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BMC Cancer
Open Access
Research article
The epidemiology and survival of extrapulmonary small cell
carcinoma in South East England, 1970–2004
Yien Ning S Wong*, Ruth H Jack, Vivian Mak, Møller Henrik and
Elizabeth A Davies
Address: King's College London, Thames Cancer Registry, 1st Floor, Capital House, 42 Weston Street, London SE1 3QD, UK
Email: Yien Ning S Wong* - sophiawongyn@gmail.com; Ruth H Jack - ruth.jack@kcl.ac.uk; Vivian Mak - vivian.mak@kcl.ac.uk;
Møller Henrik - henrik.moller@kcl.ac.uk; Elizabeth A Davies - elizabeth.davies@kcl.ac.uk
* Corresponding author
Abstract
Background: Extrapulmonary small cell carcinoma (EPSCC) is a rare cancer and few studies
describe its epidemiology. Our objectives were to compare the incidence and survival of EPSCC in
South East England with small cell carcinoma of the lung (SCLC), to determine the most common
anatomical presenting sites for EPSCC and to compare survival in EPSCC by disease stage and site
of diagnosis.
Methods: We used data from the Thames Cancer Registry database for South East England
between 1970 and 2004 to determine the incidence, most common anatomical sites, and survival
by site, and stage of EPSCC. 1618 patients registered with EPSCC were identified. We calculated
the age-standardised incidence rate for EPSCC using the European standard population and
compared this to that for SCLC. We calculated survival using the Kaplan-Meier method for EPSCC
and SCLC, and reported 3-year survival for different EPSCC anatomical sites and disease stages.
Results: The incidence of EPSCC was much lower than for SCLC, similar in males and females,
and stable throughout the study period, with incidence rates of 0.45 per 100,000 in males and 0.37
in females during 2000–2004. In general, patients with EPSCC had a better 3-year survival (19%)
than SCLC (5%). The most common anatomical sites for EPSCC were oesophagus (18%), other
gastrointestinal (15%), genitourinary (20%), head and neck (11%), and breast (10%). Breast EPSCC
had the best 3-year survival (60%) and gastrointestinal EPSCC the worst (7%).
Conclusion: This study suggests that EPSCC has a stable incidence and confirms that it presents
widely, but most commonly in the oesophagus and breast. Site and extent of disease influence
survival, with breast EPSCC having the best prognosis. Further studies using standardised diagnosis,
prospective case registers for uncommon diseases and European cancer registries are needed to
understand this disease.
Background
Neuroendocrine tumours can be broadly classified into
three groups: well differentiated tumours (true carci-
noids), moderately differentiated tumours (atypical carci-
noids) and poorly differentiated tumours (small cell
carcinomas) [1]. The latter group includes extrapulmo-
Published: 29 June 2009
BMC Cancer 2009, 9:209 doi:10.1186/1471-2407-9-209
Received: 15 October 2008
Accepted: 29 June 2009
This article is available from: http://www.biomedcentral.com/1471-2407/9/209
© 2009 Wong et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
BMC Cancer 2009, 9:209 http://www.biomedcentral.com/1471-2407/9/209
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nary small cell carcinoma (EPSCC) and small cell lung
cancer (SCLC). EPSCC is a rare entity, and in the United
States it accounts for approximately 2.5 to 5% of all small
cell carcinomas [2-4]. The term came into use in the 1990s
and various descriptions including "oat cell" and
"extrapulmonary oat cell carcinoma" have been used
since the 1970s. The first description by Duguid and
Kennedy in 1930 was of the disease occurring in the medi-
astinum [5], and since then EPSCC has been reported to
have arisen in virtually every site of the body [3,5-7].
EPSCC often presents with a mixed morphology of small
cell carcinoma and various other epithelial cell types. It is
now widely accepted that it derives from a pluri-potent
stem cell that develops neuroendocrine features [8], rather
than the initial speculation of its origin being from the
Amine Precursor Uptake and Decarboxylase (APUD)
cells. There is also recent molecular evidence that small
cell neoplasms may occur as a late-stage phenomenon in
genetically associated organ-typical carcinomas [9].
Despite these new findings, EPSCC is still poorly appreci-
ated and clinically it may be confused with metastases
from SCLC.
The prognosis of patients with EPSCC is generally unfa-
vourable as is the case for those with SCLC. This is due to
an aggressive natural history of EPSCC – a course charac-
terised by rapid local progression, early, widespread
metastases and recurrence after treatment [3]. The epide-
miological and clinical literature describing EPSCC is rel-
atively limited. One of the most recent and largest studies
reported a series of 101 patients and found an overall
median survival of 9.83 months after diagnosis [6].
Although there are a number of single institution studies
of EPSCC [10,11] we are not aware of any large scale Euro-
pean population-based studies. The present study aimed
to gain a better understanding of the incidence and out-
come for this under-recognised clinicopathogical entity,
by using the database of the Thames Cancer Registry for
South East England to obtain new information on EPSCC.
Registry datasets are potentially an efficient initial way of
using existing information before undertaking a more spe-
cific and extensive clinical study of an uncommon cancer.
Our objectives were to 1) compare the incidence and sur-
vival of EPSCC with that for SCLC (a related but more
common neuroendocrine tumour), 2) determine the
most common anatomical presenting sites for EPSCC,
and 3) compare survival in EPSCC by disease stage and
site of diagnosis. We hoped the study might stimulate fur-
ther clinical and epidemiological studies investigating this
disease.
Methods
Data
In the United Kingdom cancer registries record the occur-
rence of cancer in their residential populations. Registry
data and analyses are held in publically funded data
repositories and can be requested by researchers, clini-
cians, health care organisations, governments and the
public. However this is subjected to ethical approval
depending on the level of data requested. The Thames
Cancer Registry (TCR) was originally established in 1960
as the South Thames Metropolitan Cancer Registry. This
was a population-based registry covering the areas of
South London, Kent, Surrey, Sussex and Wessex. In 1971–
2 Wessex was excluded from the area and in 1985 the
Thames Cancer Registry (TCR) was named and its area
extended to cover North Thames areas including Essex,
Hertfordshire and Bedfordshire. In 1996 Bedfordshire was
excluded and by 2004 it covered an area of South East
England including a population of 14 million people liv-
ing in London, Essex, Hertfordshire, Kent, Surrey and Sus-
sex. This study included cases from South London, Surrey,
Sussex and Kent for the period 1970–1984 and from
1985–2004 it also included cases from North London,
Hertfordshire and Essex. These well-defined areas have
complete registration coverage for each time period and
are recorded in TCR reports. In this area registration is
now initiated by clinical and pathology information
received from hospitals and by information about deaths
provided by the National Health Service Central Register
through the Office for National Statistics. Trained data
collection officers collect information from the medical
records on demographic, tumour details and on treat-
ments received in the first six months after diagnosis. This
includes the date of the first surgery, radiotherapy, chem-
otherapy and hormonal therapy. These data are added to
a central database, quality assured and continually
updated. Data on clinical performance status is routinely
recorded in the UK in some clinical datasets for common
cancers, but not yet in clinical practice or by the cancer
registration system and was therefore not available for
analysis.
During the Registry's history the data collection methods
used (in line with those for other UK registries) have
evolved from manual methods of recording information
from medical records and copies of death certificates to an
increasingly electronic transfer of pathology records from
hospitals and death certificate data. Pathology reports
have remained the main source of the diagnostic informa-
tion since its inception. Only very occasionally will a path-
ological diagnosis be queried during the quality assurance
process, and validation studies on the diagnoses made by
pathologists are not routinely performed. The rate of mis-
classification of diagnoses is therefore unknown. Data on
an unusually rare diagnosis like EPSCC are very likely to
have been recorded from a pathology report and only very
occasionally based on information from a death certifi-
cate. During some periods of the study the rate of registra-
tions made in the TCR by death certificate only (DCO)
was as high as 25%, leading some investigators to ques-
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tion the accuracy of survival figures calculated when these
cases were excluded [12]. A recent study showed that the
DCO rates declined substantially between the period
1990–4 and 1997–2001 across all sites [13]. The overall
rate for 2004 data was 5% [14]. There is concern about
comparing survival over area or time periods where DCO
rates vary [13]. However, incidence and survival calcula-
tions for EPSCC are unlikely to be influenced unduly by
varying DCO rates throughout the study because of the
reliance on pathology reports.
Selection of patients
The ICD-O morphology codes for small cell carcinoma
(8041/3), oat cell carcinoma (8042/3), small cell carci-
noma, fusiform cell (8043/3), small cell carcinoma, inter-
mediate cell (8044/3), and combined small cell
carcinoma (8045/3) were used to identify cases for the
study. Using these definitions, data on a total of 29128
patients registered with small cell carcinoma between
1970 and 2004 were extracted from the database. Of
these, 1618 (702 men and 916 women) were found to be
diagnosed with EPSCC (5.8%). This group therefore
excluded SCLC, secondaries and Merkel cell carcinomas of
the skin. We also excluded data on patients diagnosed
before 1970, as we were less certain about the reliability of
diagnoses before this point. After this point we included
all patients with this diagnosis and did not exclude any
patients with missing data items.
Anatomical site and disease stage
To determine the most common anatomical sites the data
were grouped into the following main sites: head and
neck, gastrointestinal tract, chest, breast, genitourinary
tract, unknown primary of lymph nodes and others.
Within these groups the data were further divided by indi-
vidual site. The staging data received from hospitals by the
Registry are not always complete, and a simplified scheme
was therefore used for this study, taking into account all
the information available. This defined three groups – 1)
"limited disease" (a tumour confined to the primary site
with or without local lymph node involvement), 2)
"extensive disease" (any indication of disease spread
beyond local boundaries) and 3) "unknown" (not
recorded or not known). Detailed information on treat-
ment protocols was not available, has changed during the
study period and many of the site groups still include rel-
atively small numbers of patients. We therefore decided
not to present treatment analyses in this study.
Statistical analyses
Age-standardised incidence rates for EPSCC and SCLC per
100,000 population were calculated using the European
standard population for each five years of diagnosis to
allow comparison with any future studies in the European
region. These were plotted using a logarithmic scale to
accommodate the large difference between them. Crude
survival was measured from the time of diagnosis to the
date of death or to the study censor date of 31/12/2004,
and calculated using the Kaplan-Meier method. The crude
overall survival of patients with EPSCC was compared to
those with SCLC. Within the EPSCC group survival was
then compared by stage of disease and by anatomical site.
Due to the relatively small number of patients reaching
five years for some sites in some of the analyses we only
report the 3-year survival rates.
Ethical Approval
Cancer registries in England carry out cancer surveillance
using the data they collect under Section 60 of the Health
and Social Care Act 2002. The study used an anonymised
dataset and separate ethical approval was not required.
Results
The incidence and survival of EPSCC and SCLC
Figure 1 shows the age-standardised incidence rates for
SCLC and EPSCC in South East England between 1970
and 2004. The incidence of SCLC remained higher in
males than in females although it declined in males and
increased in females during the study period. By 2000–
2004 the incidence of SCLC was 6.72 per 100,000 in
males and 4.15 per 100,000 in females. That for EPSCC
was stable throughout the study period and was 0.45 per
100,000 during 2000–2004 in males and 0.37 in females.
This represents a 15-fold difference in incidence between
the two diseases.
Figure 2 shows that patients with EPSCC had a better 3-
year survival (19%) than those with SCLC (5%).
Age-standardised incidence rates (ASR) per 100,000 for EPSCC and SCLC in South East England, 1970–2004Figure 1
Age-standardised incidence rates (ASR) per 100,000
for EPSCC and SCLC in South East England, 1970–
2004.
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The median age at diagnosis for patients with EPSCC was
70 years (range, 0–85 years while that for SCLC was 65
years (range 20–85). The male: female ratio was 1:1.3 in
EPSCC compared to 1.7:1 in SCLC. Table 1 shows that for
EPSCC the most common presenting sites were gastroin-
testinal tract (33%), genitourinary tract (20%), head and
neck (11%), and breast (10%). Oesophagus (18%, 293/
1618) and breast (10%, 167/1618) were the two most
common locations. As expected the rate of registrations
made from death certificate only (DCO) is very generally
low (1–3% for specific sites), suggesting that these patho-
logical diagnoses and their registrations are nearly always
made before death.
Figure 3 shows that patients with limited disease at diag-
nosis had a better overall 3-year survival (28%) than those
with extensive disease (9%) (median survival 1 year com-
pared to 0.28).
Figure 4 shows the survival after the diagnosis of EPSCC
by disease site. The 3-year survival for the site groups were
as follows: breast (60%), genitourinary system (23%),
unknown primary of lymph nodes (22%), head and neck
(16%), others (11%), chest (8%) and gastrointestinal
(7%).
Discussion
This study of 1618 patients registered with EPSCC in
South East England is one of the largest studies so far pub-
lished on this clinicopathological entity. Our findings
confirm its rare nature in contrast to SCLC, which is a
more widely studied and recognised cancer. There was a
15-fold difference in incidence between the two diseases.
The incidence of EPSCC between 2000 and 2004 was 0.45
per 100,000 in males and 0.37 per 100, 000 in females
and remained stable throughout the study period. This
stable incidence and very little difference between the
sexes in EPSCC suggest that its aetiological factors are
more likely to be genetic and developmental rather than
environmental, although this finding needs to be con-
firmed by other epidemiological studies. By contrast
although the incidence of SCLC remained higher in males
than females, it declined in males and increased in
females reflecting different smoking patterns that are a
known risk factor for the disease. Although we have com-
pared EPSCC and SCLC to show the differences between
them, they could be conceptualised as part of the same
disease. The possibility that EPSCC may be a non-pulmo-
nary cause of exposure to carcinogens related to smoking
at lower doses has not often been considered. One Turk-
ish study [15] suggested that fewer patients with EPSCC
were smokers than with SCLC but it included only nine
patients with EPSCC. A larger case control study should be
undertaken to investigate this hypothesis more thor-
oughly.
In our study we found that the gastrointestinal (33%) and
genitourinary (20%) tracts were the most common sites
involved, whereas the oesophagus (18%) and breast
(10%) were the two major organs affected. We also found
a male-to-female ratio of 1:1.3, which differs from most
other published studies, that find males are more com-
monly affected [6,16]. Previous studies have reported sim-
ilar results to ours with the most common primary disease
sites being oesophagus, breast, cervix, colon and rectum,
head and neck and urinary bladder, although the most
common site varies by study [3,6,7,16-18].
Our study found that the survival of EPSCC was higher
(19%) than for SCLC (5%). Our analyses suggest that
within EPSCC disease site is an important predictor of sur-
vival, with breast EPSCC standing alone as being associ-
ated with a better outcome compared to the rest of EPSCC
as shown in Figure 4. Haider et al reported that patients
with EPSCC of the breast had a good prognosis (median
overall survival, 40.9 months) [6], and this trend was seen
in patients with breast and genitourinary disease in other
studies [6,7,16,19,20]. Generally these sites had a better
survival than EPSCC of other sites. Similarly, in our study
we found patients with gastrointestinal disease had the
worst prognosis. Brenner et al also reported that the
median survival of patients treated for EPSCC of the gas-
trointestinal tract ranged from 6 months to 12 months,
and that very few patients survived in the longer term [21].
The overall 3-year survival of 30% for patients with lim-
ited disease and 10% for those with extensive disease is
discouraging. The favourable outcome of 60% 3-year sur-
vival for patients with breast EPSCC compared to those
with other sites may be attributed to earlier stage at pres-
entation, since the majority of breast EPSCC in this study
was limited stage disease. This may be due to the effect of
Crude survival for patients with EPSCC and SCLC in South East England, 1970–2004Figure 2
Crude survival for patients with EPSCC and SCLC in
South East England, 1970–2004.
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the National Health Service (NHS) breast screening pro-
gramme, introduced in 1988 [22], and the development
of more effective treatments for breast cancer. Unfortu-
nately data on screen-detected breast cancer is not availa-
ble since the inception of the programme to test this
hypothesis or to determine whether those detected
through screening had a better prognosis. We do know
that the incidence of breast cancer in England and Wales
has increased during this period, in part due to the screen-
ing programme [23].
Despite being one of the largest series of patients so far
there are several limitations to our study. The selection of
cases was not based on a review of the pathology of cases.
It is possible that some of the cases were misclassified sec-
ondaries from SCLC. This is most likely to be the case for
EPSCC in the chest, and we have not analysed these cases
separately. Conversely it is possible that cases of EPSCC
were misdiagnosed by pathologists and not registered cor-
rectly, but the extent of any such misclassification is
unknown. However, the steady rate of ascertainment of
EPSCC in this population suggests that there was not a
bias towards over-diagnosis due to increasing awareness
of EPSCC during the years of study. Nonetheless, the over-
all survival for EPSCC of the breast and gastrointestinal
tract, resemble other studies as mentioned above
Table 1: Primary disease sites in patients with EPSCC in South East England, 1970–2004
Disease site Number of Patients (%) Location (n) Ratio (M:F) Stage (n) [LD; ED; U]
Head and Neck 182 (11%) Trachea 50 1:1.1 64; 30; 88
Thyroid 41
Larynx 34
Oral Cavity 22
Sino-nasal 19
Pharynx 12
Others 2
Gastrointestinal 532 (33%) Oesophagus 293 1:1.3 181; 159; 192
Stomach 92
Colorectal 60
Pancreas 55
Biliary Tract 15
Others 17
Chest 115 (7%) Heart, mediastinum and pleura 111 1.8:1 58; 14; 43
Others 4
Breast 167 (10%) 1:82 104; 13; 50
Genitourinary 305 (20%) Prostate 90 1:1 109; 86; 110
Bladder 79
Cervix 76
Ovary 44
Others 16
Unknown Primary of Lymph
Nodes
69 (4%) 1:1 0; 0; 69
Others 248 (15%) Skin 11 1:1 16; 112; 120
Others 237
EPSCC 1618 (100%) 1:1.3 532; 482; 604
SCLC 27510 (100%) 1.7:1 9284; 7651; 10575
M: male; F: female; LD: limited disease; ED: extensive disease; U: unknown
Crude survival for patients with EPSCC by disease stage, South East England 1970–2004Figure 3
Crude survival for patients with EPSCC by disease
stage, South East England 1970–2004.
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[6,7,16,17]. Exactly what factors contribute to the better
or worse prognosis of various EPSCC sites could not be
fully evaluated in our series. We cannot rule out the pos-
sibility that differences in natural history of these disease
sites accounted for their better or worse survival. One
problem with interpreting the literature is that there are
many small studies of single disease sites. European stud-
ies [10,11] have generally included fewer than 25 patients.
Meta-analyses of existing studies (where classification per-
mits) might reveal more about the prognosis for disease at
different sites.
Limited data are available in the literature describing the
optimal management of patients with EPSCC. Because of
the poor prognosis, combined treatment modalities have
been increasingly used, with radiotherapy and/or surgery
proposed for localised control and platinum-based chem-
otherapy proposed for systemic control [6]. However,
there are no randomised controlled trials of treatment and
it is difficult to draw conclusions about effective treatment
from clinical series alone. This strongly suggests the need
for further clinical studies.
At the time of the study, the Thames Cancer Registry data-
base represents one quarter of the English cancer popula-
tion. Further studies using the national UK database, the
national cancer registration databases of other European
countries and prospective case registers are recommended
to confirm the results of this study. Such studies might
include more patients with disease at individual sites,
and, if augmented by case record review of patients with
selected sites, could obtain more detailed information on
treatment. The development of a co-ordinated research
programme in these areas is clearly essential for better
understanding of this under-recognised disease.
Conclusion
EPSCC was identified in various anatomical sites, with the
most common primary anatomical sites being the gas-
trointestinal and genitourinary tracts. The outcome for
patients with EPSCC differed according to the primary dis-
ease site. Patients with EPSCC of the breast had the best
prognosis, while EPSCC of the gastrointestinal tract had
the worst survival. Consequently, the most sensitive pre-
dictor of survival was the presenting site and the extent of
disease at diagnosis. Further studies using standardised
diagnosis, prospective case registers for uncommon dis-
eases and European cancer registries are needed to under-
stand this disease.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
YNW conceived the idea for the study, helped design it,
analysed the data and wrote the first draft of the paper.
RHJ helped analyse the data, interpreted the findings and
commented on the paper. VM helped to analyse the data,
Crude survival for patients with EPSCC by disease site, South East England 1970–2004Figure 4
Crude survival for patients with EPSCC by disease site, South East England 1970–2004.
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interpret the findings and commented on the paper. HM
helped to design the study, interpret the findings and
write the paper. EAD helped interpret the findings and
revised all subsequent drafts of the paper. All authors have
read and approved the final manuscript.
Acknowledgements
We thank two reviewers for their insightful comments on a previous ver-
sion of this manuscript.
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