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Abstract
Objective. Current surgical treatment of cervical carcinoma is based on the assumption of undirected intra- and transcervical local tumor
propagation and is executed by tailored excision of the paracervical tissues. We have recently demonstrated that cervical carcinoma spreads for
extended phases during its malignant progression within the permissive compartment of the Mllerian morphogenetic unit (Lancet Oncol
2005;6:75156) and proposed Mllerian compartment resection as the new principle for surgical treatment of cervical cancer. Do we need a new
classification of radical hysterectomy?
Methods. The therapeutic index of the surgical treatment of cervical carcinoma FIGO stages IB1IIB by extirpation of the Mllerian compartment
through total mesometrial resection (TMMR) without adjuvant radiation is evaluated by an ongoing controlled prospective trial at the University of
Leipzig.
Results. From 7/1998 to 12/2006, 163 patients with cervical carcinoma, FIGO stages IB1 (n = 94), IB2 (n = 21), IIA (n = 14) and IIB (n = 34) have
been treated with TMMR and nerve-sparing therapeutic lymph node dissection. Twenty-five patients received (neo)adjuvant chemotherapy. No
patient underwent adjuvant radiotherapy although 95 patients (58%) would have needed this additional modality in case of conventional radical
hysterectomy because of their high-risk histopathological tumor features. At a median follow-up time of 45 months (3104 months), recurrence-free
and disease-specific overall survival is 93% and 96%. Maximum treatment-related morbidity according to the Franco-Italian score has been grade 2 in
12 patients (8%).
Conclusions. The developmental view of local tumor spread and surgical anatomy holds a great promise for improving the therapeutic index of
surgical cervical cancer therapy and challenges both the classification of radical hysterectomy based on tailored paracervical resection and the
indication for adjuvant radiation.
2007 Elsevier Inc. All rights reserved.
Keywords: Cervical cancer; Radical hysterectomy; Human embryology; Pelvic anatomy; Adjuvant radiation
Introduction
Conventional concepts of local tumor spread follow the
model of undirected perifocal tumor growth. Tumor propagation
per continuitatem is considered to be a random process with
migrating tumor cells or cell clusters favoring paths of low
mechanical resistance such as vascular or perineural spaces. The
translation of that view into clinical practice has led to radical
organ resection and wide tumor excision as surgical treatment
for local tumor control. Radical organ resection removes the
macroscopically complete tumor-bearing organ together with
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E-mail address: michael.hoeckel@medizin.uni-leipzig.de.
0090-8258/$ - see front matter 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2007.07.049
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Tumor related:
evidence for tumor involvement of the vesicouterine/-vaginal space from
clinical and/or MRI evaluation;
neuroendocrine tumor histology;
distant metastases except in the periaortic lymph nodes.
The tumors are initially staged strictly according to the FIGO criteria [5]. In
addition, all patients undergo pelvic MRI and the scans are presented during the
clinical examination under anesthesia. Patients with locally advanced tumors
(FIGO stages IB2, IIA N4 cm and IIB) and those with suspected lymph node
metastases are screened for distant metastases with CT abdomen, thorax, bone
scan or PET/CT.
TMMR is supplemented by nerve-sparing therapeutic pelvic lymph node
dissection [7]. In case of pelvic lymph node metastases detected by
intraoperative frozen section investigation, nerve-sparing staged periaortic
lymph node dissection is added. Bilateral ovariectomy is recommended in case
of adenocarcinoma [8] and with proven lymph node metastases. The step-bystep surgical techniques of TMMR and nerve-sparing pelvic and periaortic
lymph node dissection have been described earlier [6,7].
Patients with tumors of 5 cm clinical size receive neoadjuvant
chemotherapy (56 weekly courses cisplatinum 40 mg/m2). All patients are
informed about the concept and details of the surgical procedure. They have to
give informed consent before initiation of the treatment.
The TMMR specimens and the resected lymph node-bearing tissues are
prepared for histopathological investigation according to the protocol of the
Cancer Committee of the College of American Pathologists [9]. Resection status
is examined in paraffin tissue blocks covering the resection margins of the
vaginal cuff and the vascular as well as suspensory mesometrial tissue. The
anterior (bladder) and posterior (rectal) resection margins of the cervical stroma
are evaluated from tissue blocks containing the tumor and the adjacent surgical
margin of the cervix which have been inked.
From 2006 on patients with two and more pelvic lymph node metastases and
all patients with periaortic lymph node metastases have been offered adjuvant
chemotherapy with up to 6 courses cisplatinum 75 mg/m2 at 3 weeks intervals.
All patients treated with TMMR are enrolled in a follow-up program of 3 months
intervals for the first 2 years postoperatively and 6 months intervals thereafter.
All complications (intra- and postoperative) and sequelae of the treatment are
specified and graded according to the Franco-Italian glossary [10]. Diseasespecific overall and relapse-free survival is analyzed with the KaplanMeier
method using SPSS software (version 14.0). The study has been approved by the
Ethics Committee of the Medical Faculty of the University of Leipzig.
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Table 1
Histopathologic characterization of 163 TMMR, 163 extended pelvic and 45
periaortic lymph node specimens
Number of patients
Stage
pT1b1 + ypT1b1
pT1b2 + ypT1b2
pT2a
pT2b + ypT2b
pT3a
pN0 + ypN0
pN1 + ypN1
pM0(LYM) + ypM0(LYM)
pM1(LYM)
Resection state
R0/R1
Lymphvascular involvement
L0/L1/LX
V0/V1/VX
Histologic types
Squamous cell carcinoma
Adenocarcinoma
Adenosquamous carcinoma
Other
Invasion depth
1/3/2/3/3/3
101 + 6
15 + 5
6
20 + 9
1
116 + 15
27 + 5
23 + 15
7
162/1
61/98/4
146/14/3
125
28
9
1
47/41/74
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Fig. 2. KaplanMeier curves of relapse-free survival (left panels) and disease-specific survival (right panels) of the whole patient cohort (A, B) and of subgroups stratified for
FIGO stages (C, D) and histopathologic risk factors (E, F). High-risk factors were pN1, pT2b stages and combinations of lymph vascular space involvement, cervical stroma
invasion and tumor size according to the GOG#92 trial in pT1b pN0 stages.
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Table 2
Total number of complications according to the Franco-Italian glossary by organ
system and grade which occurred in 163 patients treated with TMMR
Gastrointestinal
Urinary
Vascular
Cutaneous
Peripheral nerves
Total
G1
G2
7
12
34
3
3
59
2
3
7
1
2
15
G3
G4
Total
9a
15b
41c
4d
5e
74
The 3-year relapse-free and disease-specific survival probabilities are 93% and 96% for the whole group; 98% and 100% for
the histopathological low-risk subgroup of 68 patients and 90%
and 95% for the 95 patients with histopathological high-risk
factors (pN1; pT2b; lymphvascular space involvement, cervical
stroma invasion and tumor size according to the GOG#92 trial
[11]) who did not receive adjuvant radiation.
By histopathological investigation macroscopic and microscopic extracervical continuous local tumor spread (pT2a, pT2b
and pT3a) was detected in 36 patients. In 59 additional cases
exhibiting pelvic and periaortic lymph node metastases or poor
prognostic combinations of tumor size, deep cervical stroma
invasion and lymph vascular space involvement, a high risk of
occult extracervical local tumor spread had to be assumed [12].
Since additional radiation has been used not at all, the high R0
resection rate and the low local failure rate strongly support the
hypothesis that macroscopic, microscopic and occult local tumor
spread is confined to the resected Mllerian compartment in
FIGO stages IBIIB cervical carcinomas.
The complications and sequelae of the TMMR treatment in
163 patients assessed according to the Franco-Italian glossary
[10] are compiled in Table 2. TMMR treatment did not lead to
severe (grades 3 and 4) complications/sequelae. The most
frequent sequelae were lymph edema of the legs or the mons
pubis region classified as mild (grade 1) in 16 patients (10%)
and moderate (grade 2) in 6 patients (4%). One hundred and
three patients (63%) had a completely uneventful posttreatment
course without sequelae other than infertility/menopause and a
laparotomy scar.
Resection margin status, pelvic control, relapse-free and
disease-specific survival and treatment-related morbidity
obtained by TMMR without adjuvant radiation are favorable
Table 3
Terminology of subperitoneal pericervicovaginal tissues
Uterocentric view
Ligamentfocused view
Developmental view
Anterior parametrium
Vesicouterine
ligament
Pubocervical
ligament
Anterior leaf
Vesicocervical
ligament
Posterior leaf
Vesicovaginal
ligament
Cardinal ligament
Transverse
cervical ligament
Mesobladder
Lateral parametrium,
paracervix, paracolpium
Posterior parametrium
Uterosacral
ligament
Rectouterine
ligament
Rectovaginal
ligament
Anterior mesobladder
Posterior mesobladder
Vascular mesometrium
Deep internal iliac
(paracervical) lymph nodes
Distal inferior hypogastric
plexus
Suspensory mesometrium
Proximal inferior
hypogastric plexus
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