Beruflich Dokumente
Kultur Dokumente
Gynecologic Oncology
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
Review
Division of Gynecologic Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5
a r t i c l e
i n f o
Article history:
Received 16 July 2009
Available online 31 October 2009
Keywords:
Adenocarcinoma
Cervix
Differences
Management
Prognosis
a b s t r a c t
Adenocarcinoma of the cervix constitutes only approximately 20% of all cervical carcinomas; therefore,
specic Level 1 evidence to guide patient management is lacking. Most trials have included this histologic
subtype but in insufcient numbers to do more than generate hypotheses from subset analyses. As a
consequence, our understanding of the natural history and optimal management of adenocarcinoma of the
cervix is limited. The optimal management of adenocarcinoma of the cervix continues to be a subject of
debate among practitioners as to whether or not it should be different from squamous cell carcinoma and
what would constitute this management. The purpose of this review was to give an overview of the current
knowledge on adenocarcinoma of the cervix and its differences from squamous cell carcinoma with regard to
risk factors, prognosis, survival rates, patterns of recurrence, and response to treatment. This article will
focus on possible specic therapeutic directions to explore in the management of locally advanced
adenocarcinomas.
2009 Published by Elsevier Inc.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . .
Literature search strategy . . . . . . . . . . . . . . .
Differences in epidemiology . . . . . . . . . . . . . .
Prognostic factors and differences in survival . . . . . .
Differences in patterns of dissemination and recurrences
Differences in response to treatment in randomized trials
Differences in response to chemotherapy . . . . . . . .
Future directions and conclusions . . . . . . . . . . .
Conict of interest statement . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . .
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Introduction
Carcinoma of the cervix has showed a marked decline in
developed countries over the past 40 years, due to wider implementation of cytologic screening and increased detection of premalignant
disease. Although the decline is mainly attributable to a decrease in
incidence of the most common histologic variant, squamous cell
carcinoma (SCC), there has also been an increase in relative and
absolute incidence of adenocarcinoma and adenosquamous carcinoma (AC) of the uterine cervix over the same period, especially among
younger women [18]. The relative increase in the proportion of AC
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140
141
141
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143
143
144
145
145
145
has resulted in this histology comprising more than 20% of all cervical
cancers in North America [3,5,6,9].
Most of our knowledge on the treatment of cervical cancer comes
from studies where the majority of the patients had SCC; AC only
comprised on average 10% of the cases [1021]. Very few of these
studies reported separate outcome results for AC of the cervix even on
exploratory subset analyses. No prospective study has focused on the
treatment of AC as the sole histology. As a consequence, our
understanding of the natural history and optimal management of
AC is limited. For the purposes of this review, the two most common
histologies of non-SCC, adenocarcinoma and adenosquamous carcinoma of the cervix, will be labeled as AC and analyzed together given
the scarce data separating these two histologies.
It appears that AC and SCC of the cervix behave differently. They
are different in epidemiology, prognostic factors, and patterns of
failure after similar treatments. Available data suggest that they may
141
associated with uterine cancer. Data from the International Collaboration of Epidemiological Studies of Cervical Cancer [25] included
13,541 women with cervical carcinoma, 15% of which were AC, and
23,017 women without cervical carcinoma from 23 epidemiological
studies. There was no association between smoking and the incidence
of AC with a relative risk of 0.89 (CI 0.741.06) and 0.89 (CI 0.721.10)
for current and past smokers, respectively. This is in contrast to SCC
where smoking is strongly associated, and the risk is correlated with
the number of cigarettes smoked per day and with the age of starting
smoking [25].
For many years, there were concerns that AC of the cervix was
linked with the use of oral contraceptives (OC) [26]. However, a recent
large systematic review that included 28 eligible studies and 12,531
women with cervical cancer demonstrated that although there was an
increased relative risk of cervix cancer with increasing duration of OC
use compared to never users of OC, the results were no different when
comparing SCC and AC of the cervix [27].
Finally, studies have shown that AC and SCC have slightly different
associations with HPV. Castellsague et al. [8] found that HPV-16 and
HPV-18 were the two most commonly detected HPV types in AC of the
cervix, present in 82% of their study patients. Data suggest that HPV18 accounts for about 50% of AC compared with only 15% of SCC [6].
Furthermore, the attributable fraction of HPV-18 and HPV-16 to AC is
higher relative to that of SCC, which is associated with a greater
diversity of HPV types [6].
Prognostic factors and differences in survival
Controversy exists as to whether histologic type is an independent
prognostic factor for survival. Although some studies have shown no
differences in survival between AC and SCC [2833], the majority have
shown that AC carries a worse prognosis with 10%20% differences in
5-year overall survival rates [9,3441]. The most important prognostic
factors for survival are clinical stage and lymph node status.
Clinical stage is a consistent prognostic factor for survival in all
cervix cancers. For AC, Baalbergen et al. [42] demonstrated in a study
of 305 patients that 5-year overall survival rates decreased with
advancing FIGO stage (stage I 80%, stage II 37%, stage III b11%). The
same trend was shown by Eifel et al. [1] for relapse-free survival in
367 cases of AC (stage I 73%, stage II 32%, stage III/IV 31%). As clinical
stage increases, a difference in survival between AC and SCC becomes
apparent. Comparing stage for stage, patients with AC had a
signicantly lower survival rate than those with SCC [2,9,36,37]. The
differences in survival rates according to stage are summarized in
Table 1.
Size of the tumor lesion is also a signicant prognostic factor. The
differences between AC and SCC may be negligible in small tumors,
as demonstrated by Marchiole et al. [43], where 118 radical
trachelectomy patients were compared to 139 radical hysterectomy
patients. Only tumor size and lymphvascular space invasion (LVSI),
and not histology, were shown on multivariate analysis to be
independent prognostic factors for recurrence. Thirteen of the 16
recurrences occurred in patients with tumors 2 cm. Conversely, as
the size of the tumor increases, the relative survival rate of patients
with AC signicantly decreases. Both Nakanishi et al. [38] and Eifel et
al. [9] found that tumor size N4 cm was a signicant adverse
prognostic factor for survival. The 5-year survival rate is 88%97% for
tumors b23 cm, but only 50%62% for tumors 45 cm [1,34]. In the
largest dataset, Eifel et al. [9] compared 1538 stage IB SCC to 229
stage IB AC patients, all treated with radical irradiation. Patients with
tumors N4 cm had an overall survival of 73% for SCC, but only 59%
for AC, and the estimated risk of death was 1.9 times greater for
patients with AC (p b 0.01), although the locoregional control rates
were similar in both groups. This reected the greater risk of
developing distant metastases in patients with AC (25%) compared
to those with SCC (14%) [9].
142
Table 1
Comparison of overall survival rates by histology and by stage.
Author, year [ref]
Treatment
Stage
p-Value
AC
SCC
I
II
III
IB
Overall
I
II
III
IV
IB & II
60
47
8
72
67
76
63
29
0
74
90
62
36
82
81
81
75
42
26
83
b 0.0001
0.01
0.002
b 0.01
0.0009
0.0039
0.0103
Overall
IB
II
78
96
61
92
94
90
0.0034
NS
0.0007
0.0136
AC, adenocarcinoma; SCC, squamous cell carcinoma; RT, radiation therapy; CT, chemotherapy; PA, para-aortic; NS, not signicant; ref, reference.
1.8 times greater than SCC (p = 0.02) and 2.8 times greater than AC
(p = 0.007) [30,44]. Grisaru et al. [46] conducted a retrospective study
of 880 surgically treated stage IAIB cervical carcinomas evaluating
the prognostic signicance of histology for recurrence-free survival.
Median tumor size was 2 cm (range 0.16 cm). Pathologic data were
recorded by gynecologic pathologists at one center. Patients with AC
were divided into two groups: mucinous/endometrioid adenocarcinoma (n = 225) and adenosquamous/clear cell adenocarcinoma
(n = 81). There was a signicantly worse 5-year recurrence-free
survival on univariate analysis associated with AS compared to AC and
SCC (81% vs. 90%, p = 0.03). Despite some studies nding no
difference in survival in AS compared to AC and SCC [32,47,48], Farley
et al. [45] summarized in a specic review of the literature that on
average, AS histology had a worse overall survival compared to that of
AC alone, or AC and AS combined together (stage I, 69% vs. 80% vs.
80%; stage II, 27% vs. 59% vs. 48%, respectively). This highlights the
hypothesis that AC histology seems to have a worse prognosis
compared to SCC but could be partially attributed to AS being grouped
with AC histology.
There has been suggestion from retrospective studies that poorly
differentiated or grade 3 histology is an adverse prognostic factor for
recurrence in early stage AC of the cervix [31,49]. Eifel et al. [49]
observed that among 160 patients who had initial treatment for stage
I AC 4 cm in diameter, the 34 patients with grade 3 disease had a 5year survival rate of 67% compared to the other 126 patients whose 5year survival rate was 85% (p = 0.0018). Similarly, Kilgore et al. [31]
demonstrated that among 162 patients with AC, those with grade 2 or
3 lesions had a 5-year survival of 70% compared to 92% in those with
grade 1 lesions. Neither of these studies, however, included pathologic
Table 2
Comparison of overall survival rates by histology and by pathologic lymph node status.
Author, year [ref]
Stage
LN status
51 AC
IBIIB
I
IBIIB
IB
200
IIIA
Positive
Negative
Positive
Positive
Negative
Positive
Negative
Positive
Negative
AC, adenocarcinoma; SCC, squamous cell carcinoma; NA, not applicable; NS, not signicant; ref, reference.
SCC
10
92
33
48
92
63
94
34
91
NA
NA
76
77
90
84
98
NA
NA
p-value
b 0.0001
b0.01
b0.05
NS
b0.001
b0.067
b0.003
143
Table 3
Differences in pelvic and distant relapse rates at 5 years by histology and by stage (data
from Eifel et al., 1995 [9]).
Stage
IB1
IB2
Number of
patients (n)
p-Value
Distant (%)
113
706
106
797
6
3
17
13
b 0.01
15
7
37
21
AC
SCC
AC
SCC
0.16
p-Value
0.01
b 0.01
144
Table 4
Comparison of 5-year survival, local and distant recurrence rates by histology, and treatment modality (data from Monk et al., 2005 [20]).
SCC
5-Year survival
Local recurrence
Distant recurrence
AC
RT% (patients)
RT + CT% (patients)
p-Value
RT% (patients)
RT + CT% (patients)
p-Value
69
20 (19/95)
14 (13/95)
80
9 (9/98)
10 (10/98)
0.019
55
29 (6/21)
24 (5/21)
82
7 (2/29)
10 (10/98)
0.014
SCC, squamous cell carcinoma; AC, adenocarcinoma; RT, radiation therapy; CT, chemotherapy.
145
Table 5
Summary of results of randomized trials in cervix cancer with adenocarcinoma subset analyses.
Author, year [ref]
Stage
Prognostic factors
Treatment arms
59 (21)
IB
243
50 (21)
IA2IIA
337
46 (14)
IBIIA
Adjuvant pelvic RT
(4650.4 Gy)
Adjuvant pelvic RT
(49.3 Gy)
RT (pelvis 47 Gy,
point A 76 Gy)
Total
AC (%)
277
Obs
Adjuvant RT + CT
(5FU + cisplatin)
Surgery +/ adjuvant RT
AC, adenocarcinoma; SCC, squamous cell carcinoma; CLS, capillary lymphatic space; hyst, hysterectomy; LN, lymph node; RT, radiation therapy; CT, chemotherapy; Obs, observation;
OS, overall survival; PFS, progression-free survival; ref, reference.
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