Key words
ovarian cancer - cervical cancer - endometrial cancer - epidemiology
Schlüsselwörter
Ovarmalignom - Zervixkarzinom - Endometriumkarzinom - Epidemiologie
Introduction
In addition to breast cancer, gynaecological malignancies also include cervical,
endometrial and ovarian cancers. Cancer of the corpus uteri is the most common
malignancy of the female genital tract, followed by ovarian and cervical cancer.
In Germany, these malignancies account respectively for 5.1 % (fourth most common
malignancy in women), 3.5 % (sixth most common) and 2.2 % (twelfth most common) of
all newly diagnosed cancers in women. As most cervical and endometrial cancers,
particularly oestrogen-dependent endometrial tumours, are diagnosed at an early
stage, these cancers have a favourable prognosis. Ovarian cancer however is usually
diagnosed at a later stage and, in addition, has a high risk of recurrence. Ovarian
cancer therefore has an unfavourable prognosis [1], [21], [23].
Infection with human papillomavirus (HPV) is now considered a prerequisite for the
development of cervical cancer [2]. HPV DNA has been
detected in around 90 % of cervical cancers. HPV has numerous phenotypes and they
exhibit different pathogenicities in humans. HPV can be differentiated into
high-risk types (16, 18, 31, 45) and low-risk types. The majority of cervical
cancers are caused by high-risk HPV types [3]. HPV type 16
was detected in around 50–60 % of patients with cervical cancer and HPV type 18 was
found in around 10–20 % of women with cervical cancer. As HPV vaccines against these
particular types have been available since 2006, vaccination can reduce the risk of
contracting HPV. Since the spring of 2007, the German Standing Committee on
Vaccinations (STIKO) has recommended vaccinating girls between the ages of 12 and 17
years against HPV [4]. If HPV infection is present, then
the presence of the following co-factors will increase the risk of developing
cervical cancer: taking oral contraceptives for five years or more, smoking,
carrying a large number of pregnancies to term (5 or more live births) as well as
previous exposure to other sexually transmitted diseases such as chlamydia or herpes
simplex virus type 2. Moreover women with an existing HPV infection have a higher
risk for HPV infection and the development of cervical cancer [5], [6].
Cancer of the corpus uteri is commonly divided into 2 types: oestrogen-dependent
(type I) and non oestrogen-dependent (type II). Oestrogen intake increases the risk
for oestrogen-dependent endometrial cancer, but this type of cancer is commonly
diagnosed at an early stage and has a more favourable prognosis than type II [7]. Women with early onset of menarche, late onset of
menopause and no children are at a higher risk. Tamoxifen intake or long-term
oestrogen intake without concurrent administration of gestagen can also increase the
risk of developing disease. Obesity leads to increased endogenous oestrogen
production and represents, in addition to diabetes mellitus and hypertension, a
further risk factor [8]. Women with breast cancer are at
increased risk of developing cancer of the uterine corpus [9]. Physical activity, taking oral contraceptives, several pregnancies
and a soy-rich diet reduce the risk. A lower risk has also been noted in women who
smoke [10].
Around 10 % of ovarian cancers are caused by genetic mutations (BRCA1, BRCA2
mutation, MLH1, MSH2, TP53) [4]. As ovulation inhibitors
have a protective effect, hormonal prevention can play an important role in women
with mutations. The risk of developing cancer can be reduced by up to 50 % if women
at risk take oral contraceptives for many years (i.e., at least 10 years). However,
the impact of hormone therapy on the risk of developing ovarian cancer is still
controversially discussed. Current data appear to indicate an increased risk for
women receiving hormone therapy. Women with breast cancer or polycystic ovarian
syndrome also have a higher risk of additionally developing ovarian cancer [4], [11].
It is safe to assume that the observed trends over time for the incidence of obesity,
hypertension and diabetes mellitus and hormone intake – whether used to inhibit
ovulation or for hormone therapy – combined with changed sexual and smoking
behaviour in women will have an impact on the epidemiology of cancers of the female
genital tract. Important epidemiologic and clinical data on cervical cancer, cancer
of the corpus uteri and ovarian cancer are therefore presented below.
Incidence and Mortality in Germany
Incidence and Mortality in Germany
In 2008 almost 24 000 women in Germany were diagnosed with cervical cancer, cancer of
the corpus uteri or ovarian cancer. This corresponds to a raw annual incidence rate
of approx. 57.1 per 100 000 women. If morbidity rates are based on the European
standard population, then 38.9 of 100 000 women were diagnosed with cancer of the
female genital tract. Cancer of the corpus uteri was the most common of the 3 tumour
types with just under 48 %, while cervical cancer had an incidence of 20 % and
ovarian malignancies accounted for the remaining 31 % [12]. The average patient age at the time of cervical cancer diagnosis was
52 years, making these patients 17 years younger on average than patients with
ovarian cancer or cancer of the corpus uteri ([Table
1]).
Table 1 Overview of the most important epidemiological
figures for Germany 2008/2009, Data obtained from the German Centre for
Cancer Registry Data (ZfKD), the Association of Population-based Cancer
Registries in Germany e. V. (GEKID) and the Federal Statistical Office
of Germany.
|
|
Cervix uteri
|
Corpus uteri
|
Ovary
|
|
ASR [E] = Age-standardised rate, European standard
Data
sources unless otherwise stated: ZfKD [1], GEKID [12], German
Federal Statistical Office [13]
* Source: the Population-based Cancer Registry
of Schleswig-Holstein, data from October 2012
|
|
Incidence
|
ZfKD 2008
|
GEKID 2009
|
ZfKD 2008
|
GEKID 2009
|
ZfKD 2008
|
GEKID 2009
|
|
Mean age at diagnosis
|
|
|
|
|
|
|
|
|
52
|
|
69
|
|
69
|
|
|
|
|
35*
|
|
not specified
|
|
not specified
|
|
Incidence
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
4 880
|
4 845
|
11 280
|
11 561
|
7 790
|
7 428
|
|
|
11.6
|
11.6
|
26.9
|
27.6
|
18.6
|
17.7
|
|
|
9.5
|
9.6
|
17.2
|
17.8
|
12.2
|
11.5
|
|
|
|
|
|
|
|
|
|
|
14 400–19 200
|
|
not specified
|
|
not specified
|
|
|
5-year survival
|
|
|
|
|
|
|
|
|
65 %
|
|
70 %
|
|
37 %
|
|
|
|
68 %
|
|
79 %
|
|
40 %
|
|
|
5-year prevalence
|
17 000
|
|
42 700
|
|
20 300
|
|
|
|
40.6
|
|
102.0
|
|
48.5
|
|
|
Mortality
|
Federal Statistical Office of Germany 2009
|
Federal Statistical Office of Germany 2009
|
Federal Statistical Office of Germany 2009
|
|
Mean age at death
|
66
|
76
|
73
|
|
Mortality
|
|
|
|
|
|
1 596
|
2 420
|
5 529
|
|
|
3.8
|
5.8
|
13.2
|
|
|
2.6
|
3.0
|
7.6
|
In the same year, 9545 patients died from one of these three tumour types (raw rate:
22.8 pro 100 000 women). The age-standardised mortality rate was 13.2 per 100 000
(European standard population) [12], [13]. 17 % of these deaths (based on absolute numbers) were
due to cervical cancer, 25 % were due to cancer of the corpus uteri, and 58 % of
deaths were attributable to ovarian cancer. Ovarian cancer has the most unfavourable
ratio of deaths compared to newly diagnosed cases with 1.4 new diagnoses for every
one death. For cervical cancer, the ratio is 3.1 new diagnoses to 1 death, and 4.7
new cases are diagnosed with cancer of the corpus uteri for every death [24].
Incidence and Mortality Trends
Incidence and Mortality Trends
Since the 1970s, the incidence and mortality of cervical cancer has dropped
significantly in many countries (most of them developed countries) all over the
world. In the Scandinavian countries, for example, the incidence dropped from around
17 per 100 000 (1970; ASR [world]) to 8 per 100 000 women (2000). In the same
period, mortality dropped from around 6 per 100 000 to about 2 per 100 000 women
[14]. Since the year 2000, in many countries the
incidence and mortality rates for cervical cancer stabilised at around one quarter
to one third of the rates recorded for the 1970s [14], [15].
The (recent) incidence and mortality trends in Germany are shown in [Fig. 1]. In the period from 2003 to 2009, the
age-standardised incidence rate (European standard population) for both cervical
cancer and cancer of the corpus uteri hovered around a constant figure of 9.6 new
diagnoses per 100 000 women and 17.9 new diagnoses per 100 000 women, respectively.
Mortality rates for the period from 1998 to 2009 dropped continually. In 2009 the
age-standardised mortality rate for cervical cancer was 2.6 per 100 000; for cancer
of the corpus uteri it was 2.9 per 100 000. For both cancer entities this represents
a drop of 30 % from the mortality rates recorded 11 years earlier. The decreased
mortality among patients with cervical cancer is primarily associated with
systematic and opportunistic screening programmes such as routine Papanicolau tests
(Pap test) [16] which can be used to detect cytological
changes. Moreover, with the help of HPV vaccinations and the removal of precancerous
lesions discovered at screening, certain invasive tumours can be almost entirely
prevented [4]. After Germany introduced annual screening
using conventional cytological smear in 1971, the incidence of this tumour decreased
by about two thirds [17].
Fig. 1 Age-standardised incidence and mortality rates in Germany over time
(European standard; sources: the Association of Population-based Cancer
Registries in Germany and the Federal Statistical Office of Germany [12], [13]).
The picture for ovarian malignancies is very different. A significant decrease of
20 % in the cancerʼs incidence, from 14.3 to 11.5 per 100 000 women, was noted
between 2003 and 2009. This resulted in a slight decrease of mortality but less so
than the mortality decrease recorded for cervical cancer and cancer of the corpus
uteri. The age-standardised mortality rate in 2009 was 7.7 per 100 000 women and
thus 18 % lower than in 1998.
Tumour Stages
Patients with malignant cervical tumours or cancer of the corpus uteri are
predominantly diagnosed at a very early stage of disease: every second woman with
cervical cancer and three of five women with cancer of the corpus uteri are in stage
T1 at the time of diagnosis (47 and 60 %, respectively), meaning that the tumour is
limited to the cervix or the corpus uteri. A further 15 and 8 % of cervical cancers
and cancers of the corpus uteri are stage T2 at diagnosis, the stage in which the
tumour has already spread to immediately adjacent regions. Advanced stages, i.e.,
stage T3 or T4, are only found in 9 and 8 % of women, respectively. Only around 7 %
of death certificates give these cancers as the sole cause of death. However, it
should be noted that the tumour stage of every fifth patient with cervical cancer or
cancer of the corpus uteri (22 % respectively) is unknown, so that the true
percentage of early or late stage tumours could be much higher. Similarly, no
information is available about the tumour stage of every fifth patient with ovarian
cancer (21 %). The percentage of these tumours diagnosed at an early stage is much
lower compared to patients with uterine cancer (cervix uteri, corpus uteri); only
one in four women are diagnosed as stage T1 or T2 (18 and 7 %, respectively).
Instead, the majority of ovarian cancers diagnosed are stage T3 (37 %). Due to this
unfavourable distribution at diagnosis and the associated poorer prognosis, the
percentage of patients with ovarian cancer given as the cause of death on their
death certificate is 17 %, significantly higher than for other malignant
gynaecological tumours.
Age Groups
In principle, older women have a higher risk of developing cancer of the female
genital tact compared to younger women ([Fig. 2]). For
cervical tumours the age distribution is bimodal, with most cases occurring in the
5-year age groups “women between 40 and 44 years”, “women between 45 and 49 years”
and “women aged over 85 years” (> 18 per 100 000). Cancer of the corpus uteri
occurs most commonly in women after menopause [7]. The
number of new diagnoses also increases for every increase in age group, with most
new diagnoses found in the group of women aged between 70 and 74 years and between
75 and 79 years (> 80 per 100 000). The incidence of ovarian cancer increases
continually with age. It is most common in the group aged between 80 and 84 years
(60 per 100 000).
Fig. 2 Age-specific incidence (red) and mortality (blue) per 100 000 women
in Germany in 2008 (sources: the Association of Population-based Cancer
Registries in Germany and the Federal Statistical Office of Germany [12], [13]).
Histology and Degree of Differentiation
Histology and Degree of Differentiation
Cervical cancer, cancer of the corpus uteri and ovarian cancer differ with regard to
their histology.
Two out of three malignant cervical tumours are classified as basal cell carcinomas
(68.7 %) and every sixth to seventh tumour is classified as an adenocarcinoma
(15.4 %). Sarcomas are rare (0.3 %). The histology of the remaining tumours is not
specified (data obtained from the Population-based Cancer Registry of
Schleswig-Holstein, October 2012). Adenocarcinomas are the most common corpus uteri
tumours, with two of three tumours classified as adenocarcinoma (62.3 %). Sarcomas
are rare (2.5 %). The range of histologies is broader for ovarian malignancies:
every third tumour is a serous carcinoma (32.1 %) and every fifth cancer an
adenocarcinoma (22.6 %). Other less common histologies include endometrioid
carcinoma (8.2 %), mucinous carcinoma (5.8 %), sex cord-stromal tumour (1.4 %),
clear cell carcinoma (1.0 %) and germ cell tumour (0.7 %).
Tumour differentiation indicates how clearly the tumour tissue can be differentiated
from adjacent normal tissue. Well differentiated tumours are associated with a
better prognosis than poorly differentiated tumours.
Three of four patients with cervical cancer have moderately or poorly differentiated
tissue (40.1 and 32.1 %, respectively). Only a few patients present with well
differentiated tumours (5.6 %). Undifferentiated tumours are even rarer (0.7 %).
Tumour differentiation was not recorded for every fifth tumour (21.5 %). The picture
is similar for ovarian cancer: around two thirds of patients have moderately or
poorly differentiated tumours (26.2 and 37.3 %, respectively) compared to patients
with well differentiated or undifferentiated tumours (6.1 and 1.1 %, respectively).
Differentiation tends to be slightly better in tumours of the corpus uteri. Every
fourth tumour of the corpus uteri is well differentiated (28.5 %). Around two of
five tumours are moderately differentiated (38.6 %) and only every fifth tumour is
poorly differentiated (19.9 %). Undifferentiated tumours are rare (0.3 %). No
differentiation was recorded in 12.8 % of tumours, a lower figure than that for the
two other cancers of the female genital tract.
Survival
Currently, the overall 5-year survival rate for women with cancer is 57 %. Compared
to this, the survival rates for women with cervical cancer (65 %) or cancer of the
corpus uteri (70 %) are better while the 5-year survival rate for women with ovarian
cancer is significantly lower (37 %). However, this absolute 5-year survival rate
does not take account of the fact that some of the patients with cancer of the
female genital tract also die from other causes. The relative 5-year survival rate
which only factors in the percentage of deaths which occur in addition to normal
mortality rates is 64 % for cancer in general. Compared with this, the rates for
women with cervical cancer (86 %) and for patients with cancer of the corpus uteri
(79 %) are much better, while the rates for patients with ovarian cancer (40 %) are
significantly worse [1].
When the current relative survival rate is compared to the figure for the years
2002/2003, the relative survival rates for cancer of the corpus uteri (82 %) and for
ovarian cancer (48 %) have remained at comparatively stable levels [18]. As the figure for 2002/2003 is based only on data
obtained from the Saarland Cancer Registry, the limited variation is probably not
due to any systematic long-term trend. However a significant improvement in the
relative 5-year survival for cervical cancer from 55 to 86 % has been observed.
Other calculations have shown a significant increase in relative survival from 62 %
in 2002 to 67 % in 2006 [19]. Suggested reasons for this
include improvements in early detection and optimised therapy, among other things
through the introduction of gynaecological cancer centres [25].
International Comparison
Below are some international comparisons with regard to the incidence, mortality and
prevalence, although the information available for cervical cancer is more detailed
than for the two other gynaecological cancer entities.
Cancer of the cervix uteri is the third most common tumour in women world-wide with
an estimated number of newly diagnosed cases of 530 000. More than 85 % of all cases
with cervical cancer occur in developing countries [15],
where it is the most common cancer in many areas. The regions where women have the
highest risk of developing disease include Eastern and Western Africa (ASR [world]
> 30 per 100 000 women), Southern Africa (26.8 pro 100 000), South-Central Asia
(24.6 per 100 000), South America and Middle Africa (23.9 and 23.0, respectively,
per 100 000). Rates are lowest in Western Asia, North America and Australia/New
Zealand (< 6 per 100 000). In Europe, the incidence of cervical cancer varies
widely, ranging from 2.1 per 100 000 (Malta) to 23.9 per 100 000 (Romania). Germany
is in the lower third of European countries ([Fig. 3]).
Fig. 3 Comparison of age-standardised incidence and mortality for cervical
cancer (world standard) world-wide and across Europe (source: Globocan 2008
[15]).
With around 290 000 cases, cancer of the corpus uteri is the sixth most common cancer
in women [15]. In Germany, cancer of the corpus uteri is
the fourth most common cancer in women [1]. The
age-standardised incidence rate (world standard) in Europe ranges from 7 (Czech
Republic) to 18 (Romania) per 100 000 women. Germany, which has a rate of 12 per
100 000 women, ranks somewhere in the middle [15].
The number of women with incidental ovarian cancer is estimated to be around 225 000
world-wide, making ovarian cancer the seventh most common cancer in women [15]. In Germany, ovarian cancer is the sixth most common
cancer in women [1].
In 2008, around 275 000 women died from tumours of the cervix uteri, with 88 % of
deaths occurring in developing countries (53 000 in Africa, 31 700 in Latin
America/the Caribbean and 159 800 in Asia) [15]. There
are also clear differences with respect to mortality – both world-wide and
Europe-wide. World-wide mortality ranges from 3 (Western Europe) to 25.3 (Eastern
Africa) per 100 000 women; mortality in Europe ranges from 0.8 (Iceland) to 11.8
(Romania) per 100 000 (ASR [world]; [Fig. 3]).
In 2008, around 75 000 women died from cancer of the corpus uteri [15]. The age-standardised mortality rate (world standard)
in Europe ranges from around 0.5 (Luxembourg) to 4.5 (Malta) per 100 000 women.
Germany is one of the European countries with the lowest mortality rate [15].
The number of deaths due to ovarian malignancies was reported to be 140 000 which is
significantly higher than that reported for cancer of the corpus uteri [15] but nevertheless lower than that for cervical
cancer.
The raw 5-year prevalence rate for cervical cancer in Europe is between 16.2 (Malta)
and 128.2 (Macedonia) per 100 000 women. Eastern Europe has the highest rates.
Germany has a raw rate of 40.4 per 100 000, i.e. around 14 745 women were diagnosed
with cervical cancer in the last 5 years, which puts Germany in the lower third of
European countries [20].
The 5-year prevalence of tumours of the corpus uteri in Europe ranges from 48.7
(Romania) to 147.8 per 100 000 women (Czech Republic, raw rate). The highest rates
are recorded in Scandinavia. Germany has a raw rate of 110.3 per 100 000 women, that
is, around 40 220 women in Germany were diagnosed with cancer of the corpus uteri in
the last 5 years. Germany ranks therefore near the middle of all European countries
[20].
The 5-year prevalence for ovarian cancer in Europe ranges from 27.8 (Portugal) to
67.9 per 100 000 women (Luxembourg, raw rate). Once again, the highest rates are
found in Scandinavia. Germany has a raw rate of 54.2 per 100 000, i.e. 19 779 women
were diagnosed with ovarian cancer in the last 5 years, putting Germany in the top
third of European countries [20].
Conclusion
The number of women newly diagnosed with ovarian cancer has decreased significantly
in the last decade, while the number diagnosed with cancer of the corpus uteri or
with cervical cancer has remained fairly stable with few variations. Currently (in
2009), around 24 000 women in Germany are diagnosed every year with an invasive form
of one of the tumour entities described above. Overall, cancer of the female genital
tract amounts to around 11 % of all new cancer diagnoses in women in Germany. The
prognosis for cervical cancer and for cancer of the corpus uteri is good as
increasing numbers of tumours are diagnosed at an early stage, while ovarian cancer
has a poor prognosis. Around 80 000 women living in Germany today were diagnosed
with a cancer of the female genital tract in the last five years [22].
Since 2007 STIKO has recommended vaccinating young girls and women against HPV before
they become sexually active to reduce the incidence of cervical cancers and
pre-cancerous lesions. Current data indicate that in Germany around one third of
girls aged between 12 and 17 years have received the full vaccine of three doses. It
remains to be seen whether this percentage could be increased in the long term and
whether this will result in reduced mortality later on. Further studies of these
developments will be warranted.
