Lymphatic and nerve distribution throughout the parametrium by DANILO ALDO BALTAZAR CHACON

Gynecologic Oncology 131 (2013) 708–713

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Lymphatic and nerve distribution throughout the parametrium C. Bonneau a, A. Cortez b, R. Lis a, M. Mirshahi a, A. Fauconnier c, M. Ballester d, E. Daraï d, C. Touboul a,d,⁎,1 a

UMRS 872, Centre de Recherche des Cordeliers, 15 rue de l'école de médecine, 75006 Paris, France Department of Pathology, Hôpital Tenon, Université Pierre et Marie Curie Paris VI, 4 rue de Chine, 75020 Paris, France c Department of Obstetrics and Gynecology and Reproductive Medicine, Univ Saint-Quentin-en-Yvelines, Hôpital de Poissy, 10 r Champ Gaillard, 78300 Poissy, France d Department of Obstetrics and Gynecology, Hôpital Tenon, Institut Universitaire de Cancérologie, Université Pierre et Marie Curie Paris VI, 4 rue de Chine, 75020 Paris, France b

H I G H L I G H T S • All parts of the parametrium contained a network of numerous nerve structures. • The distal part of the posterior parametrium has a high nerve density and low lymphatic density. • This raises the question of the relevance of resecting this part of the parametrium during radical hysterectomy.

a r t i c l e

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Article history: Received 10 July 2013 Accepted 4 October 2013 Available online 11 October 2013 Keywords: Cervical cancer Lymph node Nerve Anatomy Parametrectomy Radical hysterectomy

a b s t r a c t Background. Our objective was to concomitantly assess distribution of lymphatic and nerve structures in the parametrium. Methods. Twenty hemipelvises from ten fresh cadavers were dissected to differentiate between, three different parts of the parametrium: the lateral parametrium, the proximal and the distal part of the posterior parametrium. Histologic and immunoﬂuorescence analyses of nerve and lymphatic structures were performed using NSE and LYVE-1 staining, respectively. The percentage of structures was independently scored as 0 (0%), 1 (1–20%), 2 (20–50%), 3 (50–80%), 4 (N80%). Results. The lateral parametrium and the proximal part of the posterior parametrium contained both nerve (scored 2.25 and 2.50, respectively) and lymphatic (scored 2.50 and 2.00, respectively) structures. The distal part of the posterior parametrium also contained numerous nerve structures (scored 2.00) but lymphatic structures were rare (scored 0.88). No difference in nerve distribution was found according to the parts of parametrium while a signiﬁcantly lower distribution of lymphatic vessels was observed in the distal part of the posterior parametrium (p = 0.03). Conclusion. The distal part of the posterior parametrium is of high nerve density and low lymphatic density raising the issue as to whether it should be removed during radical hysterectomy. © 2013 Elsevier Inc. All rights reserved.

Introduction Radical hysterectomy including the removal of the parametrium and either pelvic lymphadenectomy or sentinel lymph node sampling is the gold standard to treat women with early stages of cervical cancer. However, this procedure is associated with a risk of serious intra- and postoperative complications related to the radicality of the operation [1–3]. Morbidity is related not only to the risk of ureteral lesions but also to the denervation associated with parametrectomy. Anatomically, a close relationship between the posterior parametrium and the hypogastric plexus has been shown [4,5]. Part of the hypogastric ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Hôpital Tenon, Paris, Université Pierre et Marie Curie Paris VI, 4 rue de Chine, 75020 Paris, France. Tel.: + 33 1 45 17 55 43; fax : + 33 1 45 17 55 42. E-mail address: cyril.touboul@gmail.com (C. Touboul). 1 Present address: Department of Obstetrics and Gynecology, Hôpital Intercomunal de Créteil, 12 avenue de Verdun, 94000 Créteil, Université Paris Est, Paris XII, France. 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.10.006

plexus – innervating the rectum, the vagina and the bladder – is included in the posterior parametrium, and this explains why resection is associated with a risk of nerve injury causing bladder and rectal dysfunction [1,6]. However, this morbidity has to be balanced against the overriding oncologic goal of the surgery which is to limit risks associated with incomplete resection. To limit the incidence of hypogastric plexus injury during radical hysterectomy, nerve-sparing techniques have been developed over the past ten years [7,8]. Moreover, a new classiﬁcation of radicality has been put forward to include these nerve-sparing techniques in this type of radical hysterectomy [9]. However, the extent to which the different regions of the parametrium are involved by cervical cancer is not completely known. The risk of parametrial involvement – 15% of Ib1 early cervical cancer – is highly associated with lymph node dissemination [10] and seems to be different according to the extent of parametrial involvement [11]. Unfortunately, few data are available which concomitantly analyse the lymphatic

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and nerve distribution in the parametrium and which part of the parametrium could be spared during radical hysterectomy for cervical cancer. Therefore, the objective of this study was to analyse the distribution of nerve and lymphatic structures in the different parts of the parametrium with a view to guiding parametrectomy resection during radical hysterectomy. Material and methods Anatomical dissections of twenty hemi-pelvises from ten fresh cadavers were performed at the surgery school of Paris, to remove the different parts of the parametrium and analyse them histologically and by immunofluorescence to assess both lymphatic and nervous distribution. The chair of our Ethics Committee stated that approval was not necessary for this study. We obtained approval from the Scientific Committee of the School of Surgery of Paris ensuring that the patients had granted permission during their lifetime to use their anatomic parts. Terminology To clarify the terminology of the parametrial region, we used the terminology described by Ercoli et al. [12,13]. We called the tissue located inside the ureter and the deep uterine vein, the “posterior parametrium” (known as the paracervix by some) as reported in a previous anatomic study [14]. We defined three distinct parametrial parts of interest: the lateral parametrium, the proximal posterior parametrium and the distal posterior parametrium (Fig. 1). According to the classification reported by Ercoli et al. [13], the lateral parametrium is included in the supraureteral paracervical pathway; the proximal posterior parametrium in the infraureteral paracervical parametrium (proximal portion); and the distal posterior parametrium in the neural paracervical pathway (deep and distal portion) [13]. Cadaver dissection Bilateral pelvic dissection of ten fresh female cadavers was performed with 20 hemi-pelvises available for anatomical analysis

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and parametrium removal. All subjects were Caucasians. The cadavers were prepared as described in our previous work [14]: an arciform incision was made connecting the lower margin of the twelfth right rib, right anterior superior iliac spine, pubic symphysis, left anterior superior iliac spine and lower margin of the twelfth left rib. The lateral peritoneum and the round ligament were cut and the retrorectal, pararectal and paravesical spaces widely opened. The bladder was dissected after opening the vesicouterine peritoneum. The uncrossing manoeuvre with complete bilateral ureterolysis was performed as previously described [15–17] allowing the lateral parametrium to be removed. The posterior parametrium was then dissected from the cervix to the lateral part of the rectum. We removed the proximal part (i.e. the portion of 1.5 cm from the cervix) and the distal part of the posterior parametrium (i.e. the portion of 1.5 cm up to the lateral part of the rectum) separately (Fig. 1). One hemi-pelvis was used from each subject for histologic analysis and the other for the immunofluorescence procedure. Histology The parametrial samples were fixed with 3.7% paraformaldehyde and were dehydrated through ethanol baths of increasing concentration. The tissues were then cleared by toluene to remove the alcohol and infiltrated with molten paraffin wax. The pieces were placed into molds along with liquid embedding wax. Each piece was then cut with a microtom into 10-micrometer sections – in a sagittal plane for posterior parametrium and in a frontal plane for the lateral parametrium – and stained with Haematoxylin Eosin and Safran. Immunofluorescence Blocks of parametrium were embedded in OCT then snap-frozen in liquid nitrogen and stored at − 80 °C; 20, 25 and 30-μm sections were prepared using an AS 620 SME cryostat (Thermo Shandon, Cergy-Pontoise, France). The sections were fixed with 3.7% paraformaldehyde (Sigma) before staining. The primary antibodies used were the mouse anti human NSE (Abcam, Ab 8324, clone 5G10) and the rabbit anti human LYVE-1 (Abcam, Ab36993, polyclonal). The nerves were stained by surface staining and the lymphatic components by both a surface and intracytoplasmic vesicular staining. The secondary antibodies used were the antimouse Fluorescein isothiocyanate (goat polyclonal secondary antibody to mouse FITC, Abcam ab6785) and the anti-rabbit Texas Red (donkey polyclonal antibody to rabbit, TR, Abcam ab6800). The non-specific sites were blocked with PBS with 1% bovine serum albumin and the sections permeabilized overnight with 0.3% triton. The sections were incubated with the primary antibodies (1:250) overnight and washed three times in PBS. They were then incubated for three hours with the secondary antibody (1:1000), before being washed three times in PBS. The nuclei were counterstained by 4-, 6-diamidino-2- phenylindole (Invitrogen) for five minutes and the slides mounted with the Slowfade Gold Antifade Reagent ® (Invitrogen) before being analyzed with a Zeiss confocal microscope Laser Scanning Microscope 710 (Carl Zeiss). Pictures were analyzed with Zen 2009 V5, 0,0228 software (Carl Zeiss). Histometric analysis

Fig. 1. Representation of the different parts of the parametrium resected for further analysis: A) lateral parametrium and paracervix; B) proximal part of the posterior parametrium; B′) distal part of the posterior parametrium; Bl = bladder; Ut = uterus; Va = vagina; Re = rectum; Ur = ureter.

A pathologist who was unaware of the origin of the samples screened the slides. The proportion of nerve and lymphatic structures in each slice was evaluated separately using the score detailed below. For each type of analysis, we repeated the test on three different slides of the same sample. The percentage of nerve and lymphatic structures was independently scored as 0 (0%), 1 (1–20%), 2 (20–50%), 3 (50–80%), 4 (N80%) [18].

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Statistical analysis

Immunoﬂuorescence

The Kruskal–Wallis test was used to compare intensity scores. P b 0.05 was considered to denote a signiﬁcance.

Confocal analysis of the samples also revealed three different structures depending on the part of the parametrium. At the level of the lateral parametrium, we observed wide cellular regions without any staining for lymphatic and nerves and accounting for around 50% of the sections. Next to these areas, a nerve staining surrounded large lymphatic regions containing lumen (Fig. 2b). Mean scores were 2.25 and 2.50 respectively for the nerves and the lymphatic structures (Table 1). At the level of the proximal posterior parametrium, there were more nerve structures organized in a dense and complex network in regions rich in cells (Fig. 3b). The mean nerve score was 2.50 (Table 1). We also observed more compact lymphatic structures with a small lumen passing through the nervous network (Fig. 3b). The mean score was 2.00 for the lymphatic structures, which was not statistically different from the lateral parametrium content (Table 1). At the level of the distal posterior parametrium, there was also a considerable amount of nerve structures but organised in a less dense network. The distribution was homogeneous in the sections in regions with a moderate amount of cells. The nerve mean score was 2.00, without signiﬁcant difference with the other parts of the parametrium (Table 1). There were no or very few lymphatic signals at this level, representing a mean score of 0.88 (Fig. 4b). The proportion of lymphatic structures at the level of the distal posterior parametrium was statistically lower compared to the other parts of the parametrium (p = 0.03).

Results Results of cadaver dissection Open dissection of twenty hemi-pelvises from fresh cadavers confirmed our previous findings [14] regarding the different parts of the parametrium. The lateral parametrium was oblique ventrally, caudally and inward, formed by the paravesical space ventrally, the pararectal space dorsally, and comprised the fatty tissue accompanying the uterine artery from its origin (Fig. 1). The posterior parametrium was oblique dorsally and caudally, constituted by a dense connective tissue from the lateral side of cervix and vagina to the lateral part of the rectum located between the pararectal and rectovaginal spaces (Fig. 1). The most cephalic and internal part of this tissue adjoining the rectum was fused with the uterosacral ligament and the caudal portion was part of the sacrorectogenitopubic blade. We found that the “paracervix” and “paravagina” were contained within the posterior parametrium, medially to the ureter and the deep uterine vein. We removed the lateral parametrium (A), the proximal part (B) and the distal part (C) of the posterior parametrium separately (Fig. 1). Histologic findings

Discussion Histologic examination of the samples revealed three different structures in relation to the level of the parametrial resection. Examination of the lateral parametrium revealed a fatty tissue rich in adipocytes – accounting for more than 60% of the tissue – with neurovascular structures. It was thus easy to distinguish. Nerves constituted a mean histologic score of 1.63 as summarised in Table 1 (Fig. 2a). The proximal posterior parametrium was a dense fibrous tissue containing numerous conjunctive and neurovascular structures but no or very few adipocytes. The conjunctive and nervous structures were very similar and therefore difficult to differentiate. The nerves constituted a mean histological score of 1.50 as summarised in Table 1 (Fig. 3a). The distal part of the posterior parametrium was a mix of the fatty tissue of the lateral parametrium and the dense fibrous tissue of the proximal posterior parametrium (Fig. 4a). Nerves constituted a mean histologic score of 2.00 (Table 1). The nerve structures were not statistically different according to the different parts of the parametrium. Neither the lymphatic structure nor the lymph nodes could be observed with this technique in the whole of the parametrium.

Table 1 Mean score (SD) of the lymphatic and nervous constitution according to the level of parametrial resection.

Nerves Lymphatic

HES IF HES IF

Lateral parametrium

Proximal part of the posterior parametrium

Distal part of the posterior parametrium

1.63 (0.74) 2.25 (0.46) 0 2.50 (0.53)

1.50 (0.93) 2.50 (0.93) 0 2.00 (0.75)

2.00 (0.53) 2.00 (0.53) 0 0.88 (0.35)

NS NS NS 0.001

a Using a Kruskall–Wallis test. HES: Hematoxylin eosin safran staining. IF: Immunoﬂuorescence.

The present study demonstrates that the parametrium is rich in nerves with various distributions according to the anatomical location. We also showed that the lateral parametrium and the proximal part of the posterior parametrium contained lymphatic structures as opposed to the distal part of the posterior parametrium which was poor in lymphatic structures. These dissections reveal that the current terminology used to describe the parametrium could be simpliﬁed. The parametrium could be divided into the three main regions we already described in a previous anatomic study [14]: i) the supraureteral lateral parametrium; (ii) the anterior parametrium; (iii) and the posterior parametrium. The lateral parametrium is the parametrial blade following the uterine artery and removed after the uncrossing manoeuvre of a type C radical hysterectomy, corresponding to the supraureteral paracervical pathway described by Ercoli et al. [13]. This step is consensual in the literature [19–22]. The parametrial blade containing the uterosacral ligament, the rectovaginal fascia and the paracervix, running medially to the ureter we called the posterior parametrium, corresponding to the infraureteral paracervical pathway (for the proximal part) and the neural paracervical pathway (for the distal part) described by Ercoli et al. [13]. The description of this posterior parametrectomy is less precise and consensual. After the lateral parametrium is dissected and uncrossed from the ureter, a wide resection of this posterior parametrium was historically reported by Piver and Meigs [23–25]. However, since the ﬁrst description of the technique, there has been a tendency to reduce the radicality of hysterectomy to limit postoperative morbidity. Moreover, resection of the posterior parametrium is no longer consensual. The length of posterior parametrium from the uterine cervix which should be removed is not clearly established and varies from team to team. Furthermore, the oncologic importance of this region also remains unclear partly related to the lack of data about nerve and lymphatic distribution. Selman et al. reported a mere 8% of parametrial involvement among 110 women with early-stage cervical cancer and negative pelvic nodes [26]. These results are in keeping with those of Benedetti et al. who demonstrated, in 225 patients with IB to IV cervical cancer, that the uterosacral ligaments

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Fig. 2. Histologic and immunoﬂuorescence analysis of the lateral parametrium: (a) The histologic examination (magniﬁcation ×10) reveals the presence of nerves (arrow) within large regions rich in adipocytes (star). (b) The 3D reconstruction in confocal microscopy reveals the presence of lymphatic channels (LYVE-1_TR; red) and nervous (NSE_ FITC; green) structures within cellular unstained regions (nuclei in dapi; blue).

contained only 5% of all parametrial lymph nodes and that none of them were metastatic [11]. Therefore, the analysis of the balance between risk to the nerves and benefits of parametrial resection remains to be defined. The originality of the present study is that the nerve and lymphatic distribution in the parametrium was analysed concomitantly by immunostaining. Ercoli et al. [13] already reported a macroscopic description of the parametrium based on the lymphatic drainage after injecting Lipiodol dye solution into the uterine cervix. They divided the parametrium into three entities according to anatomical landmarks, i.e., the ureter and the deep uterine vein: (i) the supraureteral paracervical pathway; (ii) the infraureteral paracervical parametrium; (iii) the neural paracervical pathway, less frequently encountered. The distal part of what we called the posterior parametrium had very few lymphatic structures and contained mainly nerves. This tissue is indeed included in the deep neural paracervical pathway reported by Ercoli et al. [13] confirming their data at the microscopic level. In the same way, we found a higher proportion of microscopic lymphatic structures in the proximal part of our posterior parametrium, corresponding to their infraureteral paracervical parametrium. They also reported a higher proportion of macroscopic lymph channels (6/27) in their study [13]. The quantity of nerves present in the different parts of the parametrium was similar in our study. We used Neuron Specific Enolase (NSE) antibody, which has the advantage of recognising sympathetic, parasympathetic and sensitive nerve fibres. The posterior parametrium contains part of the inferior hypogastric plexus innervating the rectum,

the uterus and the bladder [6,27]. Postoperative morbidity including neurogenic bladder and rectum dysfunction is associated with the resection of this part of the parametrium, as previously reported [2,14]. Rob et al. [27] reported where the pelvic plexus and nerves were located within the different regions of the parametrium. The resection of the posterior parametrium (i.e. the dorsal paracervix for Rob or the uterosacral ligament) leads to injury of the nerves that originate from the inferior hypogastric plexus. With our methodology we were not able to assess the type of nerves or their target organs. However, the vesical and rectal fibres are more likely to be damaged during posterior parametrectomy, in the region of the inferior hypogastric plexus [17,27]. This is in accordance with the data reported by Butler-Manuel et al. [28], showing a lower nerve content in the superficial uterosacral ligaments compared with the deep uterosacral ligaments, near the origin of these ligaments at the pelvic side wall. The experience of other diseases leading to posterior parametrectomy, such as deep infiltrating endometriosis, may also shed light on the consequences of uterosacral ligament resection. The extensive resection of the uterosacral ligaments (i.e. distal posterior parametrium) for endometriosis leads to more sequelae of the nerve structures [6]. These findings suggest that the target organ of nerves of the proximal and the distal parametrium may differ. The next step will be to relate the type of nerve resected in patients undergoing radical hysterectomy to postoperative symptoms. Nerve-sparing techniques have allowed extension of the radicality of hysterectomy while preserving the hypogastric nerves and hypogastric

Fig. 3. Histologic and immunofluorescence analysis of the proximal part of the posterior parametrium: (a) The histologic examination (magnification x20) reveals a fibrous tissue rich in conjunctive structures (asterisk) containing numerous nerves (arrow) and no or few adipocytes (star). (b) The 3D reconstruction in confocal microscopy reveals the presence of lymphatic structures (LYVE-1_TR; red) next to the dense nervous network (NSE_ FITC; green) within regions rich in cells (nuclei in dapi; blue).

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Fig. 4. Histologic and immunofluorescence analysis of the distal part of the posterior parametrium: (a) The histologic examination (magnification ×10) reveals a tissue with both conjunctive structures (asterisk) and adipocytes (star) containing numerous nerves (arrow). (b) The 3D reconstruction in confocal microscopy reveals the absence of lymphatic structures (no or very few LYVE-1_TR staining, red) next to the nervous fibers (NSE_ FITC; green) in moderate cellular regions (nuclei in dapi; blue).

plexus [17,27,29–32]. Many techniques or guidelines have been suggested: specific resection limits, such as the deep uterine vein, isolation of the hypogastric nerve and uterine branch in the lateral rectal wall to the inferior hypogastric plexus, intraoperative electrical stimulation of the pelvic splanchnic nerves and liposuction-assisted nerve sparing [5,7,8,29–31,33,34]. Possover et al. developed the concept of Laparoscopic Neuro-Navigation (LANN) in radical pelvic surgery [7]. The dissection and electrostimulation of the pelvic parasympathetic nerves by transection of the parametria during surgery allow significant preservation of the postoperative bladder function [7]. However, these techniques are multiple and most of them require high surgical expertise and standardization before being used in routine use. Moreover, they increase operating time and require additional materials for neurostimulation leading to increased cost. In our study, the lateral parametrium and the proximal part of the posterior parametrium were found to be rich in lymphatic and nerve structures and they appeared strongly intertwined, closed and amalgamated. Furthermore, the distal part of the posterior parametrium, which is at high risk of hypogastric nerve and plexus injury, was found to contain no or very few lymphatic structures. The easiest technique for nervesparing may therefore be to spare the distal part of the posterior parametrium. Our result is consistent with previous studies reporting no or very few lymph nodes within the uterosacral ligaments [10,11] as well as Ercoli et al.'s report describing low frequency of the neural paracervical pathway [13]. These data support the recommendations of radicality proposed by Morrow and Querleu [9] who simplified previous categories by balancing adverse and curative effects according to the anatomical extent. Nerve sparing is based on two main concepts: limitation of the radicality and nerve sparing after identification. The first one has the advantage of being simple and reproducible [17]. Nonetheless, as cervical cancer spreads both via lymphatic structures and directly, the risk of direct spread to the distal posterior parametrium remains and needs to be taken into account, especially for large tumours. Some limitations of the present study have to be underlined. First, the small sample size cannot exclude bias linked to variability in anatomical distributions of both nerves and lymphatic vessels. Second, artefacts linked to cadaver analysis can also contribute to underestimating lymphatic distribution. Indeed, we did not manage to identify the lymphatic structures with conventional histology probably because lymphatic vessels collapse at death. This would explain why it was impossible to see the lumen of the vessel. Plus, as there was no postmortem dissection of cancer-free women, no oncologic survival analyses were possible, which would be the only way to evaluate the real impact of sparing the distal posterior parametrium. Finally, correlation with fresh samples from radical hysterectomy is required to confirm our results and to correlate the findings to postoperative symptoms and to survival.

In conclusion, the distal part of the posterior parametrium has a high nerve density and low lymphatic density probably explaining its low contribution to lymphatic dissemination. This raises the question of the relevance of resecting this part of the parametrium during radical hysterectomy.

Conﬂict of interest statement The authors have no conﬂict of interest to declare in connection to this study.

Acknowledgments The authors would like to thank Professor Frileux, scientiﬁc director of the Surgery School of Paris (7 rue du Fer à Moulin, 75221 Paris Cedex 05) and all the members of the staff. We also thank Felicity Neilson for editing.

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