cancers

Article A Concise Paradigm on Radical : The Comprehensive Anatomy of Parametrium, Paracolpium and the Pelvic Autonomic Nerve System and Its Surgical Implication

Mustafa Zelal Muallem 1,* , Thomas Jöns 2, Nadja Seidel 2, Jalid Sehouli 1, Yasser Diab 3 and Denis Querleu 4 1 Department of Gynecology with Center for Oncological Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Virchow Campus Clinic, Charité Medical University, 13353 Berlin, Germany; [email protected] 2 Department of Anatomy, Mitte Campus Clinic, Charité Medical University, 10117 Berlin, Germany; [email protected] (T.J.); [email protected] (N.S.) 3 Department of Gynecology, Portland Hospital, Portland, VIC 3305, Australia; [email protected] 4 Department of Surgery, Institut Bergonié, 33076 Bordeaux, France; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +49-30-450-664373; Fax: +49-30-450-564900  Received: 24 May 2020; Accepted: 4 July 2020; Published: 8 July 2020 

Abstract: The current understanding of radical hysterectomy is more centered on the and little is discussed regarding the resection of the vaginal cuff and the paracolpium as an essential part of this procedure. The anatomic dissections of two fresh and 17 formalin-fixed female cadavers were utilized to understand and decipher the anatomy of the pelvic autonomic nerve system (PANS) and its connections to the surrounding anatomical structures, especially the paracolpium. The study mandates the recognition of the three-dimensional (3D) anatomic template of the parametrium and paracolpium and provides herewith an enhanced scope during a nerve-sparing radical hysterectomy procedure by precise description of the paracolpium and its close anatomical relationships to the components of the PANS. This enables the medical fraternity to distinguish between direct infiltration of the paracolpium, where the nerve sparing technique is no longer possible, and the affected lymph node in the paracolpium, where nerve sparing is still an option. This study gives rise to a tailored surgical option that allows for abandoning the resection of the paracolpium by FIGO stage IB1, where less than 2 cm resection is demanded.

Keywords: nerve-sparing radical hysterectomy; parametrium; paracolpium; pelvic autonomic nerve system; tailoring the radicality

1. Introduction While the radical hysterectomy, first described by Ernst Wertheim [1], has been in routine medical practice as a standard therapy for locally invasive cervical cancer for more than a century, many discrepancies still persist concerning the terminology, anatomical description and surgical technique. Surgical procedures have been dealing with the parametrium (web, paracervix), a term used to describe the connective tissue around the , for quite a long period as being composed of three (viz., cardinal , sacrouterine ligament and vesicouterine ligament). Moreover, there are no supporting structures in the parametrium [2–4] to rationalize the use of the term ligament. The composition of the parametrium is controversial and nevertheless an issue of anatomic confusion

Cancers 2020, 12, 1839; doi:10.3390/cancers12071839 www.mdpi.com/journal/cancers Cancers 2020, 12, 1839 2 of 10 and surgical misconception [5,6]. However, the resection of these parametrial ligaments is a surgical standard and indispensable during radical hysterectomy [7,8]. In 2017, Querleu et al. [9] took up an initiative to standardize the anatomic nomenclature and redefine the technical descriptions of various radical hysterectomy procedures. Nevertheless, specific published literature [5,10,11] reveal that there is still a need for a comprehensive and precise anatomy of radical hysterectomy with extensive knowledge of the pelvic spaces, blood supplies, autonomic nerve system and connective pillars to enable the surgical procedure to be carried out accurately with the right balance as regards radicality, prognosis and quality of life. A cadaver study was undertaken in addition to our long experience with nerve-sparing radical hysterectomy [12] to arrive at a comprehensive and precise anatomy of the parametrium, paracolpium and the pelvic autonomic nervous system and its connections to surrounding anatomical structures.

2. Results

2.1. In-Depth Literature Analysis of the Parametrium and Paracolpium The current understanding of radical hysterectomy is more centered on the uterus, especially the uterine cervix, and little or nothing is discussed on the significance of the resection of the vaginal cuff (which generally runs up to one third or half of the ) and the paracolpium as an essential part of a radical hysterectomy [8,9,13]. Since the radical resection of any organ obviously implies the dissection and resection of the vascular supply, lymph vessels and surrounding lymph nodes, there is no published literature available on radical that details the dissection and resection of vaginal vessels or offers a precise description of the paracolpium. Fujii and Sekiyama [14] have described the paracolpium as lateral vaginal tissue (an artery and a vein) that could be distinguished during the final crucial steps of a radical hysterectomy directly before dividing the vagina without clearing where these vessels arise from. However, detailed description of the paracolpium is not lucid in spite of their anatomical positioning in the vesicouterine and vesicovaginal ligament. Further, the ventral and lateral parametrium (and of course the paracolpium) have extensive vascularization for the blood supply of the uterus (and the upper vaginal region as well), populated with the numerous local lymph nodes and lymphatic supply. It is worth mentioning the contribution of Girardi [15] and Benedetti [16] who have lucidly shown that 78% to 96% of the parametrium contains lymph nodes. Palfalvi and Ungar [17] and Querleu et al. [18] have further elucidated that the border between parametrial dissection and lymphadenectomy is not rigid and could be positioned in different planes, while the same connective tissue is being extirpated. Thus, according to these studies and our experience, the ventral and lateral parametrium and paracolpium are only the vasculatures that run in these structures to supply blood to the uterus and upper vagina, and their surrounding lymph nodes (Figure1). By dissecting the surrounding lymph nodes, the parametrium and paracolpium resection will only mean the resection of the uterine vessels and the vessels supplying the upper part (one third to one half) of the vagina.

2.2. The New Three-Dimensional Precise Anatomic Description of the Parametrium and Paracolpium as a Result of Our Anatomical and Surgical Studies The cadaver studies and their interpretation in surgical steps primarily mandate the recognition of the three-dimensional (3D) anatomic template proposed as early as 2011 [19] for parametrectomy, and at the same time, a need for an addition of a parallel 3D anatomic template for paracolpectomy too. The dissection has shown the dorsal parametrium as the sacrouterine ligament and the dorsal paracolpium as the sacrovaginal ligament that has been previously described as the deep by Ramanah et al. [6], and as the vaginorectal ligament by various other authors [5]. Cancers 2020, 12, 1839 3 of 10 Cancers 2020, 12, x 3 of 10

(a) (b)

Figure 1. The lateral parametrium and paracolpium after removing the lymph nodes and fat tissue: (a) original photo; (b) with explanation of anatomic structures: U: ureter, MUL: medial umbilical Figureligament, 1. The IIA: lateral internal parametrium iliac artery, IIVand internal paracolpium iliac vein, after EIA: removing external the iliac lymph artery, nodes EIV: and external fat tissue: iliac vein,(a) original ON, obturator photo; ( nerve,b) with IVV: explanation inferior vesical of anatomic vessels (thestructur dottedes: whiteU: ureter, line showsMUL: themedial distribution umbilical of ligament,these vessels IIA: in internal the bladder iliac wall),artery, SVV: IIV superiorinternal vesicaliliac vein, vessels EIA: (dotted external black iliac line artery, shows EIV: the external distribution iliac vein,of these ON, vessels obturator in the nerve, bladder IVV: wall), inferior UV: uterinevesical vein,vessels UA: (the uterine dotted artery, white VV: line vaginal shows vein, the distribution VA: vaginal ofartery, these PSN: vessels pelvic in splanchnicthe bladder nerves, wall), LSF: SVV: lesser superior sciatic vesical foramen. vessels (dotted black line shows the distribution of these vessels in the bladder wall), UV: uterine vein, UA: uterine artery, VV: vaginal vein,A precise VA: vaginal dissection artery, of PSN: the areapelvic reveals splanchnic that nerves, whilst LSF: there lesser is no sciatic clear foramen. border between the stated structures, the dorsal paracolpium is denser, connects the vaginal part beneath the cervix to the lateral 2.2.mesorectum The New Three-Dimensional and is located in the Precise same Anatomic level in D betweenescription the of rectalthe Parametrium and and the pelvicParacolpium nerve-vessel as A Resultguiding of plateOur Anatomical laterally (this and plateSurgical has Studies also been referred to as the lateral sheet of the presacral visceral pelvicThe fascia cadaver [20]). studies Therefore, and thetheir sacrovaginal interpretation ligament in surgical is located steps with primarily a part mandate that is closely the recognition connected ofto the three-dimensional hypogastic nerves (3D) and anatomic the dorsal template part of pr theoposed inferior as hypogastricearly as 2011 plexus. [19] for Theparametrectomy, sacrovaginal andligament at the is same connected time, toa need the endopelvic for an addition fascia (fasciaof a parallel pelvis 3D visceralis) anatomic and template it would for be paracolpectomy also appropriate too.to term The it dissection the tendinous has shown arch of the the dorsal pelvic parametriu fascia (arcusm tendineusas the sacrouterine fasciae pelvis) ligament located and dorsallythe dorsal at paracolpiumthe level of S2 as/3 the [2]. sacrovaginal It is essential ligament to differentiate that has between been previously the tendineus described arch as of the the deep pelvic uterosacral fascia the ligamenttendineus by arch Ramanah of levator et al. ani [6], muscle. and as the vaginorectal ligament by various other authors [5]. AThe precise lateral dissection paracolpium of the is area where reveals the vaginalthat whilst vascular there is supply no clear originates border between from (artery) the stated and structures,discharges intothe dorsal (vein) theparacolpium internal iliac is arterydenser, and conne veincts beneath the vaginal the ureter. part beneath the cervix to the lateralIn mesorectum this way, it isand possible is located to label in the the same ureter level as anin anatomicalbetween the marker rectal fascia that splits and thethe lateralpelvic parametriumnerve-vessel guiding (cardinal plate ligament) laterally into (this thelateral plate parametriumhas also beenabove referred the to ureter, as the containing lateral sheet theuterine of the presacralartery and visceral vein, and pelvic the fascia lateral [20]). paracolpium Therefore, beneath the sacrovaginal the ureter, ligament containing is located the vaginal with arterya part that and veinis closely (Figure connected2). These to two the vessels hypogastic have beennerves misidentified and the dorsal as a part deep of uterine the inferior vein by hypogastric some researchers, plexus. whilstThe sacrovaginal there is no mentionligament of is this connected deep uterine to the vein endo in thepelvic available fascia published(fascia pelvis literature visceralis) or textbooks and it wouldon human be also anatomy. appropriate Thus, thisto term vaginal it the vein tendinous as per this arch study of the (misinterpreted pelvic fascia as(arcus the deeptendineus uterine fasciae vein) pelvis)originates located at the dorsally level of at the the superior level of third S2/3 of [2]. the It vagina is essential [20]. to differentiate between the tendineus arch However,of the pelvic it isfascia imperative the tendineus to mention arch thatof levator the vaginal ani muscle. artery goes undetected laterally in about 14/33The hemi- lateral paracolpium in a cadaver is studywhere (42.4%)the vaginal and invascular 37/84 hemi-pelvises supply originates in a clinical from (artery) study (44%). and Thisdischarges is due tointo the (vein) fact that the thisinternal artery iliac in suchartery instances and vein is beneath construed the to ureter. come in as a branch of the uterine artery,In crossingthis way, directly it is possible into the ventralto label parametriumthe ureter as above an anatomical the ureter marker and travelling that splits caudally the lateral to the parametriumanterolateral side(cardinal of the vagina.ligament) Both into of thesethe latera variationsl parametrium could be noticedabove inthe the ureter, same patientcontaining in 23 the/42 uterine artery and vein, and the lateral paracolpium beneath the ureter, containing the vaginal artery and vein (Figure 2). These two vessels have been misidentified as a deep uterine vein by some

Cancers 2020, 12, x 4 of 10

researchers, whilst there is no mention of this deep uterine vein in the available published literature or textbooks on human anatomy. Thus, this vaginal vein as per this study (misinterpreted as the deep uterine vein) originates at the level of the superior third of the vagina [20]. However, it is imperative to mention that the vaginal artery goes undetected laterally in about 14/33 hemi-pelvises in a cadaver study (42.4%) and in 37/84 hemi-pelvises in a clinical study (44%).

CancersThis is2020 due, 12 to, 1839 the fact that this artery in such instances is construed to come in as a branch of4 ofthe 10 uterine artery, crossing directly into the ventral parametrium above the ureter and travelling caudally to the anterolateral side of the vagina. Both of these variations could be noticed in the same patientspatient in from 23/42 a clinicalpatients study from a (55%) clinical [21 ]study and in(55%) 16/28 [21] cadavers and in 16/28 with eligiblecadavers bilateral with eligible hemi-pelvises bilateral (57.1%).hemi-pelvises This finding(57.1%). falls This in finding tandem falls with in thetandem investigations with the investigations of Ercoli et al. of [ 20Ercoli] in largeet al. [20] numbers in large of embalmednumbers of and embalmed fresh cadavers. and fresh cadavers.

(a) (b)

Figure 2. The lateral and ventral parametrium and paracolpium. (a) The ureter as an anatomical marker between the lateral parametrium and the lateral paracolpium and between the ventral parametrium Figure 2. The lateral and ventral parametrium and paracolpium. (a) The ureter as an anatomical and the ventral paracolpium. (b) The parametrium and paracolpium after resecting and sparing the marker between the lateral parametrium and the lateral paracolpium and between the ventral pelvic autonomic nerve system. IHP: inferior hypogastric plexus. parametrium and the ventral paracolpium. (b) The parametrium and paracolpium after resecting Hence,and sparing the ventralthe pelvic paracolpium autonomic nerve is nothing system. but IHP: the inferior deep layer hypogastric of the vesicouterine plexus. ligament (lateral and caudal portions from the distal ureter in the vesicouterine ligament, described in Yabuki et al. [7] Hence, the ventral paracolpium is nothing but the deep layer of the vesicouterine ligament as the paravaginal portion of the paracervix) and the superficial layer of the vesicouterine ligament is (lateral and caudal portions from the distal ureter in the vesicouterine ligament, described in Yabuki actually the ventral parametrium (cranial and medial portions from the distal ureter). et al. [7] as the paravaginal portion of the paracervix) and the superficial layer of the vesicouterine Thus, in our dissection, the following vessels: a ureteral branch of the uterine artery, a ureteral ligament is actually the ventral parametrium (cranial and medial portions from the distal ureter). vein discharging in the uterine vein (described by Fujii as a superficial vesical vein [22]) and the Thus, in our dissection, the following vessels: a ureteral branch of the uterine artery, a ureteral vaginal branch of the uterine artery (a variation of vaginal artery arising from the internal iliac artery in vein discharging in the uterine vein (described by Fujii as a superficial vesical vein [22]) and the 56–57.6% of cases) have been clearly identified in the ventral parametrium. In the ventral paracolpium, vaginal branch of the uterine artery (a variation of vaginal artery arising from the internal iliac artery two veins have been spotted discharging into the vaginal vein and making vein anastomoses with in 56–57.6% of cases) have been clearly identified in the ventral parametrium. In the ventral branches from the inferior vesical vein. These are the same two veins described as the middle and paracolpium, two veins have been spotted discharging into the vaginal vein and making vein deep vesical vein by Fujii [22]. However the present detailed cadaver dissection study and our surgical anastomoses with branches from the inferior vesical vein. These are the same two veins described as experience mandates describing them as the lateral vesicovaginal vein (instead of the middle vesical the middle and deep vesical vein by Fujii [22]. However the present detailed cadaver dissection vein) and the medial vesicovaginal vein (instead of the deep vesical vein) because they are anastomotic study and our surgical experience mandates describing them as the lateral vesicovaginal vein connections between the vaginal vein and inferior vesical vein (Figure3). These vessel anastomoses (instead of the middle vesical vein) and the medial vesicovaginal vein (instead of the deep vesical could be explained as the vesical venous plexus that envelops the lower part of the bladder and the upper part of the vagina. The vaginal artery crosses over the inferior hypogastric plexus from the dorsolateral side to the ventromedial side to continue at the ventrolateral sidewall of the vagina. Cancers 2020, 12, x 5 of 10

vein) because they are anastomotic connections between the vaginal vein and inferior vesical vein (Figure 3). These vessel anastomoses could be explained as the vesical venous plexus that envelops the lower part of the bladder and the upper part of the vagina. The vaginal artery crosses over the Cancersinferior2020 hypogastric, 12, 1839 plexus from the dorsolateral side to the ventromedial side to continue at5 the of 10 ventrolateral sidewall of the vagina.

FigureFigure 3. 3.The The lateral lateral and and ventral ventral paracolpium paracolpium with the with vesicovaginal the vesicovaginal veins in theveins ventral in paracolpiumthe ventral andparacolpium their connection and their to the connection inferior vesical to the vein.inferior VV: vesi vaginalcal vein. vein, VV: IVV: vaginal inferior vein, vesical IVV: vein, inferior IIA: vesical internal iliacvein, artery, IIA: internal IIV internal iliac arte iliacry, vein, IIV PSN:internal pelvic iliac splanchnic vein, PSN: nerves.pelvic splanchnic nerves.

2.3.2.3. TheThe PelvicPelvic AutonomicAutonomic NervousNervous System and Its Course Across the the Paracolpium Paracolpium TheThe pelvicpelvic splanchnicsplanchnic nervesnerves have been found to to run run directly directly from from the the sacral sacral roots roots in in front front of of thethe commoncommon trunktrunk ofof thethe internalinternal pudendalpudendal and infe inferiorrior gluteal gluteal vessels vessels at at the the dorsal dorsal edge edge of of the the lesserlesser sciatic sciatic foramen, foramen, and and then then medial medial from from the inferiorthe inferior vesical vesical vein craniallyvein cranially to merge to merge in the inferiorin the hypogastricinferior hypogastric plexus. plexus. TheThe inferiorinferior hypogastrichypogastric plexusplexus lies on the endo endopelvicpelvic fascia fascia at at the the lateral lateral vaginal vaginal and and rectal rectal sidewall.sidewall. TheThe bladderbladder branchesbranches of the inferior hypo hypogastricgastric plexus plexus leave leave the the plexus plexus medial medial from from the the medialmedial vesicovaginal vesicovaginal veinvein ca.ca. 22 cm beneath the vaginal vault (Figure (Figure 44).). ThisThis study study also also shows shows that that most most of the of injuries the injuri to thees inferiorto the hypogastricinferior hypogastric plexus or theplexus components or the ofcomponents the autonomic of the nerve autonomic system nerve in the system radical in the hysterectomy radical hysterectomy procedure procedure occur during occur the during resection the ofresection the vaginal of the vault. vaginal This vault. element This haselement been reportedhas been andreported substantiated and substantiated by published by published literature, whichliterature, conclude which that conclude the more that extensive the more the extensiv vaginale the and vaginal surrounding and surrounding tissue ablation, tissue the ablation, greater the the resultantgreater the bladder resultant denervation bladder denervation [23]. This supposition [23]. This supposition is further supported is further by supported the finding by thatthe finding voiding dysfunctionthat voiding after dysfunction a radical after hysterectomy a radical ishysterecto significantlymy is more significantly common more in cases common where in more cases than where 2 cm ofmore the vaginathan 2 cm has of been the ablatedvagina has [20 ].been ablated [20]. Therefore,Therefore, itit isis essentialessential toto emphasizeemphasize the accurate identification identification of of all all the the components components of of the the autonomic nerve system, especially while attempting a nerve-sparing radical hysterectomy autonomic nerve system, especially while attempting a nerve-sparing radical hysterectomy procedure, procedure, complying with only the resection of the uterine branches and the dissection of the complying with only the resection of the uterine branches and the dissection of the endopelvic fascia directly at the level of the first bladder branch of the inferior hypogastic plexus [11,12,14] (Figure5). Cancers 2020, 12, x 6 of 10 Cancers 2020, 12, 1839 6 of 10 endopelvic fascia directly at the level of the first bladder branch of the inferior hypogastic plexus [11,12,14] (Figure 5).

(a) (b)

Figure 4. The lateral appearance of the right inferior hypogastric plexus after nerve-sparing radical hysterectomy:Figure (a) original4. The lateral photo; appearance (b) with of the explanation right inferior of hypogastric the anatomic plexus structures.after nerve-sparing MUL: radical medial umbilical ligament, IIA:hysterectomy: internal iliac(a) original artery, photo; IIV internal(b) with explanation iliac vein, of EIA:the anat externalomic structures. iliac artery, MUL: medial EIV: external iliac umbilical ligament, IIA: internal iliac artery, IIV internal iliac vein, EIA: external iliac artery, EIV: vein, ON, obturatorexternal iliac nerve, vein, ON, IVV: obturator inferior nerve, vesical IVV: inferior vessels, vesical PSN: vessels, pelvic PSN: pelvic splanchnic splanchnic nerves, nerves, LSF: lesser sciatic foramen,LSF: LA:lesser levatorsciatic foramen, ani, IHP: LA: levator inferior ani, IHP: hypogastric inferior hypogastric plexus, plexus rHN:, rHN: right right hypogastric hypogastric nerve. nerve. Cancers 2020, 12, x 7 of 10

Figure 5. Cranial appearance of the right inferior hypogastric plexus during nerve-sparing radical Figure 5. Cranialhysterectomy. appearance U: ureter, of IIA: the internal right iliac inferior artery, IIV hypogastric internal iliac plexusvein, EIA: during external nerve-sparingiliac artery, radical hysterectomy.EIV:U: external ureter, iliac IIA:vein, internalON, obturator iliac nerve, artery, IVV: IIVinferior internal vesical vessels, iliac vein, PSN: pelvic EIA: splanchnic external iliac artery, EIV: externalnerves, iliac LSF: vein, lesser ON, sciatic obturator foramen, nerve,LA: levator IVV: ani,inferior IHP: inferior vesical hypogastric vessels, plexus, PSN: rHN: pelvic right splanchnic hypogastric nerve. nerves, LSF: lesser sciatic foramen, LA: levator ani, IHP: inferior hypogastric plexus, rHN: right hypogastric2.4. The nerve. Surgical Impact of the Comprehensive Anatomy of Paracolpium and the Pelvic Autonomic Nervous System During a radical hysterectomy, the resection of vaginal length that is deemed appropriate for the disease stage has to be calibrated according to the tumor size and infiltration into the vagina. Furthermore, cutting the vaginal cuff without highlighting and isolating the endopelvic fascia (at the pelvic nerve-vessel guiding plate) would lead to injuries of the inferior hypogastric plexus from its medial facets [11]. The endopelvic fascia (pubocervical fascia) runs from the lower part of the symphysis pubis around the bladder neck directly above the pelvic floor (levator ani muscle) to the lateral side of the middle vagina and the lateral side of the rectum. The part from the endopelvic fascia that goes into the rectum is the dorsal parametrium and paracolpium (generally described as the sacrouterine and sacrovaginal ligaments). These two parts are again connected with the superior fascia of the levator ani at the tendinous arch of the pelvic fasciae [24]. Lateral and cranial from this endopelvic fascia is the vascular supply of the vagina and cervix, consisting of the lateral and ventral paracolpium and parametrium. The vaginal vessels cross over

Cancers 2020, 12, 1839 7 of 10

2.4. The Surgical Impact of the Comprehensive Anatomy of Paracolpium and the Pelvic Autonomic Nervous System During a radical hysterectomy, the resection of vaginal length that is deemed appropriate for the disease stage has to be calibrated according to the tumor size and infiltration into the vagina. Furthermore, cutting the vaginal cuff without highlighting and isolating the endopelvic fascia (at the pelvic nerve-vessel guiding plate) would lead to injuries of the inferior hypogastric plexus from its medial facets [11]. The endopelvic fascia (pubocervical fascia) runs from the lower part of the symphysis pubis around the bladder neck directly above the pelvic floor (levator ani muscle) to the lateral side of the middle vagina and the lateral side of the rectum. The part from the endopelvic fascia that goes into the rectum is the dorsal parametrium and paracolpium (generally described as the sacrouterine and sacrovaginal ligaments). These two parts are again connected with the superior fascia of the levator ani at the tendinous arch of the pelvic fasciae [24]. Lateral and cranial from this endopelvic fascia is the vascular supply of the vagina and cervix, consisting of the lateral and ventral paracolpium and parametrium. The vaginal vessels cross over the inferior hypogastric plexus to run lateral to the vaginal sidewall; therefore, the last step of a radical hysterectomy will be the resection of the descending vaginal vessels at the lateral side of the vagina. The inferior vesical artery arises from the common trunk of the internal pudendal artery and the inferior gluteal artery (sometimes directly from the internal iliac artery as its last medial branch) and the inferior vesical vein discharges into the internal iliac vein. The inferior vesical vessels are chiefly engaged in supplying the lower wall of the retrovesical ureter [25,26].

3. Discussion The implications of this comprehensive anatomy identification of the parametrium and paracolpium have a fundamental relevance not only in the nerve-sparing radical hysterectomy procedure, but more so with the empowerment of the surgeon to modify the radical hysterectomy according to the tumor size and infiltration. The study outcomes provide an enhanced scope during a nerve-sparing radical hysterectomy procedure by precise identification, isolation and sparing of the inferior vesical vessels to avoid ureteral ischemia at the distal part of the ureter, which usually is prevalent in 6.4% of cases after a radical hysterectomy procedure [1]. Since the ventral and lateral paracolpium are closely connected to the pelvic autonomic nerve system and the vaginal vessels pretty close to the pelvic splanchnic nerves running above the pelvic nerve-vessel guiding plate medially along the lateral vaginal sidewall (Figure3), the present study enables the medical fraternity to distinguish between direct (continuous) and lymphatic infiltration of the paracolpium, where direct (continuous) infiltration of the paracolpium with involvement of the endopelvic fascia will make it impossible to go for a nerve-sparing technique. On the other hand, if there is only lymphatic spread to the paracolpium (affected lymph node in the paracolpium region or lymph vascular space infiltration in the paracolpium), a nerve-sparing radical hysterectomy can still be performed. The study also gives rise to a tailored surgical option that allows for abandoning the resection of the paracolpium (ventral, dorsal and lateral) if the tumor is restricted to the cervix, and less than 2 cm in size (demanding less than 2 cm vaginal vault resection). This will allow for revising the classification of radical hysterectomy [8,9] to redefine type B radical hysterectomy (abandoning the unclear definitions like partial excision) as a radical hysterectomy with resection of the new defined ventral (at the vesical trigone), lateral (at the internal iliac vessels) and dorsal parametrium (at the rectum sidewall) but without paracolpium resection and with minimal (less than 2 cm) vaginal vault, which will be the surgery of choice in stages IA and IB1 (FIGO -International Federation of Gynecology and Obstetrics- 2018 [27]). The type C radical hysterectomy will then be the radical hysterectomy with parametrium and paracolpium resection for stage IB1 (the old FIGO classification [28]) with deep stromal invasion and IB2-IIA or early IIB cervical cancers. This procedure could be performed nerve sparingly (C1) if there Cancers 2020, 12, 1839 8 of 10 is no direct infiltration in the paracolpium and tendinous arch of the pelvic fascia (endopelvic fascia), or without sparing the inferior hypogastric plexus (C2) only by the direct infiltration of the paracolpium and/or the tendinous arch of the pelvic fascia. Tumor size plays no role whilst making the decision about sparing the autonomic nerve system, which has to be the standard of care for even a >4 cm size tumor [12].

4. Materials and Methods The anatomic dissections of 2 fresh and 17 formalin-fixed female pelvis cadavers were utilized to study, understand and decipher the hitherto ambiguously annotated anatomy of the pelvic autonomic nerve system and its connections to the surrounding anatomical structures, especially the paracolpium, with reference to radical hysterectomy. Since medical students had previously dissected the formalin-fixed cadavers, we excluded five hemi-pelvises where the pelvic sidewall was grossly over-dissected. The new anatomical knowledge from a cadaver study used to enhance and develop the Muallem technique for nerve-sparing radical hysterectomy was described in a previous study [12]. All data was obtained in accordance with Charité guidelines for cadaveric use in research. The findings are extrapolated by applying strategies to navigate these structures during a live nerve-sparing radical hysterectomy using ultrasonic liposuction (SonoSurg; Olympus Deutschland GmbH, Hamburg, Germany) for the visual illustration of the pelvic autonomic nervous system with less aggressive dissection. Pelvic intraoperative neuromonitoring (pIOM) was used to support the nerve-sparing radical hysterectomy and to confirm the intraoperative functional integrity of the inferior hypogastric plexus. The modular technology consisted of an ISIS Xpert neuromonitoring system including a neurostimulator and multichannel amplifiers for electromyographic recording (EMG). The NeuroExplorer operating software included the pIOM application, providing simultaneous stimulation and recording with the help of a hand-guided disposable 400 ball-tip stimulation probe and needle electrodes (inomed Medizintechnik GmbH, Emmendingen, Germany). The needle electrodes were placed in the internal and external sphincter. At the end of this study, PubMed and PMC (PubMed Central) were searched for studies pertaining to radical hysterectomy, radical hysterectomy and anatomic complications, anatomy of the pelvic autonomic nerve system and its connections to surrounding anatomical structures, especially the paracolpium and parametrium, and surgical challenges in radical hysterectomy for a complete literature search for comparison and reference.

5. Conclusions The comprehensive anatomy of the parametrium, paracolpium and pelvic autonomic nerve system as presented in this study is a contradictory concise paradigm for radical hysterectomy, which provides a precise concept of the nerve-sparing radical hysterectomy that shall enable surgeons to perform such a complex procedure without the ensuing common ureter related complications. The key steps are to distinguish between direct (continuous) and lymphatic infiltration of the paracolpium, rethink the needed radicality and devise tailored surgical procedures to suit individual cases.

Author Contributions: Conceptualization, M.Z.M. and T.J.; methodology, M.Z.M., N.S. and T.J.; investigation, M.Z.M., N.S.; resources, J.S. and T.J.; data curation, Y.D.; writing—original draft preparation, M.Z.M.; writing—review and editing, Y.D. and D.Q.; visualization, supervision and project administration, M.Z.M. and D.Q. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. Cancers 2020, 12, 1839 9 of 10

References

1. Wertheim, E. The extended abdominal operation for carcinoma uteri (based on 500 operative cases). Am. J. Obstet. Dis. Women Child. 1912, 66, 169–232. 2. Fritsch, H.; Zwierzina, M.; Riss, P. Accuracy of concepts in female pelvic floor anatomy: Facts and myths! World J. Urol. 2012, 30, 429–435. [CrossRef] 3. Fritsch, H.; Hötzinger, H. Tomographical anatomy of the pelvis, visceral pelvic connective tissue, and its compartments. Clin. Anat. 1995, 8, 17–24. [CrossRef][PubMed] 4. Murakami, N.; Norihisa, Y.; Isohashi, F.; Murofushi, K.; Ariga, T.; Kato, T.; Inaba, K.; Okamoto, H.; Ito, Y.; Toita, T.; et al. Proposed definition of the vaginal cuff and paracolpium clinical target volume in postoperative uterine cervical cancer. Pract. Radiat. Oncol. 2016, 6, 5–11. [CrossRef] 5. Ceccaroni, M.; Clarizia, R.; Roviglione, G.; Ruffo, G. Neuro-anatomy of the posterior parametrium and surgical considerations for a nerve-sparing approach in radical pelvic surgery. Surg Endosc. 2013, 27, 4386–4394. [CrossRef][PubMed] 6. Ramanah, R.; Berger, M.B.; Parratte, B.M.; DeLancey, J.O. Anatomy and histology of apical support: A literature review concerning cardinal and uterosacral ligaments. Int. Urogynecol. J. 2012, 23, 1483–1494. [CrossRef] 7. Yabuki, Y.; Asamoto, A.; Hoshiba, T.; Nishimoto, H.; Nishikawa, Y.; Nakajima, T. Radical hysterectomy: An anatomic evaluation of parametrial dissection. Gynecol. Oncol. 2000, 77, 155–163. [CrossRef][PubMed] 8. Querleu, D.; Morrow, C.P. Classification of radical hysterectomy. Lancet Oncol. 2008, 9, 297–303. [CrossRef] 9. Querleu, D.; Cibula, D.; Abu-Rustum, N.R. Update on the Querleu–Morrow Classification of Radical Hysterectomy. Ann. Surg. Oncol. 2017, 24, 3406–3412. [CrossRef][PubMed] 10. Yabuki, Y.; Takagi, H. and Transverse Cervical Ligament are not Synonymous. J. Clin Med. Sci. 2018, 2, 1. 11. Muallem, M.Z.; Diab, Y.; Sehouli, J.; Fujii, S. Nerve-sparing radical hysterectomy: Steps to standardize surgical technique. Int. J. Gynecol. Cancer 2019, 29, 1203–1208. [CrossRef][PubMed] 12. Muallem, M.Z.; Armbrust, R.; Neymeyer, J.; Miranda, A.; Muallem, J. Nerve Sparing Radical Hysterectomy: Short-Term Oncologic, Surgical, and Functional Outcomes. Cancers 2020, 12, 483. [CrossRef] 13. Piver, S.; Rutledge, F.; Smith, J.P. Five classes of extended radical hysterectomy for women with cervical cancer. Obstet. Gynecol. 1974, 44, 265–272. 14. Fujii, S.; Sekiyama, K. Precise Neurovascular Anatomy for Radical Hysterectomy; Springer Nature, Singapore Pte Ltd.: Singapore, 2020; p. 56. ISBN 978-981-13-8097-6. 15. Girardi, F.; Lichtenegger, W.; Tamussino, K.; Haas, J. The importance of parametrial lymph nodes in the treatment of cervical cancer. Gynecol. Oncol. 1989, 34, 206–211. [CrossRef] 16. Benedetti-Panici, P.; Maneschi, F.; D’Andrea, G.; Cutillo, G.; Rabitti, C.; Congiu, M.; Coronetta, F.; Capelli, A. Early cervical carcinoma. Cancer 2000, 88, 2267–2274. [CrossRef] 17. Palfalvi, L.; Ungar, L. Laterally extended parametrectomy (LEP), the technique for radical pelvic sidewall dissection: Feasibility, technique, and results. Int. J. Gynecol. Cancer 2003, 13, 914–917. [CrossRef][PubMed] 18. Querleu, D.; Narducci, F.; Poulard, V.; Lacaze, S.; Occelli, B.; Leblanc, E.; Cosson, M. Modified radical vaginal hysterectomy with or without laparoscopic nerve-sparing dissection: A comparative study. Gynecol. Oncol. 2002, 85, 154–158. [CrossRef][PubMed] 19. Cibula, D.; Abu-Rustum, N.R.; Benedetti-Panici, P.; Köhler, C.; Raspagliesi, F.; Querleu, D.; Morrow, C.P. The new classification system of radical hysterectomy: Emphasis on a three-dimensional anatomic template for parametrial resection. Gynecol. Oncol. 2011, 122, 264–268. [CrossRef] 20. Ercoli, A.; Delmas, V.; Gadonneix, P.; Fanfani, F.; Villet, R.; Paparella, P.; Mancuso, S.; Scambia, G. Classical and nerve-sparing radical hysterectomy: An evaluation of the risk of injury to the autonomous pelvic nerves. Surg. Radiol. Anat. 2003, 3–4, 200–206. [CrossRef][PubMed] 21. Muallem, M.Z. Nerve Sparing Radical Hysterectomy- Muallem Technique. Available online: https://www. youtube.com/watch?v=dr675cXra9c (accessed on 5 July 2020). 22. Fujii, S.; Takakura, K.; Matsumura, N.; Higuchi, T.; Yura, S.; Mandai, M.; Baba, T. Precise anatomy of the vesicouterine ligament for radical hysterectomy. Gynecol. Oncol. 2007, 104, 186–191. 23. Ralph, G.; Winter, R.; Michelitsch, L. Radicality of parametrial resection and dysfunction of the lower urinary tract after radical hysterectomy. Eur. J. Gynecol Oncol. 1991, 12, 27–30. Cancers 2020, 12, 1839 10 of 10

24. Hinata, N.; Hieda, K.; Sasaki, H.; Kurokawa, T.; Miyake, H.; Fujisawa, M.; Murakami, G.; Fujimiya, M. Nerves and fasciae in and around the paracolpium or paravaginal tissue: An immunohistochemical study using elderly donated cadavers. Anat. Cell Biol. 2014, 47, 44–54. [CrossRef][PubMed] 25. Anson, B.J.; McVay, C.B. Surgical Anatomy, 6th ed; WB Saunders: Philadelphia, PA, USA, 1984; p. 556. 26. Fröber, R. Surgical anatomy of the ureter. BJU Int. 2007, 100, 949–965. [CrossRef][PubMed] 27. Bhatla, N.; Berek, J.S.; Fredes, M.C.; Denny, L.A.; Grenman, S.; Karunaratne, K.; Kehoe, S.T.; Konishi, I.; Olawaiye, A.B.; Prat, J.; et al. Revised FIGO staging for carcinoma of the cervix uteri. Int. J. Gynaecol. Obstet. 2019, 145, 129–135. [CrossRef][PubMed] 28. Quinn, M.A.; Benedet, J.L.; Odicino, F.; Maisonneuve, P.; Beller, U.; Creasman, W.T.; Heintz, A.P.; Ngan, H.Y.; Pecorelli, S. Carcinoma of the cervix uteri. Int. J. Gynecol. Obstet. 2006, 95, 43–103. [CrossRef]

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