{"paper_id":"d7d3f839-b094-4a43-bd2f-9b1e85a4dc7f","body_text":"Ital J Gynaecol Obstet  2023, 35, N.1\n41\nCorrelations between hysteroscopy and histopathology to consider for the \ndiagnosis of impaired inflammatory states of the endometrium: a narrative review\nAmal Drizi 1,*, Mehran Ghahremani 2, Bruno Johan van Herendael 3,4\n1 Independent Consultant in Obstetrics and Gynaecology, Algiers, Algeria.\n2 Independent Consultant in Anatomoclinical Pathology, Tehran, Iran.\n3 Departement of Obstetrics and Gynaecology, Ziekenhuis Netwerk Antwerpen, AZ Stuivenberg, Antwerp, Belgium.\n4 Study University of Insubria, Varese Italy.\nGynæcology & Obstetrics\nItalian Journal of\nNARRATIVE REVIEW\nMarch 2023 - Vol. 35 - N. 1 - Quarterly - ISSN 2385 - 0868\nARTICLE INFO\nHistory\nReceived: 16 April 2022\nReceived in revised form: N/A \nAccepted: 10 June 2022\nAvailable online: 21 March 2023\nDOI: 10.36129/jog.2022.43\n*Corresponding author: Amal Drizi, M.D. Inde-\npendent Consultant in Obstetrics and Gynaecology, \nCité 80 logements Bt 6 N° 3 Baba Hassen, Algiers, \nAlgeria. \nEmail: dr.a.drizi@gmail.com.\nORICD: 0000-0001-6604-2906.\nCopyright 2023\nABSTRACT\nObjective. Endometrial inflammatory disorders are histologically character -\nized by a number of features, which to date, are not fully taken into consider-\nation in our practice of diagnostic hysteroscopy. A part of the current clinical \nand hysteroscopic consensual approach is in contradiction with many basics \nof histopathology and immunology, ultimately biasing research. Analysis of \nthe histopathological features of endometrial inflammation which provide a \nground for correlations with hysteroscopy in order to improve the endome-\ntrial sampling and to standardize the diagnosis of inflammatory disorders for \nthe benefit of practice and research.\nMaterials and Methods. A narrative review via a search in MEDLINE, EM-\nBASE, Global Health, The Cochrane Library and Web of Science. Pertinent \nbook chapters, original and review articles, published in English until Decem-\nber 31st, 2021, were selected, focusing on the changes of endometrial glands \nand stroma during inflammatory disorders. Those which can be correlated \nwith hysteroscopy have been selected in order to define a list of well-found-\ned diagnostic criteria, serving as guidelines for an optimal visually guided \nbiopsy.\nResults. A list of correlations between hysteroscopy and histopathology is es-\ntablished, with a particular focus on the morphological patterns to guide the \nhysteroscopist during diagnosis. The histopathological changes to be screened \nby the pathologist are also defined.\nConclusions. Growing awareness of the well-established features of the endo-\nmetrial histopathology provides the right basis for a standardized well-found-\ned practice of diagnostic hysteroscopy in inflammatory disorders, which is a \nsine qua none prerequisite for evidence-base and interpretable clinical trials.\nKey words \nImpaired inflammatory state of the endometri-\num; targeted biopsy; non shed endometrium; \ninflammatory vs dysfunctional disorders.\n\nItal J Gynaecol Obstet  2023, 35, N.1\n42\nHysteroscopy and histopathology correlations in IISE\nINTRODUCTION\nThe new concept of impaired inflammatory state \nof the endometrium (IISE) acknowledges chronic \ninflammation as a crucial component of normal \nendometrium and defines impairment as whatev-\ner disrupts the physiological inflammatory process \ninvolved therein [1]. Unlike chronic endometritis \n(CE) which always reflects excessive inflammation \ncaused by germs, IISE could result either from im-\nmune suppression or disproportionate inflamma-\ntory response to whatever perturbs homeostasis [1, \n2]. Consequently, IISE is a more proper terminology \nthan CE as it separates physiological inflammation \nfrom pathological; excessive from deficient and \ntransient from chronic [3]. For this reason and in \nthis paper, we will refer to CE with the term chron-\nic IISE (C-IISE). The latter is susceptible of causing \nvarious obstetrical and gynaecological conditions \nsuch as infertility, repeated miscarriage, placenta \nrelated complications, endometrial polyps, hyper -\nplasia and carcinoma [1, 4-8].\nIn terms of endometrial inflammation, however, the \nmajor problem research is facing today is the ab-\nsence of well-founded consensual definitions and \ndiagnostic criteria. Some of those which continue to \nbe used today are in violation of the basics of immu-\nnology and histopathology. They have been severely \ncriticized for a long time, presented as seriously hin-\ndering our understanding of this disorder, as they \nunavoidably result in biased studies and hence, in a \nwronged interpretation of data [9-11].\nAmong the contradictory statements, the current \ndefinition of CE reflects a limited vision of endo-\nmetrial inflammation. In the literature, it is still \nconsidered as a histopathological entity whose di-\nagnosis requires the presence of plasma cells with-\nin the endometrium. Ironically, this approach has \nbeen seriously questioned by pathologists them-\nselves, since 1911 [10]. Moreover, in hysteroscopy, \nthe international working group on CE has defined \n5 hysteroscopic patterns suggestive of C-IISE: mi-\ncropolyps, strawberry aspect, hyperaemia, oede-\nma and haemorrhagic spots [12]. However, the \nthree last ones are also typical signs of the very first \nstages of acute inflammation [3].\nThe absence of a consensus to guide endometrial sam-\npling in case of inflammatory or dysfunctional disor-\nders is another essential problem we face in our prac-\ntice. In a uterine cavity free of organic anomalies like \npolyps, fibroids or malignancies, there are to date no \nspecific guidelines for a targeted biopsy allowing op-\ntimal sampling. Only the technique is stressed, not the \nmorphological patterns of the biopsy site [13-15]. In an \n“empty uterine cavity”, hysteroscopy is usually con-\nducted in a “come in-come out” fashion, and blind bi-\nopsies with Pipelle or Novak continue to be used [16]. \nEven in symptomatic patients suffering from Abnor-\nmal Uterine Bleeding (AUB) or unexplained infertility, \nblind sampling continues to be recommended [17].\nMeanwhile, many authors have been urging the \nscientific community to look into more consistent \ncriteria, both hysteroscopically and pathologically \n[1, 3, 11, 18]. Defining pertinent diagnostic criteria \nis essential to start consistent multicentre studies \nwhere a standardized medical terminology and di-\nagnostic approach are adopted.\nIn this paper, we aim at defining diagnostic hys-\nteroscopic patterns based on a histopathological \nbasis. The analysis of the histopathological fea-\ntures of C-IISE provides precious fundamentals for \nan improved practice of diagnostic hysteroscopy, \nhopefully contributing to improving the quality of \ndiagnosis and research. \nMETHODS \nA non-systematic review was done via a search \nin the following databases: MEDLINE, EMBASE, \nGlobal Health, The Cochrane Library and Web of \nScience. Pertinent book chapters, original and re-\nview articles, published in English until December \n31st, 2021, focusing on the changes of endometrial \nglands and stroma during inflammatory disorders, \nwere selected. Those which can be correlated with \nhysteroscopy in order to define a list of well-found-\ned diagnostic criteria, serving as guidelines for an \noptimal visual-guided biopsy were determined.\nRESULTS \nThe already described histopathological features \nother than plasma cells\nEven in the last century, pathologists were attrib -\nuting endometrial inflammation to other possible \ncauses than germs, such as prior biopsy, intrauter-\nine contraceptive device, cervical stenosis, and the \npresence of an organic lesion such as polyps, leio-\nmyomas, hyperplasia or carcinoma [19, 20]. \nHowever, the use of plasma cells as the sole criteri-\non was first introduced in 1907 but has continuously \n\n43\nHysteroscopy and histopathology correlations in IISE Amal Drizi, Mehran Ghahremani, Bruno Johan van Herendael\nbeen criticized since then. In fact, in addition to in-\nflammatory cells, there is a constellation of histologi-\ncal changes that facilitate recognition of endometrial \ninflammation [20]. The importance of implementing \nthese additional criteria has been stressed mostly by \npathologists because, on the one hand, the presence \nof sporadic plasma cells can be identified in histo-\nlogically normal endometrium [11, 20]. On the oth-\ner hand, if C-IISE reaches a disease state, this would \nlogically imply stromal and/or glandular changes \nwithin the mucosa [10, 21]. In the absence of these ad-\nditional morphological changes of the endometrium, \nan exhaustive search for plasma cells is even thought \nto be unnecessary [10, 21]. This approach has recent-\nly been recommended by McQueen et al., addition-\nally stressing the cost savings when CD138 staining \nis only used for the cases where endometrial stromal \nchanges are identified and no plasma cells are detect-\ned via haematoxylin and eosin (H&E) staining [11]. \nAlthough the quantity of the required changes still \nremains to be defined, most pathologists agree that \nthe diagnosis of C-IISE should not rest on the finding \nof an apparent plasma cell in an endometrium that \notherwise appears normal, because the background \npattern is as important as the quantity of plasma cells \nfor establishing the diagnosis of C-IISE [10, 11, 20].\nThe morphological changes that have already been \nretained in the literature as diagnostic criteria for \nC-IISE are listed in Table 1 and their relevance was \nascertained by studies [10, 11, 20, 23]. It is import-\nant to note that pleomorphic inflammatory infil-\ntrates are physiologically observed in late secreto-\nry and menstrual phases [20, 22]. \nThe notion of “non shed endometrium” in chronic \ninflammation\nIn some references of histopathology, it is high-\nlighted that endometritis becomes chronic only if \na part of the endometrium is not shed during men-\nstruation [24]. To better understand this notion, it is \nimportant to recall the mechanism of endometrial \nshedding during menses, where the duet proges-\nterone-endometrial inflammation plays a pivotal \nrole. In fact, under the effect of progesterone, uter-\nine natural killer (µNK) cells considerably increase \nduring secretory phase, yet with an inhibited cyto-\ntoxic effect [25]. Progesterone is well known for its \nanti-inflammatory properties [26]. Its withdrawal \nat the end of the menstrual cycle causes activation \nof some pro-inflammatory mediators, neutrophils \nrecruitment and resumption by µNK cells of their \ncytolytic activity, all leading to glandular and stro-\nmal breakdown [25-28]. Progesterone is also in \ncharge of the pre-decidualization of stromal cells \nwhich do contribute to this process as well. At the \nlysis of the corpus luteum, progesterone’s drop \ncauses the pre-decidual cells to free the cytolytic \nenzymes of their granules into the mucosa, addi-\ntionally contributing to the shedding process [29].\nIn case of luteal insufficiency and/or progester -\none-resistance, these physiological self-limiting in-\nflammatory mechanisms are variably impaired, de-\npending on the severity of the disorder [27]. Areas \nwithin the endometrium will not benefit from the \ncyclical changes orchestrated by progesterone, thus \nresulting in a lack of pre-decidualization of stromal \ncells as well as an impaired recruitment and ac-\ntivity of the inflammatory cells (mainly µNK cells \nand neutrophils). On the other hand, the cytolytic \nactivity of the recruited µNK cells will not be suffi-\nciently inhibited. Consequently, irregular bleeding, \nwith stromal and glandular breakdown, will coex-\nist with areas of poorly pre-decidualized non shed \nendometrium, containing stromal cells which re-\nmain spindle-shaped, not plump as they normally \nbecome in an optimal progesterone environment.\nChronic inflammation is already known to in-\nduce a progesterone-resistant state [20, 21, 26, \n27, 30]. Conversely, plasma cells have been ob-\nserved in hormonally mediated endometrial dis-\norders, in association with gland architectural \nchanges [23]. IISE and hormone imbalances both \nhave common consequences on the endometri-\num. Impaired inflammation provokes impaired \nexpression of hormone receptors by glandular \nand stromal cells. Meanwhile, hormonal anom-\nalies directly impact the recruitment and activity \nof the endometrial inflammatory cells and cyto-\nkines. The two protagonists do thus very closely \ninterfere with one another in a vicious circle whose \nstarting point could be any of the two. This is why \nTable 1. Additional histopathological criteria for C-IISE.\nStromal changes Epithelial changes\nSuperficial stromal edema\nSpindled stroma\nIncreased stromal density: areas of \nhypercellularity\nPleomorphic stromal inflam-\nmatory infiltrate dominated by \nlymphocytes, neutrophils, plasma \ncells and even eosinophils and \nhistiocytes  \nStromal pigment deposition\nAbnormal glandular development: \nunderdeveloped glands with less \ntortuosity and distension; and/or \ndisturbance in maturation of the \nendometrium, with focal areas \nthat are out of cycle: irregular or \nretarded maturation\nGlandular and stromal breakdown \n\nItal J Gynaecol Obstet  2023, 35, N.1\n44\nHysteroscopy and histopathology correlations in IISE\nthe new concept of IISE acknowledges hormone \nimbalances as one of the aetiologies to endome-\ntrial inflammatory disorders, unlike the entity CE \nwhich is described to be only caused by germs [1]. \nNon shed endometrium is presented as a sine qua \nnon criterion for C-IISE, be it non-specific or spe-\ncific [24]. The areas where the endometrium does \nnot shed display spindled-shaped stromal cells, as \nwell as glandular changes. In fact, glands present as \natrophic, resting, insufficiently proliferated, irreg-\nularly proliferated or hyperplastic. These 5 terms \nhave each one a specific signification in patholo-\ngy and are described to be very relevant of C-IISE \n[24, 31]. In Table 2 the main features of stromal and \nglandular changes of a non-shed endometrium are \nlisted. Quite interestingly, many of them offer the \npossibility of being correlated with hysteroscopy.\nAuthors report presence of plasma cells in the ma-\njority of disordered proliferative endometria and \nstromal breakdown [23]. However, the spindled \nstroma seems to need revision. In fact, this criterion \nseems pertinent when a biopsy is performed during \nthe secretory phase, when pre-decidualization is \none of the capital parameters to assess. At this stage, \nprogesterone has caused transformation of Endo-\nmetrial Stromal Cells (ESC) from spindle shape (typ-\nical of proliferative phase) to a plump rounded one \n(typical of luteal phase). However, hysteroscopy is \nnowadays performed during proliferative phase for \nmany reasons. Among these reasons, plasma cells \nare easier to identify at this stage of the menstrual \ncycle [32]. This is why it is pertinent to recall that a \nspindled stroma cannot stand as a diagnostic crite-\nrion unless the sampling is performed during secre-\ntory phase, not the proliferative one. However, the \npresence of spiral arterioles during a proliferative \nstage could be considered as another sign for non-\nshed endometrium, since these vessels are typically \npresent in the late luteal phase (Table 3).\nPathologists need to be aware of all the histologi-\ncal criteria so far described for C-IISE as their pres-\nence needs to be meticulously reported especially \nTable 2. Main histological characteristics of glandular anomalies in C-IISE. \nGlandular changes in C-IISE Histopathological main characteristics\n1. Atrophic endometrium\n2. Resting endometrium \n3. Deficient proliferation \n4. Irregular (disordered) proliferation\n5. Hyperplastic\n6. Surface and glandular epithelium changes\n7. Glandular and stromal breakdown \nVery low endometrium with cuboidal surface epithelium, total or subtotal absence of glands and \nsmall, spindle-shaped stromal cells. Mitoses are lacking. Spiral arterioles are undeveloped\nFocal pressure atrophy: the same features but localized,  \nwhereas the surrounding endometrium is different  differences in height of the mucosa\nMechanical cause: pressure by a submucosal leiomyoma  \n(response to a prolonged mechanical pressure)\nAtrophic endometrium yet with more glands. They are rather straight and narrow, with a dense stroma \nGrowth of the glands and stroma remains retarded as compared with that of the normal proliferative \nphase, with moderate height of the mucosa and thin/straight glands, small glandular and stromal \ncells, contrasting with a usual presence of oedema\nGrowth of glands and stroma exceeds that of the normal proliferative phase. Variable height of the \nmucosa \nEndometrial glands: irregular in shape, width, and distribution, with pseudostratified epithelial \ncells plus stromal hypercellularity and focal oedema\nDescribed as a transitional form to simple glandular cystic hyperplasia\nIncreased ratio of glands and stroma compared with irregular proliferation\nMost or all of the endometrial glands are more or less cystically dilated and lined by pseudostratified, \nhighly proliferating epithelium\nDense undifferentiated stromal cells \nFocal hyperplasia: same features but limited to one or a few areas of the endometrium.  \nDue to focal loss of progesterone receptors with normal receptor content  \nof surrounding endometrium  different height of the mucosa\nSevere long-standing inflammation\nSquamous and eosinophilic cell changes\nA degree of architectural complexity and cytological atypia may also be seen; potential overdiagnosis \nof hyperplasia or carcinoma\nSevere long-standing inflammation \nIrregular haphazard bleeding leading to interspersed foci of regenerating and shedding endo-\nmetrium, resulting in a corrugated surface\nIn bold the criteria which can be correlated with hysteroscopy.\n\n45\nHysteroscopy and histopathology correlations in IISE Amal Drizi, Mehran Ghahremani, Bruno Johan van Herendael\nin symptomatic patients (Table 4). However, one of \nthe main problems encountered in practice is that \nnot all of them are aware thereof. It is of utmost \nimportance to spread information in this area and \ntrain both pathologists and gynaecologists on the \nbasics of endometrial histopathology to warrant \nan optimal collaboration between the two protago-\nnists. Quite interestingly, many of these criteria of-\nfer the possibility of being correlated with hysteros-\ncopy and thus are particularly interesting to study.\nThe histological criteria that can be correlated \nwith hysteroscopy\nThe analysis of the histopathological features of \nC-IISE provides precious fundamentals for an im-\nproved practice of diagnostic hysteroscopy. The \nfollowing parameters appear relevant and can be \ncorrelated with hysteroscopy:\n1. The cyclical changes of the endometrium\nThe endometrial mucosa is a cyclical changing tis-\nsue displaying characteristic features in a time-de-\npendent fashion, which allows endometrial dating. \nThis phenomenon is impaired in C-IISE, causing \nfocal or diffuse “out of cycle” areas [20, 21, 31]. Ob-\nviously, distinction between normal and impaired \nmaturation is only possible by precise statement \nof the phase of the menstrual cycle. Distinction on \nmorphologic grounds alone is not possible [31]. \nConsequently, it is mandatory to specify the day \nof the menstrual cycle in all diagnostic hysterosco-\npies. The length of the menstrual cycle is obtained \nby noting the first day of the upcoming menses, \nin order to retrospectively determine the precise \nphase where hysteroscopy was performed. This \nallows a more optimal histopathological correla-\ntion. Moreover, any hormonal treatment or distur-\nbances have to be reported and more interestingly \navoided before diagnostic hysteroscopy.\nConclusion: specification of day and the length of \nthe menstrual cycle is mandatory.\nHistological dating of the endometrium reflects ei-\nther a synchronous normal endometrium or an out \nof date one: deficient or disordered proliferation; \natrophic, resting or hyperplastic endometrium. \nTable 3. The main histological features of early, middle and late proliferative phases.\nPhase of proliferation Histological features\nEarly \nMid \nLate \nFlat epithelium\nThin endometrium\nSparse, narrow, and straight glands \nEvenly distributed glands\nCuboid or low columnar cells\nLoose stroma of spindle-shaped cells\nUndeveloped spiral arterioles\nHigher endometrium\nMore numerous glands\nBeginning of tortuosity evenly distributed\nTall columnar cells\nNo pseudo stratification yet\nInterstitial oedema\nSpiral arterioles: not seen\nSlightly less thick endometrium\nMarked tortuosity of glands evenly distributed \nPseudo stratification\nInterstitial oedema subsided\nSpiral arterioles: still absent\nTable 4.  The detailed histopathological criteria for C-IISE.\nStromal changes Epithelial changes\nSuperficial stromal oedema\nSpindled stroma\nPleomorphic stromal inflammatory infiltrate dominated by lymphocytes, neu-\ntrophils, plasma cells and even eosinophils and histiocytes  \nIncreased stromal density: areas of hypercellularity. The inflamed stroma is dense \nand less responsive to hormonal changes stromal pigment deposition\nAbnormal glandular development: \ndisturbance in maturation of the endometrium, with focal areas \nthat are out of cycle\n    Atrophic\n    Resting\n    Insufficiently proliferated\n    Irregularly proliferated\n    Hyperplastic\nGlandular and stromal breakdown\n\nItal J Gynaecol Obstet  2023, 35, N.1\n46\nHysteroscopy and histopathology correlations in IISE\nDistinction on morphologic grounds alone is not \npossible and precise statement of the phase of the \nmenstrual cycle.\n2. Proliferative phase\nThe secretory phase is well known to be particular-\nly rich in physiological and histological details, es-\npecially those related to the post-ovulatory chang-\nes of the endometrium, which is why it has long \nbeen the preferred one for subfertile patients [33].\nYet and just as interestingly, hysteroscopic exam-\nination is preferably indicated in the proliferative \nphase by most authors [33, 34]. At this stage, the \nmucosa is thinner, thus avoiding misinterpreta-\ntion with polypoid or hyperplastic endometri-\num. Moreover, the increased tonicity of the cervix \ncaused by progesterone is avoided, hence facilitat-\ning the technique, especially in office settings.\nIn the specific case of inflammatory disorders of the \nendometrium, luteal phase is additionally inter -\nesting to avoid because of the physiological pres-\nence of inflammatory infiltrates at this stage [21, \n22]. Moreover, despite the contradictory available \ndata, most studies revealed increased prevalence \nof C-IISE, up to 50% higher, when the sampling is \nperformed during the follicular phase as compared \nto the secretory one [32]. The stage of the menstru-\nal cycle is presented as a major confounder to take \ninto consideration when assessing this condition. \nThe usual presence of plasma cells in the deeper \nlayers of the endometrium is a potential explana-\ntion for this difference, as a thicker mucosa during \nluteal phase can cause a reduced portion of deeper \ntissue during sampling [32].\nConsequently, both follicular and luteal phases \nhave advantages and disadvantages and can \nboth be interesting to study. However, given the \nabove-mentioned advantages of the proliferative \nphase in the particular context of hysteroscopy \nand inflammatory disorders, our analysis is cen-\ntred thereupon. Consequently, only the histologi-\ncal and hysteroscopic features of the proliferative \nphase will be focused on this paper.\nProliferative phase is usually divided in 3 sub-\nphases: early, mid and late proliferative. The main \nfeatures are summarized in table 3 and most of \nthem can be correlated with hysteroscopy. These \nfeatures should be particularly targeted by pathol-\nogists and described in the report. \nIf out of date areas are seen within the mucosa, this \nwill be suggestive of a perturbed endometrial mat-\nuration. Altered or ambiguous gland phase – in ad-\ndition to stromal changes – are already known to \nbe associated with C-IISE [10, 11, 21, 22, 36]. \nConclusion: diagnostic hysteroscopy is to be sched-\nuled during proliferative phase.\nThe histological features to be searched for are:\n• Height of the endometrium. \n• Regular distribution of glands.\n• Form and size of glands: narrow and straight, \ncurved or tortuous.\n• Epithelial and glandular cells: cuboid, colum-\nnar or pseudostratification.\n• loose stroma of spindle-shaped cells.\n• Stromal oedema: physiological in mid-prolifer -\native phase.\n• Absence of spiral arterioles.\nSome of these histological criteria can be correlated \nwith hysteroscopy.\n3. Distribution of glands - Regular inter-glandular spaces \nIn all the references of histopathology, evenly dis-\ntributed endometrial glands represent a key fea-\nture of a normal proliferative phase [20, 21, 29, 36]. \nQuite interestingly, this criterion can also be evalu-\nated via hysteroscopy, which offers the possibility \nto see gland orifices as white dots, regularly dis-\ntributed throughout the mucosa (Figure 1).\nThe presence of areas where gland orifices are \nnot equally distant from one another needs to \nbe considered as an additional marker for a tar -\ngeted biopsy, especially if redness and irregular \nthickness are associated (Figure 1). In fact, un-\nequal inter-glandular spaces represent one of \nFigure 1. Inter-glandular spaces: evenly distributed around the left tubal ostium. \n(A) unevenly distributed; lateral view (B); associated with focal oedema (C); associated \nwith hyperaemia (D).\n\n47\nHysteroscopy and histopathology correlations in IISE Amal Drizi, Mehran Ghahremani, Bruno Johan van Herendael\nthe features of irregular disordered proliferation \nand hyperplasia, both listed among the addition-\nal histopathological criteria of C-IISE (Table 4). \nA visually-guided biopsy performed within an \nendometrial area displaying this hysteroscopic \nglandular pattern provides increased odds of his-\ntopathological correlation.\nConclusion: irregular distribution of endometrial \nglands is a hysteroscopic pattern to consider for a \ntargeted biopsy, especially when associated with \noedema, hyperaemia and micropolyps.\nHistopathological correlation: irregular disordered \nproliferation and hyperplasia: irregular distribu-\ntion, shape and width of glands.\n4. Localized stromal oedema \nStromal oedema is another histological criterion \nwhich can be correlated with hysteroscopy. It ap-\npears as a swollen area compared to the surround-\ning endometrium (Figure 2). Although it can be \nphysiological in mid-proliferative phase [29, 36], it \nis still presented as one of the hysteroscopic crite-\nria of CE [12]. In all cases, its presence needs to be \nconsidered as a marker for the targeted-biopsy site, \nespecially if micropolyps or unevenly distributed \nglands are associated (Figure 2). Histologically, if \noedema is seen within tortuous glands without \npseudo stratification, mid proliferative pattern is \nmore likely and hence physiological. If oedema is \nconcomitant with pseudo stratification or a defi-\ncient proliferation, it is considered outdated, and \nhence more relevant of an IISE, especially if associ-\nated with the other criteria (Table 3).\nMeanwhile, it is very important to recall that oe-\ndema is one of the cardinal signs of acute inflam-\nmation, and can develop during hysteroscopy be-\ncause of mechanical effect [3] (see criterion 9).\nConclusion: stromal oedema is a hysteroscopic \npattern to consider for a targeted biopsy, especial-\nly when associated with redness, micropolyps or \nunevenly distributed glands. Histopathological \ncorrelations: physiological mid-proliferative phase; \niatrogenic oedema (transient IISE); out of date stro-\nmal oedema of C-IISE.\n5. Micropolyps, strawberry pattern, hyperemia and hem-\norrhagic spots\nThese criteria, in addition to stromal oedema, con-\nsist of the five hysteroscopic patterns described as \nrelevant of CE by the international working group \non this condition [12] (Figure 3).\nMicropolyps have already been the subject of a \nstudy by Cicinelli et al. Their rich content in in-\nflammatory cells – including plasma cells – was \nhistologically demonstrated [37]. For this reason, \nthis pattern provides an interesting indicator for \nthe targeted biopsy site, offering increased odds of \nhistopathological correlation.\nHowever, hyperaemia, oedema and haemorrhagic \nspots lack specificity in terms of chronic inflam-\nmatory disorders, as they are primarily typical \nsigns of acute inflammation [3]. Their presence in \na C-IISE can be explained by the fact that chron-\nic inflammation predisposes to repeated acute in-\nflammatory episodes and vice versa. Another ex-\nplanation is their potential histological correlation \nwith glandular and stromal breakdown. The latter, \none of the additional histological criteria of C-IISE, \ncauses a mixture of acute and chronic bleeding pat-\nterns. It is also accompanied with areas of stromal \nFigure 2. Focal stromal oedema at hysteroscopy.\nWith hyperaemia (A); with unevenly distributed glands and a micropolyp (B).\nFigure 3. Hysteroscopic patterns of C-IISE by the international working \ngroup on CE (in addition to stromal oedema). \nMicropolyps (A); strawberry aspect (B); hyperaemia (C); haemorrhagic spots (D).\n\nItal J Gynaecol Obstet  2023, 35, N.1\n48\nHysteroscopy and histopathology correlations in IISE\ncollapse, glandular breakdown, stromal fibrosis, \nmacrophages, and hemosiderin deposition [20].  \nConclusion: micropolyps is a hysteroscopic pattern \nto consider for a targeted biopsy and is histologi-\ncally correlated with inflammatory infiltrates rich \nin plasma cells.\nHyperaemia and haemorrhagic spots are inflam-\nmatory patterns encountered both in transient and \nC-IISE.\n6. Areas of irregular endometrial thickness\nUniformity of the histological changes induced \nby hormones in the endometrium depends on \nfactors such as the distribution of estrogen and \nprogesterone receptors, the local blood supply as \nwell as various metabolic factors [21, 29, 35]. In \na normal follicular phase, the height of the endo-\nmetrium is regularly thin. If there are focal areas \nof irregular thickness, this could be suggestive \nof an underlying disorder: stromal oedema; fo-\ncal atrophic, deficient or resting endometrium; \nstromal breakdown; irregular proliferation and/\nor focal hyperplasia (Table 4). In fact, when a \nC-IISE reaches disease state, disturbance of stro-\nmal and glandular maturation and shedding can \nresult in areas of unequal endometrial growth \n[20, 21, 24, 35, 36]. \nThis criterion, interestingly, can be correlated with \nhysteroscopy. Depending on the surface of the af-\nfected areas, unequal thickness is susceptible of \ncausing different hysteroscopic patterns of an ir -\nregular surface: corrugated surface as well as em-\nbossed or debossed patterns, whose limit with the \nsurrounding endometrium is marked by a slope or \na stairstep-like elevation (Figure 4). \nThese patterns can be associated with redness, mi-\ncropolyps and unevenly distributed glands and \nneed to be meticulously searched as the irregular -\nities can be quite subtle (Figure 5). They need to \nbe considered as an indicator for a targeted biopsy \nbecause they can be correlated with the above cited \nhistopathological changes which need to be partic-\nularly investigated by pathologist. \nConclusion: irregular endometrial surface is a hys-\nteroscopic pattern to consider for a targeted biopsy, \nespecially when associated with redness, micropo-\nlyps or unevenly distributed glands: slope, stair -\nstep, embossed or debossed patterns.\nHistopathological correlation: stromal oedema, \nfocal atrophic, deficient or resting endometrium; \nstromal breakdown; irregular proliferation and/or \nfocal hyperplasia.\n7. IISE: more commonly focal than diffuse\nOne of the overlooked capital features of inflam-\nmatory and dysfunctional disorders is their focal \ncharacter, although they can also be diffuse [20, 22] \n(Figures 1-5).\nThis fact stresses the impertinence of blind biopsy \nwhich increases the odds of missing the diagnosis \nif the specimen is not sampled within the inflam-\nmatory site itself [33]. Unfortunately, the available \nstudies on CE continue to use blind sampling with \nPipelle, curette or Novak, even when hysteroscopy \nis performed, thus biasing the evaluation of hys-\nteroscopy-histopathology correlations [16, 32, 33]. \nConclusion: in histopathology, inflammatory dis-\norders are well known to be more commonly focal. \nCorrelation with hysteroscopy: superiority of tar -\ngeted biopsy to blind sampling.\n8. Isthmic region of the uterus\nThe uterine isthmus, or lower uterine segment (LUS), \nis about 6 to 10 mm and connects the cervix to the \nuterine corpus. Its anatomical limits have been de-\nfined both in anatomy and in hysteroscopy, namely \nFigure 5. Focal hyperaemia observed from a distance at the entry of the \nuterine cavity (A); closer view revealing in addition to hyperaemia: a corru-\ngated surface with irregular interglandular spaces (B).\nFigure 4. Irregular endometrial thickness at hysteroscopy. \nCorrugated surface with a stairstep separating limit from the surrounding endometrium \n(A); embossed and debossed patterns with a slope separating limit from the surrounding \nendometrium (B, C); 1 seen from a distance; 2 close view; 3 mechanical resection; white \narrows: embossed surface; black arrows: debossed surface.\n\n\n49\nHysteroscopy and histopathology correlations in IISE Amal Drizi, Mehran Ghahremani, Bruno Johan van Herendael\nthe internal histological and anatomical ostia of the \nuterus [38] (Figure 6). Histologically, the isthmic en-\ndometrium is well known to be poorly responsive to \nhormones and hence does not participate in cyclical \nchanges of the mucosa [21, 29, 35, 36, 38]. It is rather \nflat, with an inactive low columnar surface and glan-\ndular epithelium, containing slender, often horizon-\ntally directed glands, surrounded by a dense, fibrous \nstroma of small spindle-shaped cells. Ciliated cells \nare normal in the lower uterine segment and should \nnot be interpreted as ciliated metaplasia [21, 35, 36].\nThese characteristics stress the importance of giv-\ning a particular attention to the anatomic limits of \nthe isthmus during a diagnostic hysteroscopy. If \nthe sampling is performed within the isthmic re-\ngion, a note has to be made to the pathologist for a \nproper interpretation. \nConclusion: the endometrium lining the LUS is \npoorly responsive to hormones and does not dis-\nplay the usual cyclical changes allowing a proper \nendometrial assessment.\nCorrelation with hysteroscopy: visualization of the \ninternal histological and anatomical ostia of the \nuterus whenever possible to permit precise delim-\nitation of this region; sampling should be avoided \ntherein and if necessary, a mention should be made \nto the pathologist in order to prevent overdiagno-\nsis of out of date dysfunctional endometrium.\n9. Iatrogenic acute inflammation\nHysteroscopy, uterine distension and deflation, as \nwell as the contact of the instruments with the mu-\ncosa, cause an inflammatory response, displaying \nsome of the cardinal signs of acute inflammation \nnamely oedema, hyperaemia and haemorrhagic \nspots [3] (Figure 7). However, these patterns can also \nbe expressed in C-IISE, as the latter provides a pre-\ndisposing ground for acute inflammatory episodes.\nThis highlights the importance of paying particular \nattention to the iatrogenic inflammatory patterns \nduring hysteroscopy, as these sites do not have to \nbe sampled. Their presence is increased by intra-\nuterine manipulation.\nConclusion: iatrogenic acute inflammation stresses \nthe importance of the following precautions:\n• Use of small diameter instruments.\n• No dilation before diagnostic hysteroscopy\n• Determination of the endometrial sites to .sam-\nple: preferably at the first passage of the scope.\n• At the second passage, the additional iatrogenic \ninflammatory lesions can be misleading and in \nall case do not have to be sampled.\nAvoid getting out of the uterus before finishing the \nprocedure.\n10. Histopathological artifacts correlated with hysteros-\ncopy: improving biopsy technique\nIn addition to iatrogenic inflammation and the \npitfall of the isthmic region, it is capital to grow \nthe awareness of gynaecologists regarding the \ntechnical difficulties pathologists face when ex-\namining an improper endometrial sample. Some \nof the main characteristics of a good sample from \nthe point of view of pathologists are sufficient \namount of tissue; presence of surface epithelium; \navoiding endometrium from lower uterine seg-\nment or basalis; avoiding tangential sectioning or \ncompression of the sample; avoiding late secreto-\nry phase as lymphoid infiltrates become promi-\nnent; correct manipulation and conservation of \nthe specimen [33, 34].\nFigure 6. Uterine isthmus at hysteroscopy. \n1: distal limit, the internal histological os of the uterus; 2: proximal limit, the internal \nanatomical os of the uterus; 3: the length of the LUS.; yellow arrows: intra-isthmic lesions.\nFigure 7. Iatrogenic acute inflammation at hysteroscopy. \nInitial view at the first passage of the scope (A); focal oedema, hyperaemia and \nhaemorrhagic spots caused by intrauterine manipulation (B).\n\n\nItal J Gynaecol Obstet  2023, 35, N.1\n50\nHysteroscopy and histopathology correlations in IISE\nFrom here, it becomes clear that a biopsy is \nbest performed under visual control, thus tar -\ngeting the suggestive hysteroscopic patterns, \nand allowing a proper sampling, avoiding the \nisthmus, and respecting the surface epithelium \n(Figure 8). Very importantly, the volume of the \nsample has to be significant. For this reason, \namong the validated hysteroscopic techniques \nof endometrial sampling, the punch biopsy \ntechnique which consists of removing the sam-\nple with the 5Fr grasping forceps through the \nworking channel, unavoidably results in a small \nvolume of tissue [39, 40]. It requires multiple \nsampling, which implies more manipulation of \nthe endometrium ultimately adding iatrogenic \ninflammation. The grasp biopsy however al-\nlows larger amount of tissue compared to the \npunch technique [13, 39, 40].\nIn post-menopausal patients, scissors and bipolar \nelectrodes are preferred due to the fibrotic stroma \nin this context especially in case of atrophy, making \nthe grasping technique difficult to perform [13].\nConclusion: blind biopsy with a Pipelle or Novak \nare impertinent in inflammatory disorders because \nin addition to their commonly focal character, these \ntools could blindly sample the isthmus, the basalis \nor a scratched endometrium without a surface epi-\nthelium, thus compromising the histopathological \nexamination.\nVisual guided biopsy is capital: ideally at first pas-\nsage, taking sufficient amount of tissue covered by \na surface epithelium, with a particular attention to \nthe isthmic bias and a proper conservation.\nThe information related to the patient has to be re-\nported, with all the previously mentioned criteria.\nInflammatory versus dysfunctional disorder: two \nsides of a single coin\nThe term “dysfunction” is etymologically the com-\nbination of “dys” (bad or difficult) and “function”. \nIt designates failure or impairment of normal func-\ntion. A uterus free from visually diagnosable malfor-\nmations, synechiae, polyps, fibroids, malignancy or \nretained products of conception is considered organ-\nically normal. However, if there are abnormalities in \nthe functions of the cells or tissues composing the \norgan, the term dysfunctional is commonly used.\nIn the hormone-sensitive female reproductive sys-\ntem, dysfunctional disorders are usually linked to \nhormone-imbalances. However, sex hormones have \nanti-inflammatory properties on the endometrium. \nIn fact, progesterone’s action is crucial in decreasing \ninflammation in the endometrium and disturbed \nprogesterone functioning results in pro-inflamma-\ntory phenotypes [27]. Conversely, chronic inflam-\nmation induces a progesterone-resistant state [27, \n30, 41]. In other terms, despite hormones being nor-\nmally secreted by the ovaries, their impact on the \nendometrium is insufficient due to the impaired \nexpression of hormone receptors caused in an in-\nflamed endometrium, subsequently resulting in \nthe dysfunctional anomalies which are already de-\nscribed for chronic inflammatory processes. \nThis explains why the limit between dysfunctional \nand inflammatory states is blurred, as both are in-\nterrelated.\nThe formerly termed “dysfunctional bleeding” is \nonly to be considered after exclusion of pregnan-\ncy-related disorders, medications, iatrogenic caus-\nes, obvious genital tract pathology and systemic \nconditions [42]. Since 2012, the PALM and COEIN \nterminology has abandoned the use of the term dys-\nfunctional AUB and recommend the term AUB-E, \nthe letter “E” standing for “Endometrial” factor [43, \n44]. This new classification separated endometrial \nfrom adenomyotic, dyscoagulative, iatrogenic and \nhyperplastic conditions. AUB-E means the function \nof the endometrium itself is impaired.\nIn terms of histopathology, the entity “dysfunction-\nal endometrium” is still used and defines alterations \nin the normal cyclical changes of the endometrial \nmucosa [31]. However, in the studies where “dys -\nfunctional bleeding” was investigated via blind \nsampling, histopathological correlations were very \nlimited, as “normal proliferative or secretory endo-\nmetrium” was prevalent irrespective of all groups \nof age [42, 45]. Hyperplasia, in its different forms, \nFigure 8. Targeted sampling using the 5F grasping forceps. \nPanoramic view (A), closer view (B), grasp and push technique (C-E); the endometrial \nsample (F).\n\n\n51\nHysteroscopy and histopathology correlations in IISE Amal Drizi, Mehran Ghahremani, Bruno Johan van Herendael\nis another predominant finding, in addition to in -\nadequate sampling. In conclusion, histologically \ndysfunctional endometrium represented the least \nfrequent finding, thus highlighting the bad correla-\ntions between these blind sampling methods and \nhistopathology. All this highlights the superiority \nof visual biopsy.\nFuture therapeutic perspective in correlation \nwith the notion of “non-shed endometrium” in \nC-IISE: cold resection of inflammatory lesions?\nThe entity of “non shed endometrium”, presented \nas a sine qua none prerequisite for a chronic inflam-\nmatory disorder to develop [11, 22, 24], stresses the \nimportance of rethinking our therapeutic approach \nto this issue. In fact, superficial cold resection of the \ninflammatory lesions appears pertinent to consid -\ner in this context, especially in case of persistence \nafter medical treatment. Micropolyps and areas \nof unequal thickness, especially if associated with \noedema and unevenly distributed glands, seem to \ndeserve a particular attention, as they are highly \ncorrelated with histological signs of non-shed en-\ndometrium, as previously addressed. Some au-\nthors have already reported eradication of inflam-\nmatory lesions in approximately 80% of patients \nafter biopsy or curettage [22].\nTaking these facets into consideration would open \nnew therapeutic doors for clinical trials. We pro-\npose that the inflammatory lesions be removed \nmechanically, either with scissors, grasping for -\nceps or the cold loop of a mini-resectoscope. In \ncase of relatively large areas to remove, and if the \n5Fr grasping forceps is used, we propose to mim-\nic the polypectomy technique introduced by Bet-\ntocchi et al. [46]: place the open jaw of the forceps \nat the base of the biopsy site, gently push toward \nthe fundus, reposition the grasper as many times \nas necessary until the endometrial area is detached \n(Figure 9). This gentle “grasp-push & repeat” tech-\nnique allows gentle mechanical removal of larger \nsurfaces. Scissors and cold loop can also be used.\nCONCLUSIONS\nToday, in our approach to endometrial inflam-\nmation, we deplore the use of consensual criteria \nwhich partly violate the very basics of histopathol-\nogy, immunology and hysteroscopy. This is caus-\ning multiple diagnostic and therapeutic biases, \nexplaining the heterogeneous data related to this \ndisorder, as it is greatly dependent on each team’s \npractice setting [20]. No interpretable studies can \ncome to fruition in the absence of pertinent defini-\ntions of the problem. \nGoing back to basics leads to a well-founded stan-\ndardized practice, a capital prerequisite to uniform \nclinical trials and thus to exploitable data. Estab-\nlishing well-grounded hysteroscopic and histo-\npathological diagnostic criteria is of utmost neces-\nsity for evidence-based research.\nIt is very important to recall that C-IISE is not only \nincriminated in fertility issues, but is a well-known \nrisk factor of life-threatening diseases like endome-\ntrial neoplasia.\nIt is big time for hysteroscopists to grow their \nknowledge on endometrial histopathology and to \nconduct diagnostic hysteroscopy in a meticulous \nfashion, with particular attention to the above ex-\nplained correlations.\nWe propose that IISE be diagnosed as follows:\n• Hysteroscopically: the presence during prolifer-\native phase of one or more of the following mor-\nphologic patterns suggestive of inflammatory \ndisorders: micropolyps, irregular thickness (slope \nor stairstep corrugated surface; embossed or de-\nbossed patterns), unevenly distributed glands and \nstrawberry pattern. Oedema, hyperaemia and hae-\nmorrhagic spots are to be cautiously considered as \nthey can reflect a transient IISE. These signs should \nstand as markers for the targeted biopsy site. The \nsampling has to be performed under visual con-\ntrol, within the inflammatory lesions, using small \ndiameter instruments without prior dilatation. \nThe good technique is the one allowing a sufficient \nFigure 9. Mechanical resection of the entire inflammatory site using the 5F \ngrasping forceps. \nIrregular thickness and micropolyps (A); gentle grasp-push-repeat until the area is \ndetached (B-D); strawberry pattern (E); removal with the 5F grasping forceps (F).\n\nItal J Gynaecol Obstet  2023, 35, N.1\n52\nHysteroscopy and histopathology correlations in IISE\namount of tissue from the inflammatory site, with \nrespect to the surface epithelium, without com-\npression and with a proper conservation. The isth-\nmic localization needs to be specified as well as the \nmenstrual phase. The lesions to biopsy need to be \ndetermined at the first entry of the scope. \nIatrogenic inflammatory patterns are not to be \nsampled. The notion of non-shed endometrium \nneeds further studies, as it would imply resec-\ntion of the localized inflammatory lesions, espe-\ncially if they persist after medical treatment.\n• Histologically: our conclusions support the re-\ncently recommended diagnostic strategy by \npathologists [11]. Additionally, we propose to \nconsider the presence of at least one epitheli-\nal/stromal change from Table 4 in the absence \nof artifacts, in addition to a polymorphic in-\nflammatory infiltrate containing at least one or \nmore plasma cells by H&E staining. CD138 and \nMUM1 staining are to consider in the failure of \nH&E staining to identify plasma cells in the set-\nting of stromal/glandular changes.\nCOMPLIANCE WITH ETHICAL STANDARDS\nAuthors contribution\nA.D.: Conceptualization, data curation, methodolo-\ngy, project administration, writing ‒ original draft, \nwriting – review & editing. Bv.H.: Critical review, \ndata curation, supervision, validation. M.G.: Crit -\nical review, validation. All authors commented on \nprevious version, read and approved the final man-\nuscript. \nFunding\nNone.\nStudy registration\nN/A.\nDisclosure of interests\nThe authors declare that they have no conflict of \ninterests.\nEthical approval\nN/A.\nInformed consent\nN/A.\nData sharing\nN/A.\nREFERENCES\n1. Drizi A, Djokovic D, Laganà AS, van Herendael \nB. Impaired inflammatory state of the endome-\ntrium: a multifaceted approach to endometrial \ninflammation. Current insights and future di-\nrections. 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