Gynecologic Oncology 125 (2012) 168–174
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Pattern analysis of regional spread and therapeutic lymph node dissection in cervical cancer based on ontogenetic anatomy Michael Höckel a,⁎, Lars-Christian Horn b, Elisabeth Tetsch a, Jens Einenkel a a b
Department of Gynecology, University of Leipzig, Leipzig, Germany Division of Breast, Gynecologic & Perinatal Pathology, Institute of Pathology, University of Leipzig, Leipzig, Germany
a r t i c l e
i n f o
Article history: Received 24 October 2011 Accepted 1 December 2011 Available online 8 December 2011 Keywords: Cervical cancer Lymph node metastasis Lymph node dissection Embryology Anatomy
a b s t r a c t Objective. In cervical cancer lymph node dissection is applied for regional tumor staging. Up to now, the use of (chemo)radiation in the nodal positive patient has prevented the exact pattern analysis of regional tumor spread and the evaluation of the therapeutic role of lymph node dissection. New surgical techniques founded on ontogenetic instead of functional anatomy for the treatment of cervical cancer dispensing with adjuvant radiotherapy offer the possibility to accurately determine the topography of regional lymph node metastases which is the prerequisite for optimized diagnostic and therapeutic lymph node dissection. Methods. Patients with cervical cancer FIGO stages IB–IIB were treated with total mesometrial resection (TMMR) and lymph node dissection after exposing the ontogenetic visceroparietal compartments of the female pelvis. Resected lymph nodes were allocated to regions topographically defined by the embryonic development of the iliac, lumbar and mesenteric lymph systems prior to histopathological assessment. Results. 71 of 305 treated patients had lymph node metastases. Topographic distribution of these metastases at primary surgery and analysis of pelvic failures showed a spatial pattern related to the ontogenesis of the abdominopelvic lymphatic system. Five-year locoregional tumor control probability was 96% (95% CI: 94–98) for the whole group and 87% (95% CI: 77–97) for nodal positive patients. Conclusions. The pattern of regional spread in cervical cancer can be comprehended and predicted from ontogenetic lymphatic compartments. In patients with early cervical cancer lymph node dissection based on ontogenetic anatomy achieves high regional tumor control without adjuvant radiation. © 2011 Elsevier Inc. All rights reserved.
Introduction Locoregional tumor control is essential and for many cancers sufficient to cure the disease. To achieve this goal for early cervical carcinoma, current clinical practice applies either primary chemoradiation or surgery followed by adjuvant (chemo) radiation in case of lymph node metastases. Systematic pelvic lymph node dissection is presently the most accurate means of determining the nodal state but its therapeutic role is not settled. There is some evidence from observational and retrospective studies that the resection of pelvic lymph nodes has a therapeutic effect in pN0 cases [1] and with bulky metastases prior to adjuvant chemoradiation [2]. Pelvic control in nodal positive patients after surgical treatment without adjuvant radiation has not been systematically assessed but is regarded as unsatisfactory. However, multimodal therapy of nodal positive cervical cancer by radical surgery and (chemo)radiation causes significant complications and still does not prevent pelvic recurrences in many instances ⁎ Corresponding author at: Department of Gynecology, Women's and Children's Center, University of Leipzig, Liebigstrasse 20a, 04103 Leipzig, Germany. Fax: + 49 341 9723409. E-mail address: michael.hoeckel@uniklinik-leipzig.de (M. Höckel). 0090-8258/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2011.12.419
[3,4]. Moreover, as long as (chemo)radiotherapy is administered sterilizing lymph node metastases left behind after lymph node dissection the accurate pattern of regional spread in cervical cancer cannot be determined, and – in consequence – optimal cancer surgery cannot be established. We have demonstrated that cancer of the lower female genital tract permeates locally within permissive ontogenetic compartments. New surgical techniques based on ontogenetic anatomy such as total mesometrial resection (TMMR) achieve excellent pelvic control and overall survival rates without adjuvant radiotherapy [5,6]. Dispensing with adjuvant radiation allowed us for the first time to elucidate the precise topography of regional spread in cervical cancer from the histopathological assessment of the resected lymph nodes and the diagnostic workup of the postsurgical pelvic recurrences and to establish the surgical criteria for lymph node dissection aiming at regional tumor control. Another aim of this study was to analyze the regional spread pattern of cervical cancer with special consideration of the development of the lymphatic system. Ontogenetically, the pelvic lymphatic system develops from the bilateral iliac lymph plexus [7]. It connects to the bilateral inguinal lymph plexus upstream and the bilateral lumbar and the single mesenteric lymph plexus downstream. Primary lymph nodes differentiate within the iliac and mesenteric
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lymph plexus (lymph basins) whereas secondary lymph nodes are intercalated into the collecting lymph vessels efferent from the pelvic visceral compartments [8,9]. Finally, with an update of the clinical results of our ongoing prospective TMMR study sustained regional tumor control through lymph node dissection based on ontogenetic anatomy without adjuvant radiotherapy should be demonstrated. Methods Surgical technique The surgical techniques of lymph node dissection supplementing total mesometrial resection (TMMR) have been described before [5,6]. The pelvic visceroparietal ground plan is exposed by dissecting the areolar fibrous tissue to create a “paravisceral space” down to the pubo- and iliococcygeus muscles and a “presacral space” to the ventral margin of the inferior hypogastric plexus separated by the urogenital mesentery. The adventitia of all iliac vessels is completely stripped off along with the lymph vessels and nodes mobilizing the vessels against each other, towards the peripheral nerves and towards the parietal muscles and fasciae. The paravisceral fat pad is resected completely, the presacral one to S2. The genitofemoral and obturator nerves, the lumbosacral trunc and the proximal sciatic nerve are exposed. The superior hypogastric plexus and the hypogastric nerves are mobilized and preserved. Parietal branches of the internal iliac vessels are sealed and cut to remove the gluteal lymph nodes. The external iliac and paravisceral fractions are intraoperatively assessed by frozen section together with the TMMR specimen containing the mesometrial lymph nodes. If metastases are diagnosed, lymph node dissection is extended downstream to the paraaortic region. The ascending colon, duodenum, and sigmoid colon are mobilized cranially to expose the vena cava and abdominal aorta. The adventitia of the vena cava and of the aorta is stripped off caudocranially followed by the removal of the paracaval, interaortocaval and paraaortal fatty tissue. The large vessels are then lifted with elastic loops to remove all dorsal lymph fatty tissue thus exposing the spine. Lumbar vessels may have to be sealed and cut for the thoroughness of the lymph node dissection, however, the sympathetic trunc and its ganglia are preserved. Unless encased by nodal conglomerates the lumbar splanchnic nerves are isolated and spared. Paraaortic lymph node dissection is performed first to the level of the inferior mesenteric artery, and the surgical specimen is again histopathologically examined using frozen sections. If no metastases are detected, the procedure is terminated, otherwise dissection proceeds further cranially in the same manner up to the level of the left renal vein. Patients and specimens Since October 1999 all consecutive patients with cervical cancer FIGO stages IB–IIA admitted to our center without comorbidity not compatible with major pelvic surgery have been included in the prospective TMMR trial after having given written informed consent. Patients with FIGO stage IIB cancers are also offered to participate if tumor invasion of the bladder can be preoperatively excluded by cystoscopy, MRI and sonography. The patients' BMI limit for inclusion was raised from 35 to >40 since 2005. The study had been approved by the local ethics committee (University of Leipzig Medical School). Until 2009 patients whose tumor size exceeded 5 cm received neoadjuvant chemotherapy (up to 6 cycles of cisplatin 40 mg/m 2 weekly). Since 2006 patients with 2 and more lymph node metastases are treated with adjuvant chemotherapy (up to 6 cycles of cisplatin 75 mg/m 2 every 3 weeks). The surgical specimens are histopathologically assessed according to Horn et al. [10]. Adjuvant radiotherapy is explicitly excluded.
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Complications Complications are prospectively specified and graded using the Franco-Italian glossary [11]. In addition, a lymph edema assessment study according to the International Society of Lymphology and the European Center for Lymphology (Földi Clinic, Hinterzarten, Germany) systematically examined patients for lymph edema specifying their location, stage and grade [12]. The investigation consisted of history taking, systematic whole body inspection and palpation (skin impression and Stemmer tests) with 100 randomly assigned patients representing the complete follow up between 3 months and 5 years postoperatively. The patients rated the distress produced by the symptoms of the lymph edema in a 4-item questionnaire. Relapse diagnostics Patients with suspected tumor relapse from the physical examination during the follow-up visit or with symptoms indicative for disease recurrence undergo pelvic MRI, gynecologic examination under anesthesia and transvaginal and transrectal core biopsies to identify and characterize pelvic lesions. For the detection of distant metastases whole body CT or PET–CT is applied. Statistical analysis Disease-free and overall survival probabilities are calculated with the Kaplan–Meier method using PASW Statistics, version 18. For the comparison of survival probabilities the log rank test is applied. Results Lymph node topography The topographic lymph node distribution compiled according to the ontogenetic anatomy of the female genital tract from more than 14.000 nodes of 305 patients with cervical cancer is demonstrated in Figs. 1, 2 and Table 1. Median age of the patients was 43 years (range: 24–79 years). The histopathological tumor features are given in the Supplementary Table S1.Two types of lymph nodes are topographically discriminated with regard to the development of the lymphatic system: (i) primary parietal nodes accompanying the large lumbopelvic vessels and (ii) secondary nodes intercalated into mesenteries. The parietal pelvic lymph nodes are subdivided into 3 bilateral fractions and one single fraction with respect to the urogenital mesentery and the large vessel axis: • The external iliac nodes located along the external iliac artery and vein between the inguinal canal and the iliac bifurcation. • The paravisceral nodes distributed within the pyramid-shaped fat pad between the pelvic brim, obturator muscle and membrane, pubo- and iliococcygeus muscles laterocaudally and the urogenital mesentery, internal iliac vessels and proximal sciatic nerve mediocranially. • The common iliac nodes topographically related to the common iliac artery and vein from the iliac to the aortic bifurcations. • The presacral nodes within another pyramidal fat pad extending from the aortic bifurcation (top) to the level of S2 (base). The intercalated pelvic lymph nodes of the lower Müllerian compartment are located in the bilateral vascular mesometria, termed mesometrial nodes. Downstream from the pelvis the paraaortic lymph nodes are divided into three fractions: • The inframesenteric nodes located laterally and dorsally to the distal vena cava inferior and abdominal aorta, interaortocavally and ventrally to the large vessels from the bifurcation up to the branching of the inferior mesenteric artery.
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Fig. 1. Pelvic (A–F) and paraaortic (G, H) lymph node regions at risk for lymphatic spread of early cervical cancer. The drawings illustrate their topography with regard to ontogenetic anatomy. In all drawings the parietal peritoneum has been omitted exposing the pelvic retro- and subperitoneum from which the fatty and lymphatic tissues have been removed. A, overview demonstrating the pelvic lymph node regions with the Müllerian compartment highlighted green. To clarify the complex spatial relations, the Müllerian compartment is dissected in the sagittal plane. On the right side the post-resection situs after TMMR is shown. The right bladder mesentery is displaced medially by a loop, the right external iliac vessels are retracted laterally. B, right external iliac lymph node region. C, right paravisceral lymph node region. D, left visceral mesometrium, site of intercalated lymph nodes of the lower Müllerian compartment. E, right common iliac lymph node region. F, presacral lymph node region. G, inframesenteric paraaortic lymph node region. H, infrarenal paraaortic lymph node region.
• The infrarenal nodes situated at corresponding sites of the large vessels between the level of the inferior mesenteric artery and the left renal vein. • The suprarenal nodes found between the level of the left renal vein and the diaphragm. (This region was not systematically dissected in this study.)
Pattern of regional spread From 370 lymph node metastases the regional metastatic pattern is deduced with respect to the lymph node topography as described above (Table 1). 71 of the 305 patients with cervical cancer stages pT1b1 to pT2b had pelvic and 19 had pelvic and paraaortic metastases
Fig. 2. Pelvic and paraaortic lymph node regions at risk for lymphatic spread of early cervical cancer. Intraoperative view on lymph node regions topographically defined with regard to ontogenetic anatomy as illustrated with Fig. 1. The lymph nodes have been completely removed by stripping the adventitia of the major vessels and extirpating the parietal pelvic and the paraaortic fat bodies. A, right external iliac lymph node region. B, right paravisceral lymph node region. C, right common iliac lymph node region. D, presacral lymph node region. E, inframesenteric paraaortic lymph node region. F, infrarenal paraaortic lymph node region. In all panels the caudal position of the patient is at the left side of the figure at ventrodorsal view. In panels A–C the right pelvic side wall is shown; panels D–F expose the central retroperitoneum.
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Table 1 Lymphatic spread of cervical cancer pT1b-2b related to the pelvic and paraaortic lymph nodes downstream from the lower Müllerian compartment. # Lymph nodes
Pelvic lymph nodes Left external iliac Right external iliac Left paravisceral Right paravisceral Left mesometrial Right mesometrial Left common iliac Right common iliac Presacral Paraaortic lymph nodes Inframesenteric Infrarenal
# Metastases
Mean ± SD
Median (range)
Mean ± SD
Median (range)
45 ± 11 5.9 ± 2.4 6.1 ± 2.5 6.1 ± 2.5 6.4 ± 2.9 2.4 ± 1.8 2.3 ± 1.8 6.3 ± 2.7 5.5 ± 2.6 6.3 ± 3.2 23.1 ± 5.6 9.8 ± 3.9 12.9 ± 5.3
44 (15–104) 6 (1–14) 6 (1–14) 6 (1–20) 6 (1–19) 2 (1–11) 2 (1–11) 6 (1–16) 5 (1–18) 6 (1–20) 24 (14–33) 9 (5–18) 12 (7–26)
3.9 ± 5.3 1.4 ± 0.9 1.5 ± 0.8 1.4 ± 0.8 1.4 ± 0.8 1.5 ± 0.8 1.1 ± 0.3 4.8 ± 3.6 2.6 ± 1.3 2.4 ± 2.1 5.0 ± 6.7 4.3 ± 4.7 4.8 ± 4.2
2 (1–33) 1 (1–5) 1 (1–3) 1 (1–4) 1 (1–4) 1 (1–4) 1 (1–2) 3 (1–11) 3 (1–4) 2 (1–9) 2 (1–20) 2 (1–15) 3 (1–11)
(Supplementary Table S1). For the pattern analysis 9 patients who received neoadjuvant chemotherapy were excluded. All 21 singular metastases were located in the external iliac (41%), paravisceral (37%), and in the mesometrial nodes (22%) representing the firstline nodes of the uterine cervix. All 41 cancers with two and more lymph node metastases (median 3, range 2–53) had at least one metastasis in the first-line nodes. In 18 patients multiple metastases were restricted to the first-line nodes; in another 18 patients the common iliac and presacral nodes were metastatically involved too. External iliac and paravisceral metastases occurred together with metastases in both the common iliac and presacral nodes whereas mesometrial metastases coexisted only with metastases in presacral nodes. Five patients with multiple metastases showed involvement of the first-line pelvic lymph nodes and the inframesenteric paraaortic lymph nodes “skipping” the downstream pelvic lymph node regions. Paraaortic lymph node metastases were located in the inframesenteric nodes in all 16 cases. Six patients had additional metastases in the infrarenal nodes. One patient developed a metastasis in a suprarenal lymph node. The median and mean numbers of lymph node metastases were similar in the pelvic and paraaortic regions. However, within these regions the median and mean numbers of lymph node metastases increased downstream. The multiplication effect was most prominent with the external iliac/paravisceral and the common iliac regions reaching a factor of 3. Analysis of tumor relapse At a median observation period of 50 months (3–140 months) 7 of the 71 pN1 patients relapsed locoregionally and 9 developed distant metastases with and without pelvic involvement. In the pN0 group 3 of 234 patients relapsed in the pelvis only, 4 had distant metastases. The characteristics of the pelvic recurrences are compiled in Supplementary Table S2. In the pN1 group MRI identified the site of pelvic relapse at the dorsolateral dissection plane of the Müllerian compartment anterolaterally to the mesorectum in 2 patients, at the endopelvic surface of the pelvic side wall medial to the lumbosacral trunc–proximal sciatic nerve corresponding to the gluteal lymph node region in 4 patients and medial to the coccygeus muscle in 1 patient. In the pN0 group 1 patient had a central vaginal stump recurrence, 2 patients exhibited relapses within the inferior gluteal lymph node region. Survival Five-year overall and relapse-free survival probabilities of the 305 patients with cervical carcinoma stages pT1b–pT2b were 96% (95% CI: 93–99) and 94% (95% CI: 91–97) at a median follow up of 50 months
Singular mets [%]
All pN1 cases Related to mets [%]
Related to location [%]
100 41 0 14 23 13 9 0 0 0 0 0 0
67 11 7 6 7 7 4 11 4 11 33 21 12
89 16 12 10 11 10 10 5 3 10 11 8 3
(3–140 months). The corresponding results for the 234 patients without lymph node metastases (pN0) are 98% (95% CI: 96–100) and 96% (95% CI: 93–99) and for the 71 patients with lymph node metastases (pN1 ± pM1 (LYM)) 87% (95% CI: 77–97) and 70% (95% CI: 57–83). Five-year locoregional relapse free survival probabilities for all patients, the pN0 and the pN1 ± pM1(LYM) patient subgroups are 96% (95% CI: 94–98), 99% (95% CI: 97–100) and 87% (95% CI: 77–97) (Fig. 3). A significant effect of adjuvant chemotherapy could not be demonstrated (see Supplementary Table S3). Complications Thromboembolism occurred in 5, symptomatic lymph cysts in 4, protracted lymphascos in 2 patients. In roughly every second patient a stage 1 lymph edema at a site of the lower body part was clinically detectable. Within this stage 78% of the patients had a fully reversible (grade 1) and 22% a partly reversible (grade 2) lymph edema. Irreversible stage 2 lymph edemas were diagnosed in 2%. Those patients had developed a progression of their stage 1 lymph edema after an erysipela of the proximal leg. 27% of the patients reported to wear occasionally compression stockings, 28% underwent temporary manual compression therapy. Lymph edema caused physical distress in 22%, social distress in 14% and emotional distress in 9% of the patients. Details of the lymph edema investigation are given in Supplementary Table S4. Discussion The current clinical practice to achieve regional tumor control in cervical cancer has led to a scientific dead end as the exact topography of lymph node metastases remains obscure. Even the most sophisticated imaging techniques are not able to detect small or micrometastases. Conventional pelvic and paraaortic lymph node dissection is performed at the discretion of the surgeon. Common to all surgical techniques is the generation of bilateral paravesical and pararectal spaces by dissection of areolar fibrofatty tissue. The more condensed tissue between these surgical artifact spaces (“paracervix”) contains numerous lymph nodes which exhibit a variable risk to harbor metastases [13]. They are retained in an uncontrolled manner when the paracervical tissue is resected tailored to the extent of the local tumor as recommended by current guidelines [14]. As a consequence, undefined amounts of lymph nodes at risk for metastases are left behind in the pelvis. Adjuvant (chemo) radiotherapy is strictly administered in high risk cases and may prevent retained lymph node metastases to become evident in the form of pelvic relapses. This bias explains the different results of previous studies regarding the lymph node topography for cervical cancer metastases [13,15–24].
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Fig. 3. Kaplan–Meier plots of locoregional control probabilities for patients treated with TMMR and therapeutic lymph node dissection. Median follow-up 50 months (3–140 months).
We have defined and mapped the ontogenetic visceral compartments of the female human pelvis differentiated from distinct primordia (anlagen) [5,6,25–27]. Surgery based on this ontogenetic anatomy allows to precisely divide the “paracervix” into (i) parietal lymphatic tissue, (ii) mesometrium and (iii) “mesobladder”. The parietal tissue and the mesometrium are completely removed with TMMR and ontogenetic lymph node dissection, the “mesobladder” is preserved. Adjuvant radiation is not applied. Detailed histopathological investigation of the surgical specimens of the primary tumors and precise diagnostic workup in case of pelvic relapse enabled us
to present the most accurate description of regional tumor spread of early cervical cancer to date. The sites of lymph node metastases in cervical cancer identified in the 71 node positive patients of our study suggest that cancer spreads regionally within ontogenetic lymphatic compartments. The observed spatial pattern of lymph node metastases is fully consistent with the following three theorems: (1) All lymph nodes of a regional lymphatic compartment (i.e. the lymph nodes of the lymph basin and those intercalated in the
Fig. 4. Schematic representation of the lymphatic spread pattern of early stage cervical cancer (FIGO stages IB–IIB) founded on ontogenetic anatomy. A, the iliac, mesenteric and lumbar lymph basins and their sub-basins are integrated into the lymph stream. The Müllerian compartment is connected to the iliac and to the mesenteric lymph basins through the collecting vessels in the mesometrium and mesocolpium which may also contain intercalated lymph nodes. B, first-line lymph nodes of early cervical cancer without infiltration of the uterine corpus. C, downstream lymph node metastases in case of external iliac metastases. D, downstream lymph node metastases in case of paravisceral metastases. E, downstream lymph node metastases in case of mesometrial metastases. F, downstream lymph node metastases in case of inframesenteric paraaortic metastases. CI, common iliac; EI, external iliac; IM, inframesenteric; IP, infundibulopelvic; IR, infrarenal; MM, mesometrial; PS, presacral; PV, paravisceral; SR, suprarenal. Red star, primary cervical cancer; red circle, sites of potential lymph node metastases; red dot, sites of potentially metastasizing lymph node metastases; dotted circle, metastatic location detected in only one instance in the study.
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lymph collectors) have the same “affinity” towards clonogenic tumor cells. (2) The probability of lymph node metastasis depends on the concentration of clonogenic tumor cells in the afferent lymph stream and the “affinity” of the lymph node. (3) Lymph node metastases may produce further metastases downstream [28].
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Nikolaus Lechenbauer made the anatomical (Fig. 1) and the schematic (Fig. 4) drawings. Katja Schmidt, R.N. provided follow-up data. The study was supported by the University of Leipzig and the Leipzig School of Radical Pelvic Surgery.
References Efferent lymph vessels from the permissive local compartment transport the highest concentration of clonogenic primary tumor cells to the intercalated nodes and to the closest nodes of the lymph basin (first-line lymph nodes). Remote downstream nodes of the lymph basin receive less primary tumor cells due to dilution but may develop secondary lymph node metastases from metastases established upstream. Efferent lymph vessels from the downstream nodes of the regional basin are connected to the upstream nodes of an adjacent lymphatic basin which may have a different and eventually higher affinity to the tumor cells than the regional nodes and may develop metastases despite the lower concentration of clonogenic tumor cells. Lymph node metastases are therefore always to be found in the firstline nodes of the regional lymph compartment and can be present in the upstream nodes of the downstream adjacent lymph compartment skipping the downstream nodes of the regional compartment. Metastasizing metastases may increase the number of involved lymph nodes within a lymph compartment downstream. The regional metastatic pattern for cervical cancer is illustrated in Fig. 4. From ontogenetic anatomy and the compartment theory the strategy of lymph node dissection for solid cancers can be defined as follows: for nodal staging the first line nodes have to be resected. The intercalated lymph nodes of non-permissive local compartments can be left in situ. In case of metastases detected in the first-line nodes the upstream nodes of the downstream adjacent lymph compartment has to be removed as well. Therapeutic lymph node dissection involves the first-line nodes and the remaining nodes of the lymph basin. The detection of regional metastases demands the additional extirpation of the upstream sub-basins of the downstream adjacent ontogenetic lymph compartment. As demonstrated with this report, the clinical results of the ontogenetic concept translated into surgery without adjuvant radiotherapy appear to be very promising regarding pelvic tumor control and treatment-related morbidity. If confirmed by others, a major improvement in the therapy of cervical cancer can be expected. There is no evidence from the literature and from the results of our study that chemotherapy significantly impacts regional tumor control in cervical cancer [29,30]. Whether distant metastases and overall survival are influenced cannot be deduced from the available data. Although the studies of sentinel lymph node biopsy for cervical cancer are based on the conventional surgical anatomy, the reported topography of the sentinel nodes is consistent with that of the firstline nodes of the ontogenetic concept [31,32]. The sentinel techniques are diagnostic procedures and appear to lack accuracy with larger tumors. Therefore, therapeutic lymph node dissection based on ontogenetic anatomy for the high risk cases and sentinel lymph node biopsy for the low risk cases may become complementary treatment options for patients with early cervical cancer in the near future with the potential to significantly improve the outcome. Supplementary materials related to this article can be found online at doi:10.1016/j.ygyno.2011.12.419. Conflicts of interest The authors declare to have no conflicts of interest. Acknowledgments Angela Steller photographed the surgical situs (Fig. 2).
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