the absence of expression of pRb immunocompetence was likely to result
from the combination of pRb with E7 protein of HPV
virus, and, in SCCC, the lack of immunocompetence of
pRb was related with the endocrine phenotype of small
cells, which contributes to its aggressive behaviors.
Stoler et al[15] detected the gene expression after in situ
hybridization between HPV and SCCC cells from 20
cases. Their results showed that 18 of them had neuroendocrine differentiation and 14 expressed HPV18
mRNA, strongly suggesting that HPV18 type was intimately related to the neuroendocrine property of SCCC.
Light microscopy is usually employed in combination with immunohistochemical detection to attain more
accurate diagnosis when SCCC is suspected. SCCC possesses no specific features and it may present as polypoid
form or inward infiltration, usually accompanied by superficial ulcer with hemorrhage or necrosis. The tumor
mass is of solid texture and of gray or yellow color.
Under light microscope, the architecture of SCCC
mimics that of small cell carcinoma of the lung. Similar
to small cell carcinoma of lung, SCCC cells are of small
size and uniformly round, oval or fusiform shape, have
scant cytoplasm and relatively big and hyperchromatic
nuclei, are rich in fine nuclear chromatin. More cells
were at mitotic phase. The cancer cells were arranged
densely in flake, diffusely infiltrating the stroma (lymphatic lumen)[16]. These features may help pathologists to
distinguish it from the typical finger-like infiltration of
poorly differentiated squamous cell carcinoma of small
cell[17]. Typical SCCC is usually composed of small cells
or medium-sized cells, with one type being predominant,
and is usually accompanied by necrosis or vascular/
lymphatic infiltration. It is sometimes mixed with multifocal squamous cell carcinoma or adenocarcinoma, including small cells over 60% in ratio, some containing
argentophilic grains[17].
The immunohistochemical marker is an important
tool for diagnosis and differential diagnosis of SCCC.
The commonly used markers include epithelial markers
such as cytokeratin (PCK), epithelial membrane antigen
(EMA) and carcinoembryonic antigen (CEA), and neurological endocrine markers, such as neuron-specific
enolase (NSE), chromogranin A (CgA), synaptophysin
(Syn) and neural cell adhesion molecule (NCAM). In

629
particular, NSE, CgA and Syn are the most important
markers. So far, however, no marker that is both highly
specific and sensitive has been found. Albores-Saavedra
et al[18] believed that CD56 (neural cell adhesion molecule) was the most sensitive marker and in their series
the positive rate was 88% (22/25). In this study, two
markers, Syn and NSE were used for immunohistochemical analysis in three cases, and three cases were
positive for Syn and two were positive for NSE [19, 20].
Compared with common types of cervical cancer,
SCCC has a higher propensity for lymphatic vessel invasion, pelvic lymph node metastases or distant metastases
at an early stage and tends to have a relatively poor
prognosis. Currently it is recommended to use comprehensive treatment (combined use of chemotherapeutic,
radiotherepetic and surgical treatments) for SCCC.
Early-stage patients should be treated by extensive hysterectomy, oophorectomy or pelvic lymphadenectomy,
plus pre- and/or post-operative adjuvant chemotherapy
and radiotherapy, which can improve survival. Late stage
patients not suitable for curative surgery are advised to
receive radiotherapy or chemotherapy, and pre-operative
chemotherapy can facilitate the excision of late local
tumors. Emphasis should be put on chemotherapy in the
treatment protocol. It is believed that chemotherapy can
significantly prolong the survival of early-stage patients.
Compared with local pelvic radiotherapy, systemic chemotherapy can significantly reduce the likelihood of distant metastases, thus improving the prognosis. The chemotherapeutic protocol for SCCC is similar to that for
small cell lung cancer (SCLC) since their biological behaviors and histological types are almost same. In
19801997, based on a comprehensive analysis of English literature on postoperative adjuvant chemotherapy
for 41 patients of SCCC, the 5-year survival rate was
68% in patients treated by VAC or PE protocol, but the
rate was only 33% in subjects not treated by the two
protocols, suggesting that the chemotherapeutic protocol
for SCLC also works for SCCC, and chemotherapy plays
an important role in the comprehensive treatment of
SCCC.
The prognosis of SCCC is disappointing, as the relapse-free interval after treatment usually lasts for less
than 2 years and most patients suffer from relapse within
12 months, and its 5-year survival rate was as low as
14%, according to one previous report[21]. The main factors affecting the prognosis include presence of lymph
node metastases or not, lesion size, clinical stage[22].
Clinical data, however scanty, showed that the survival
in subjects with lymph node metastases or tumor diameter>2 cm would be obviously shortened[23, 24]. Based on
the follow-up data obtained from 4 of 7 cases in our series, all the 4 subjects were alive and among them 3 had
received comprehensive treatment, which might provide
some guidance for the treatment of SCCC.
To sum up, SCCC is a highly malignant neoplasm
that grows fast and tends to relapse after surgical treatment. Our retrospective analysis showed that comprehensive treatment can improve the prognosis of the condition. However, it warrants further prospective
case-control study and Meta-analysis in larger population.

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