Download Surgical Approach and Long-term Clinical Outcome in Women with

ANTICANCER RESEARCH 34: 4345-4350 (2014)
Surgical Approach and Long-term Clinical Outcome
in Women with Microinvasive Cervical Cancer
FRANCESCO SOPRACORDEVOLE1, GIUSEPPE CHIOSSI2, MAGGIORINO BARBERO3,
PAOLO CRISTOFORONI4, BRUNO GHIRINGHELLO5, ANTONIO FREGA6, FRANCESCA TORTOLANI2,
FAUSTO BOSELLI2, NICOLÒ CLEMENTE7, ANDREA CIAVATTINI7, ITALIAN SOCIETY
OF COLPOSCOPY and CERVICO-VAGINAL PATHOLOGY (SICPCV)
1Department
of Gynecological Oncology, Centro di Riferimento Oncologico, Aviano, Italy;
of Gynaecological, Obstetric and Pediatric Sciences, Section of Gynaecology,
University of Modena and Reggio Emilia, Modena, Italy;
3Department of Obstetrics and Gynecology, Asti Community Hospital, Asti, Italy;
4Department of Obstetrics and Gynecology, University of Genoa, Genoa, Italy;
5Department of Pathology, University of Turin, Turin, Italy;
62nd Clinic of Obstetrics and Gynaecology, University "La Sapienza", Rome, Italy;
7Woman's Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy
2Department
Abstract. Aim: To assess the efficacy and safety of
conservative surgical approach for microinvasive cervical
cancer with regards to cone margins status and lymph vascular
space invasion (LVSI). Patients and Methods: This was a
multicentre retrospective cohort study of 153 women diagnosed
with microinvasive cervical cancer over a 10 years period
(1993-2003). Results: In conservatively-treated women (n=80),
neither cancer mortality nor disease relapse after 184.5±20.5
months of follow-up was detected. Residual disease in women
who underwent secondary surgery was significantly related to
positive margins on the primary cone excision (p=0.005) while
no correlation with LVSI emerged. Conclusion: Conization can
represent the definitive treatment for stage IA1, if surgical
margins are cancer-free, independently of LVSI. A conservative
surgical approach could also be considered in women with IA2
cervical cancer when preservation of fertility is strongly
requested. A close long-term surveillance should be scheduled
for conservatively-treated women
In the last decades, both the relative proportion and absolute
incidence of microinvasive cervical cancer have increased ten
times in developed Countries, mainly in young women aged
Correspondence to: Andrea Ciavattini, MD, Gynecologic Section Woman's Health Sciences Department, Polytechnic University of
Marche, Via F. Corridoni 11 – 60123 Ancona, Italy. Tel: +39
07136745, Fax: +39 07136575, e-mail: [email protected]
Key Words: Conization, microinvasive cervical cancer, cone
margins, lymph vascular space invasion.
0250-7005/2014 $2.00+.40
less than 40 years (1). Furthermore, we have seen a
continuous trend of delayed childbearing, which results in an
increased proportion of women diagnosed with a cervical
cancer before their first pregnancy. Even if the prognosis of
microinvasive cervical cancer is favorable, as reported by
several studies (2-5), this diagnosis actually represents a
difficult management dilemma, specifically in young women
who desire to preserve their childbearing potential.
Different approaches have been employed to treat
microinvasive cervical cancer, and controversies still exist on
the surgical procedure that should be considered for the
optimal management of the disease (6-13). Traditional
surgical therapy for cervical cancer includes hysterectomy,
with loss of childbearing potential. However, in the last
years, a trend towards a conservative surgical approach has
emerged, as preservation of fertility is desirable in young
women, and radical procedures are associated with higher
morbidity and mortality rates (14). Actually, both conization
and simple hysterectomy are considered to be effective
treatments for stage IA1 tumors. Conization is considered an
acceptable management of stage IA1 cervical cancer, if the
margin of the cone excision is clear and the lymph vascular
space invasion (LVSI) has not occurred. If fertility
preservation is desired, conization is satisfactory if all
margins are clear (15). Radical hysterectomy with bilateral
pelvic lymphadenectomy is the standard treatment of stage
IA2 tumor. For this group of patients, a fertility preserving
option is radical trachelectomy, which includes resection of
the entire cervix and surrounding parametria, preceded by a
laparoscopic bilateral pelvic lymphadenectomy (16). It is
obvious that a close long-term surveillance should be
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ANTICANCER RESEARCH 34: 4345-4350 (2014)
scheduled for conservatively-treated women and, in the
absence of specific guidelines, a 10-year follow-up should
suffice for stage IA disease (1).
The aim of the present study was to describe the
management and long-term outcome of women with
microinvasive cervical cancer in four Gynecological
Oncology Units in Northern Italy. The safety of a fertilitysparing surgical approach, with regard to prognostic factors
such as the cone margins status and the LVSI was evaluated.
The study was supported by the Italian Society of
Colposcopy and Cervico-Vaginal Pathology (SICPCV).
Patients and Methods
Patients and surgical approaches. This was a multicentre
retrospective cohort study of 153 women diagnosed with
microinvasive cervical cancer over a 10-year period (1993-2003) in
four Gynecologic Oncology Units in Northern Italy. Demographic
data, surgical and pathological data as well as follow-up information
were acquired by medical charts review. Among demographic data,
age, menopause status and parity were evaluated. Surgical data
included type of conization technique (cold knife conization, laser
conization and large loop excision of the transformation zone;
LLETZ) and type of hysterectomy (simple or radical, abdominal or
vaginal approach). Pathologic records were reviewed regarding
depth of invasion, horizontal extension of the tumor and the
presence of LVSI. For patients who were managed by conization,
the parameters of the cone specimens included also the status of
surgical margins.
In patients who underwent secondary surgery, both specimens
were analyzed to determine the total depth of invasion and horizontal
extension. All cases were retrospectively staged according the 2009
International Federation of Gynecology and Obstetrics (FIGO)
revised nomenclature: microinvasive carcinoma of the uterine cervix
(FIGO stage IA) is defined as an invasive carcinoma which can be
diagnosed only by microscopy, with deepest invasion ≤5 mm and
largest extension ≤7 mm. Stage IA1 cervical cancer has a measured
stromal invasion of ≤3 mm in depth and extension of ≤7 mm while
stage IA2 cervical cancer has a measured stromal invasion of >3 mm
and not >5 mm with an extension of not >7 mm (17).
All patients were followed-up every 3 months for the first year,
every 6 months up to the second year and yearly thereafter. Followup included pelvic examination, Pap smear and colposcopy. Disease
recurrence was defined as a histological diagnosis of Cervical Intraepithelial Neoplasia of Grade 3 (CIN3) or more.
Statistical analysis. Statistical analysis was performed with the
MedCalc database (MedCalc Software, Ostend, Belgium), assisted
by the use of the Student’s t-test, χ2 testing and the Fisher’s exact
test, as appropriate for categorical or continuous variables. A pvalue <0.05 was considered statistically significant
Results
During the study period, a total of 153 women with
microinvasive cervical cancer, according to the FIGO
classification staged as IA1 and IA2, were identified. The
mean age was 44±12 years (range=25-78 years); 42 women
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Table I. Association between primary conservative surgery and
demographic and clinical variables.
Hysterectomy Conservative surgery p-Value
(N=21)
(N=132)
Age at diagnosis
<45 years old
≥45 years old
Year of diagnosis
1993-1997
1998-2003
Tumor stage
IA1
IA2
0.001
4 (19%)
17 (81%)
79 (59.8%)
53 (40.2%)
16 (76.2%)
5 (23.8%)
53 (40.2%)
79 (59.8%)
20 (95.2%)
1 (4.8%)
123 (93.2%)
9 (6.8%)
0.004
0.9
(27.5%) were menopausal and 83 (54.2%) were <45 years old.
Mean parity was 1.3±1.4. Diagnosis of microinvasive cervical
carcinoma was made on tissue sample obtained with cervical
conization in 132 cases; the remaining 21 cases were
diagnosed after a non-conservative surgical approach without
previous conization. In particular, immediate hysterectomy
was more frequently performed on women aged ≥45 years
compared to younger women (Table I).
Overall, 143 women (93.5%) were diagnosed with stage
IA1 cervical cancer and 10 women (6.5%) with stage IA2
cancer. Stromal infiltration was <1 mm in 101 cases (66%),
ranged between 2 and 3 mm in 42 women (27.5%) and
between 3 and 5 mm in 10 (6.5 %) cases. One hundred and
forty-five (94.8%) were squamous carcinomas, 7 (4.6%)
were adenocarcinomas whilst only one was adenosquamous
carcinoma (0.6%). The median horizontal extension of
cancer was 3 mm (range=2-7 mm); LVSI was reported in 5
cases (3.3%).
Among the 132 women who underwent conization as
primary surgery, 123 (93.2%) had disease at stage IA1 and 9
(6.8%) at stage IA2. Sixty-two stage IA1 women had conization
as definitive surgery, because of free surgical margins and no
LVSI; 61 underwent secondary surgery. Only 1 out of 9 stage
IA2 carcinomas had conization as definitive surgery.
Overall, 80 women (52.3%) were definitively treated with
a conservative surgical approach during the study period,
considering 63 women who underwent cervical conization as
primary surgery, 16 women who had re-conization as
secondary surgical treatment and one woman who underwent
trachelectomy as a secondary approach. Pathological
characteristics of primary cone excision and secondary
surgical treatment of 69 women who underwent secondary
surgery are reported in Table II. The mean interval to
secondary surgery was 8±2.3 weeks while residual disease
was found in 9 cases. All cases with residual disease had a
diagnosis of stage IA1 at primary conization; the diagnosis
Sopracordevole et al: Microinvasive Cervical Cancer
Table II. Pathological characteristics of primary cone excision and secondary surgical treatment.
Pathological characteristics
of primary cone excision
Secondary surgical treatment
Conization
Simple hysterectomy
Radical hysterectomy
Trachelectomy
Total
IA1
M– LVSI–
M– LVSI+
M+ LVSI–
M+ LVSI+
Total
11
0
4
1
16
34
0
3
0
37
3
0
3
0
6
0
1
0
0
1
48
1
10
1
60
IA2
M– LVSI–
M– LVSI+
M+ LVSI–
M+ LVSI+
Total
0
0
0
0
0
1
0
0
1
2
5
2
0
0
7
0
0
0
0
0
6
2
0
1
9
M: Cone margins; LVSI: lymph vascular space invasion.
Table III. management of stage IA1 and stage IA2 cervical cancers with
regard to histological features of the primary cone excision.
Table IV. Correlation between the histological features of the primary
cone excision and the risk of residual disease at secondary surgery.
Residual disease
M- LVSI- M- LVSI + M+ LVSI- M+ LVSI+ Total
Stage IA1
Follow up
Retreatment
Residual disease
Stage IA2
Follow up
Retreatment
Residual disease
61
48
4/48
1
1
0/1
0
10
5/10
0
1
0/1
62
60
9/60
1
6
0/6
0
2
0/2
0
0
0
0
1
0/1
1
9
0/9
Presence
Absence
Total
M+
M–
Total
5
4
9
7
53
60
12
57
69
LVSI+
LVSI–
Total
0
9
9
5
55
60
5
64
69
M: Cone margins; LVSI: lymph vascular space invasion.
M: Cone margins; LVSI: lymph vascular space invasion.
of stage IA1 was confirmed in 8 out of 9 patients with
residual disease, while 1 was re-staged IA2.
The management of stage IA1 and IA2 cervical cancers,
with regard to the histological features of the primary cone
excision, is reported in Table III. Table IV reported the
correlation between the histological characteristics of the
primary cone excision and the residual disease at secondary
surgery.
After primary conization, 12 women had positive cone
margins and 5 of them (41.7%) reported residual disease at
secondary surgery. The rate of residual disease at secondary
surgery in women with negative cone margins was 7%. No
residual disease at secondary surgery in women with LVSI
was reported and all cases of residual disease were LVSInegative at primary surgery.
Residual disease was significantly related to positive
surgical margins (41.7% vs. 7%, p=0.005) but not with LVSI
on the cone excision (0 vs. 14.1%, p=0.83).
In our series, surgical treatment progressively became
more conservative. In the period between 1998-2003, 84
women were diagnosed with microinvasive cervical
carcinoma; conization was the primary treatment in 79
patients (94%) while only 5 women had immediate
hysterectomy. In the previous years, 69 women were
diagnosed with microinvasive cervical carcinoma and
conization was the primary treatment in 53 of them (76.8%):
the rate of conservative surgery was significantly higher in
the last years (94% vs. 76.8%, p=0.005). A ten-year followup was complete for each woman and no recurrence was
found after a mean follow-up of 184.5±20.5 months.
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ANTICANCER RESEARCH 34: 4345-4350 (2014)
Discussion
This survey describes the surgical approach of microinvasive
cervical cancer in four Gynecological Oncology Units in
Northern Italy, during the period between 1993-2003. During
the last decades, the incidence of microinvasive cervical
cancer is increasing, mainly in young women aged less than
40 years and a high number of women are diagnosed with a
cervical cancer before their first pregnancy. Different
approaches are employed to treat microinvasive cervical
cancer but a trend towards a conservative surgical approach
has emerged, as preservation of fertility is desirable in young
women and many studies reported the safety and efficacy of
a fertility-sparing surgery, particularly in women with stage
IA1 cervical cancer (4, 5, 15). Even in our experience, the
surgical treatment of microinvasive cervical carcinoma
progressively became more conservative and the rate of
women treated with fertility-sparing surgery in the period
1998-2003 was significantly higher than the past years.
The option of a fertility-sparing surgery appear to be
clearly desirable in young women diagnosed with a
microinvasive cervical cancer but some elements, such as the
cone margins status with particular regard to the apex of the
cone and also the LVSI must be taken into account because
of a potential risk of residual disease and recurrence.
The characteristics of the surgical margins should be
accurately considered for deciding if conization could
represent the definitive treatment for a patient with stage IA1
cervical cancer or if secondary surgery is appropriate. In our
series, residual disease detected at secondary surgery was
significantly related to positive surgical margins; multifocal
disease probably accounted for the 4 cases of cancer
identified on the specimen from secondary surgery, despite
unaffected surgical margins and lack of LVSI on the primary
cone excision.
Lymph vascular space invasion represents one of the most
controversial prognostic factors for microinvasive cervical
cancer; previous studies reported a LVSI rate between 2.2%
and 9.7% in patients with stage IA1 (14, 18, 19) and between
7.4% and 50% in stage IA2 (6, 20, 21). Nodal disease was
noted in 8% of patients with LVSI compared to only 0.8%
in patients without LVSI; likewise, a five-fold increased risk
of recurrence in women with LVSI was reported (22). In our
series, residual disease detected at secondary surgery was not
related to LVSI on the primary cone excision. Our findings
agree with those reported in a 2003 review by Creasman et
al. (23) as most of the previous published studies suggest
that LVSI does not represent an independent prognostic
factor in women with microinvasive cervical carcinoma.
However data are conflicting and other Authors have
reported different results. Recently Raspagliesi et al. (24)
and Costa et al. (25) reported that LVSI detected on the
primary cone excision was significantly related to the risk of
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cancer relapse among stage IA1 patients, indicating that the
debate on the prognostic value of LVSI is still open.
Although published data are contradictory, the present survey
did not find any correlation between LVSI on the primary
cone excision and the risk of residual disease. However, in
case of clear surgical margins and positive LVSI, the
possibility of a pelvic lymph node sampling should be
discussed with the patient.
Even if the outcome of microinvasive cervical cancer is
favorable, a close long-term surveillance should be scheduled
for conservatively-treated women. One of the strengths of the
present study is the long follow up period. The absence of
recurrence or disease-related deaths in our cases after a mean
follow-up of 184.5 months, once again confirms the efficacy
and safety of conservative fertility-sparing surgery in women
with microinvasive cervical cancer.
Previous studies reported a risk of recurrence of less than
2% and a risk of death of only 0.1% in women with stage IA1
cervical cancer (12, 26). Burghardt et al. (26) analyzed a
cohort of 344 patients with stage IA1 cervical cancer and
noted only one (0.3%) recurrence that was diagnosed 12 years
after treatment with conization. In a cohort of 494 patients
with microinvasive cervical cancer treated by conization,
Winter (27) noted four cancer-related deaths in patients with
microinvasive disease after a mean follow-up of 14 years,
without significant differences between stage IA1 and IA2.
In conclusion, our study suggests that fertility-conserving
surgery is efficacious and safe in women with IA1 cervical
cancer with unaffected cone margins and independent of LVSI.
A conservative surgical approach could also be considered in
women with IA2 cervical cancer when preservation of fertility
is strongly requested. It is the Authors' opinion that a close
long-term surveillance should be scheduled for conservativelytreated women, and, in the absence of specific guidelines, at
least 10 years of follow-up are required.
Acknowledgements
The authors would like to thank the following physicians for their
important contribution: Alberto Agarossi, Giovanni De Piero, Laura
Gallia, Vania Gardonio, Giorgio Giorda, Maria Teresa Mele, Gioia
Montanari, Massimo Moscarini, Andrea Papadia and Patrizia
Stentella.
References
1 Costa S: Colposcopy and management of microinvasive
squamous cell carcinoma. Minerva Ginecol 64(2): 121-136,
2012.
2 Benedet JL, Odicino F, Maisonneuve P, Beller U, Creasman WT,
Heintz AP, Ngan HY, Sideri M and Pecorelli S: Carcinoma of
the cervix uteri. J Epidemiol Biostat 6(1): 7-43, 2001.
3 Webb JC, Key CR, Qualls CR and Smith HO: Population-based
study of microinvasive adenocarcinoma of the uterine cervix.
Obstet Gynecol 97(5): 701-706, 2001.
Sopracordevole et al: Microinvasive Cervical Cancer
4 Gadducci A, Sartori E, Maggino T, Landoni F, Zola P, Cosio S,
Pasinetti B, Alessi C, Maneo A and Ferrero A: The clinical
outcome of patients with stage Ia1 and Ia2 squamous cell
carcinoma of the uterine cervix: a Cooperation Task Force (CTF)
study. Eur J Gynaecol Oncol 24(6): 513-516, 2003.
5 Wright JD, NathavithArana R, Lewin SN, Sun X, Deutsch I,
Burke WM and Herzog TJ: Fertility-conserving surgery for
young women with stage IA1 cervical cancer: safety and access.
Obstet Gynecol 115(3): 585-590, 2010.
6 Creasman WT, Zaino RJ, Major FJ, DiSaia PJ, Hatch KD and
Homesley HD: Early invasive carcinoma of the cervix (3 to 5
mm invasion): risk factors and prognosis. A Gynecologic
Oncology Group study. Am J Obstet Gynecol 178(1): 62-65,
1998.
7 Nam JH, Kim SH, Kim JH, Kim YM, Kim YT and Mok JE:
Nonradical treatment is as effective as radical surgery in the
management of cervical cancer stage IA1. Int J Gynecol Cancer
12(5): 480-484, 2002.
8 Steed H, Capstick V, Schepansky A, Honore L, Hiltz M and
Faught W: Early cervical cancer and parametrial involvement: is
it significant? Gynecol Oncol 103(1): 53-57, 2006.
9 Covens A, Rosen B, Murphy J, Laframboise S, DePetrillo AD,
Lickrish G, Colgan T, Chapman W and Shaw P: How important
is removal of the parametrium at surgery for carcinoma of the
cervix? Gynecol Oncol 84(1): 145-149, 2002.
10 Plante M and Roy M: New approaches in the surgical
management of early stage cervical cancer. Curr Opin Obstet
Gynecol 13(1): 41-46, 2001.
11 Tseng CJ, Chang CC, Tseng CC, Hou HC, Wang CB, Chen CH,
Soong YK and Pao CC: Loop conization for the treatment of
microinvasive carcinoma of the cervix. Int J Gynecol Cancer
16(4): 1574-1578, 2006.
12 Lee SJ, Kim WY, Lee JW, Kim HS, Choi YL, Ahn GH, Lee JH,
Kim BG and Bae DS: Conization using electrosurgical
conization and cold coagulation for international federation of
gynecology and obstetrics stage IA1 squamous cell carcinomas
of the uterine cervix. Int J Gynecol Cancer 19(3): 407-411, 2009.
13 Hertel H, Köhler C, Grund D, Hillemanns P, Possover M,
Michels W and Schneider A; German Association of
Gynecologic Oncologists (AGO): Radical vaginal trachelectomy
(RVT) combined with laparoscopic pelvic lymphadenectomy:
prospective multicenter study of 100 patients with early cervical
cancer. Gynecol Oncol 103(2): 506-511, 2006.
14 Elliott P, Coppleson M, Russell P, Liouros P, Carter J, MacLeod
C and Jones M: Early invasive (FIGO stage IA) carcinoma of
the cervix: a clinico-pathologic study of 476 cases. Int J Gynecol
Cancer 10(1): 42-52, 2000.
15 Benedet JL, Bender H, Jones H 3rd, Ngan HY and Pecorelli S:
FIGO staging classifications and clinical practice guidelines in the
management of gynecologic cancers. FIGO Committee on
Gynecologic Oncology. Int J Gynaecol Obstet 70(2): 209-262,
2000.
16 Eskander RN, Randall LM, Berman ML, Tewari KS, Disaia PJ
and Bristow RE: Fertility preserving options in patients with
gynecologic malignancies. Am J Obstet Gynecol 205(2): 103110, 2011.
17 Pecorelli S: Revised FIGO staging for carcinoma of the vulva,
cervix, and endometrium. Int J Gynaecol Obstet 105(2): 103104, 2009.
18 Chernofsky MR, Felix JC, Muderspach LI, Morrow CP, Ye W,
Groshen SG and Roman LD: Influence of quantity of lymph
vascular space invasion on time to recurrence in women with
early-stage squamous cancer of the cervix. Gynecol Oncol
100(2): 288-293, 2006.
19 Lee KB, Lee JM, Park CY, Lee KB, Cho HY and Ha SY: Lymph
node metastasis and lymph vascular space invasion in
microinvasive squamous cell carcinoma of the uterine cervix. Int
J Gynecol Cancer 16(3): 1184-1187, 2006.
20 Rogers LJ and Luesley DM: Stage IA2 cervical carcinoma: how
much treatment is enough? Int J Gynecol Cancer 19(9): 16201624, 2009.
21 Kodama J, Mizutani Y, Hongo A, Yoshinouchi M, Kudo T and
Okuda H: Optimal surgery and diagnostic approach of stage IA2
squamous cell carcinoma of the cervix. Eur J Obstet Gynecol
Reprod Biol 101(2): 192-195, 2002.
22 Mota F: Microinvasive squamous carcinoma of the cervix:
treatment modalities. Acta Obstet Gynecol Scand 82(6): 505509, 2003.
23 Creasman WT and Kohler MF: Is lymph vascular space
involvement an independent prognostic factor in early cervical
cancer? Gynecol Oncol 92(2): 525-529, 2004.
24 Raspagliesi F, Ditto A, Quattrone P, Solima E, Fontanelli R,
Dousias V, Kusamura S and Carcangiu ML: Prognostic factors
in microinvasive cervical squamous cell cancer: long-term
results. Int J Gynecol Cancer 15: 88-93, 2005.
25 Costa S, Marra E, Martinelli GN, Santini D, Casadio P, Formelli
G, Pelusi C, Ghi T, Syrjänen K and Pelusi G: Outcome of
conservatively treated microinvasive squamous cell carcinoma of
the uterine cervix during a 10-year follow-up. Int J Gynecol
Cancer 19(1): 33-38, 2009.
26 Burghardt E, Girardi F, Lahousen M, Pickel H and Tamussino
K: Microinvasive carcinoma of the uterine cervix (International
Federation of Gynecology and Obstetrics Stage IA). Cancer.
67(4): 1037-1045, 1991.
27 Winter R: Conservative surgery for microinvasive carcinoma of
the cervix. J Obstet Gynaecol Res 24(6): 433-436, 1998.
Received April 9, 2014
Revised June 2, 2014
Accepted June 3, 2014
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