Classifications of Adenomyosis and Correlation of Phenotypes in Imaging and Histopathology to Clinical Outcomes: a Review

Purpose of Review To pro vide an update on published classification and reporting systems for adenomyosis. There is an urgent need to standardize reporting of various phenotypes of adenomyosis into a validated and globally recognized sys- tem. This can be used to examine the nature and severity of adenomyosis symptoms and inform the design, evaluation, and implementation of appropriate treatment options. Recent Findings In recent years, several new proposals for adenomyosis classification have emerged. Most are MRI-based and include features such as uterine size, junctional zone thickness, size and location of the lesions, and distribution patterns. To date, none of those proposals has been validated. Only one recent classification based on transvaginal ultrasound was validated for interobserver congruence and correlated to clinical findings. However, the differentiation of diffuse and focal adenomyosis still lacks consensus. In addition, only a few authors advocated imaging-based definitions. Summary There is a need for one or a combination of a classification and r eporting system for adenomyosis. To date, there is no widely accepted and validated system.

Adenomy osis · Classifications · Imaging · Histopathology · Pathophysiology

In medicine, several disorders and conditions are poorly or incompletely understood. They might have a variety of imaging, molecular or other clinical features. Such circum- stances beg for creating systems of categorization, or “clas- sification,” that support clinical care, patient and trainee education, and the performance of basic, translational, clini- cal, and epidemiological research. At a scientific level, a classification system can serve to identify categories of a disorder that allows for the comparison of outcomes between different investigators by facilitating systematic review and meta-analysis. From a clinical perspective, classification or categorization can aid diagnosis, prognosis, or inform the selection of management options ranging from expectant to a spectrum of medical and procedural options. Classifications can be based on phenotypical traits including imaging, his- topathology, genetic markers, or molecular characteristics. Despite the first published description of adenomyosis in 1860 [1], understanding of pathogenesis, prevalence, clini- cal relevance, ideal diagnostic techniques, and appropriate and effective management of adenomyosis remain unclear. Historically, adenomyosis is diagnosed by histopathology of hysterectomy specimen. Diagnosing adenomyosis by myometrial biopsy is impractical and suboptimal. Today, imaging techniques are relatively accurate for the detection of adenomyosis. Yet, there is a lack of standardization [2–4]. While there are several proposed systems, none has been universally adopted—a circumstance that is problematic for both clinicians and investigators and the patients [2, 5]. Sonographic features of adenomyosis have been reported in about 21–34% of women attending gynecology clinics [6 ••, 7]. The clinical relevance of the disorder has been limited to the two best-known symptoms, which are heavy menstrual bleeding (HMB) and dysmenorrhea [8 ]. Recent This article is part of the Topical Collection on Uterine Fibroids and Endometrial Lesions * Tina Tellum [email protected] 1 Department of Gynecology, Oslo University Hospital Trust, Oslo, N orway 2 Department of Obstetrics & Gynecology, David Geffen School of Medicine, UCL A/Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA / Published online: 7 February 2022 Current Obstetrics and Gynecology Reports (2022) 11:1–11 1 3 studies suggest that adenomyosis may be associated with adverse effects on fertility and might contribute to obstetrical complications, such as preterm labor, fetal growth restric- tion, and preeclampsia [9–11]. The purpose of our review was to identify and compare studies evaluating adenomyosis features and their clinical relevance, as well as describe classification systems for adenomyosis, based on one or a combination of clinical, phenotypical, histological, molecular, or genetic features. Furthermore, we evaluated studies that assess adenomyosis features and those that correlate a classification or individual characteristics to clinical outcomes. Diagnostic Classifications We identified 10 manuscripts describing a histological diag- nostic classification system. Six are based on the diagnosis on the depth of myometrial involvement [12–17], two on the proportion of myometrium involvement [18, 19], and two others use other features [20, 21]. For ultrasound a system of terminology for categorizing and describing sonographic features associated with adenomyosis was presented by experts in the so-called Morphological Uterus Sonographic Assessment (MUSA) statement [22 ••]. This system is cur - rently the most recognized and widely used ultrasound clas- sification of adenomyosis. For magnetic resonance imaging (MRI), several diagnostic accuracy studies were published; however, the consensus is still lacking [23]. Disease Classifications Histopathology Identified histology-based classifications are shown in Table  1 [ 13–17, 19, 21, 24–26]. They focus primarily on dis- ease location or extent. While phenotypical features such as muscular hypertrophy or hyperplasia were described, these were not used as markers in these classifications. MRI‑Based Systems Table  2 shows the MRI-based systems using a spectrum of criteria [2, 5, 27•, 28–30]. An early proposal from Kishi et al. distinguished four subtypes of adenomyosis based on the myometrial region involved: subtype I—intrinsic (inner myo- metrium), subtype II—extrinsic (outer myometrium), subtype III—intramural (surrounded by normal outer myometrium), and subtype IV—indeterminate (not fit into any of the other types) [27 •]. The authors concluded that the pathogenesis of these different phenotypes might vary from the concept of myometrial invasion of heterotopic endometrium. Yet, it does not explain the mechanism of subtypes II and III. This classification has since been adapted and modified by many authors. A similar layered concept has been included in the Bazot system [30], which further distinguishes anterior from posterior involvement as well as disease volume and patterns (Table  2). While all other systems are purely based upon MRI char- acteristics, Grimbizis et al. added endometrial finding of a polypoid adenomyoma confirmed by histopathology [5]. Several authors postulated that adenomyosis in the out- ermost aspect of the myometrium (“extrinsic” type) may originate from endometriosis involving the myometrium by “invasion” through the serosa [29,  31–34]. However the extrinsic type is frequently found in women without endo- metriosis [29]. Since it is difficult to reliably determine the origin of the findings at least by imaging we conclude that “extrinsic” adenomyosis should not be classified as a sub- type of endometriosis. Ultrasound‑Based Systems We identified two studies describing classifications based on transvaginal ultrasound (Table  2) [34–36]. In a consen - sus work, the MUSA statement [22 ••] was later modified to allow the description of findings stratified by anterior and posterior location and by involvement with one or more of three arbitrarily defined myometrial layers [35]. Lazeri et al. proposed a system combining the pattern (diffuse adenomyosis, focal adenomyosis, or adenomyoma) with location based on a more “anatomic” two-layer myo- metrium (inner or outer myometrium) and a grade of disease (severity score 1–4) (Table 2) [36]. The inter-rater reproduc- ibility of this system has been internally validated and found to be suitable for clinical use. In a second publication, this system was correlated with clinical symptoms [34]. Others Gordts et al. proposed an imaging-based classification that could be used with either MRI or ultrasound [37]. The authors proposed identifying the affected myometrial layer (inner or outer myometrium), the location (anterior, poste- rior, or fundus), the pattern (diffuse or focal, if focal speci- fied as muscular or cystic), and disease volume. Adenomyosis Imaging Features and Correlation to Clinical Outcomes Study characteristics and detailed results of the included studies are shown in Table  3. 2 Current Obstetrics and Gynecology Reports (2022) 11:1–11 1 3 Disease Distribution: Diffuse vs. Focal Three studies found that women with diffuse adenomyo- sis were older [7, 8, 34] and suffered more frequently from HMB [34] than those with focal disease. There was no asso- ciation of the diffuse type with dysmenorrhea in one study [34], while such a relationship was found in another [8 ]. Pinzauti et al. showed that diffuse adenomyosis was associ- ated with a higher average symptom burden than women without adenomyosis. However, in this population, no focal type adenomyosis was described [7]. Women with focal findings had a higher risk of infertility and miscarriage in one study [34]. This relationship was also found in a study published by Bourdon et al. [38]. Tamura et al. reported no elevated risk of miscarriage [39]. Disease Location: Inner, Middle Outer Myometrium The terms “inner adenomyosis,” “intrinsic adenomyosis,” or “JZ disease” are often interchangeably used. Kishi et al. found no difference in pain scores (dysmenorrhea, dys- pareunia, or CPP) or HMB based on the location within the myometrium [27 •]. Naftalin et al. showed that an irregular JZ was significantly associated with higher pain scores for dysmenorrhea [40]. Iwasawa et al. showed that the location of the adenomy - otic lesion did not affect the clinical pregnancy rate in a cohort undergoing embryo transfer [41]. Still, the extrinsic group had fewer pregnancy losses [41]. In a retrospective study, Bourdon showed that infertility was related to focal findings in the outer myometrium but not to diffuse internal Table 1 Histopathological adenomyosis classification systems Author, year Category Pattern Name Depth Name Foci Sampson [21] Group 1 Invasion from within N/A N/A Group 2 Invasion from without N/A N/A Group 3 Adenomyoma (intramyometrial) N/A N/A Bird et al. [13] Grade I Sub-endometrial basalis Mild 1–3 foci/LPF Grade II Mid-myometrium Moderate 4–9 Grade III Outer myometrium Severe ≥ 10 Nishida e t al. [24] Type 1 Continuous from endometrium N/A Islands/section Type 2 Continuous from serosa N/A Glands/section McCausland [25] Superficial ≤ 1 mm depth N/A N/A Deep > 1 mm depth N/A N/A Siegler et al. [19] Grade 1 Inner 1/3 Mild 1–3 foci/LPF Grade 2 2/3 Moderate 4–9 Grade 3 Entire myometrium Severe ≥ 10 Le vgur et al. [14] Superficial 80% N/A N/A Sammour et al. [15] N/A 75% N/A N/A Hulka et al. [16] Mild Inner 1/3 (or microscopic foci) N/A N/A Focal Adenomyoma N/A N/A Severe/diffuse Outer 2/3 (include entire myometrium) N/A N/A Vercellini et al. [3] Mild Up to 1/3 Grade 1 1–3 islets Moderate 1/3 to 2/3 Grade 2 4–10 islets Severe > 2/3 Gr ade 3 > 10 islets Rasmussen et al. [26] Intrinsic ≥ 2 mm my ometrial invasion without contact to the basal endometrium Serrated junctional zone > 3 mm my ometrial invasion with contact to the basal endo- metrium (precursor of adenomyosis) Linear junctional zone: No or marginal myometrial invasion ≤ 3 mm with cont act to the basal endometrium 3Current Obstetrics and Gynecology Reports (2022) 11:1–11 1 3 Table 2 Imaging-based adenomy osis classification and grading systems. MRI magnetic resonance imaging. JZ junctional zone Author, year Criteria Classification MRI-based systems Gordts et al. [2] T2 -JZ ≥ 8 mm; < 12 JZ Hyper plasia Age ≤ 35 y ears Partial or diffuse JZ ≥ 12 mm A denomyosis T2 high-intensity foci Involvement of outer myometrium < 1/3; 2/3 My ometrial mass, indistinct margins, low signal intensity Adenomyoma Retrocervical, retrovaginal, fallopian tube, bladder Kishi et al. [27 •] Only contiguous with inner myometrium Subtype I (intrinsic) Normal JZ and myometrium between Subtype II (extrinsic) Normal JZ and surrounding myometrium Subtype III (intramural) Doesn't fit the other definitions Subtype IV (All others) Grimbizis et al. [5] 1. Diffuse adenomyosis Diffuse 2. Focal adenomyosis Focal     a. Adenomyoma     b. Cystic adenomyosis (single adenomyotic cyst) 3. Polypoid adenomyomas (endometrial masses) Polypoid     a. Typical     b. Atypical 4. Other forms Other     a. Endocervical     b. Retroperitoneal Dashottar et al. [28] Diffuse consistent (“even”) JZ thickening ≥ 14 mm thr oughout uterus Diffuse even Diffuse JZ variable (“uneven”) thickening ≥ 14 mm thr oughout uterus Diffuse uneven Focal widening of the JZ ≥ 14 mm Focal Chapr on et al. [29] Three subtypes according to location: outer, middle, and inner myometrium Focal JZmax of at least 12 mm and wallthicknes/JZ ratiomax > 40% Diffuse Bazot e t al. [30] A. Focal or multifocal Internal B. Superficial asymmetric C. Superficial symmetric D. Diffuse asymmetric E. Diffuse symmetric F. Solid adenomyoma Adenomyoma G. Cystic adenomyoma H. Submucous adenomyoma I. Subserosal adenomyoma J. External posterior External K. External anterior Transvaginal ultrasound–based systems Van den Bosch et al. [35] Presence of diagnostic signs Location: anterior posterior lateral left lateral right fundal Location diffuse, focal (> 25% surr ounded by normal myometrium), mixed, adenomyoma Differentiation Measurable, size of the largest lesion Cystic-non-cystic Inner: Type 1 Layer Middle (inner to vascular arcade): Type 2 Outer: (vascular arcade to serosa): Type 3 Multi-layer: (type 1–2, 2–3, or 1 to 3) 4 Current Obstetrics and Gynecology Reports (2022) 11:1–11 1 3 adenomyosis. They defined adenomyosis as a JZ 12 mm or more in thickness and involving at least 40% of the total myometrial thickness [38]. These findings appear to be in contrast to a prospective study from Maubon et al. that demonstrated that embryo transfer failure was more com- mon when the mean JZ thickness was more significant than 7 mm and the maximum thickness more than 10 mm [42]. Disease Pattern: Cystic vs. Hypertrophic Role of disease patterns in clinical manifestations is unclear. Naftalin et al. found that the presence of myome- trial cysts was not explicitly associated with a higher dys- menorrhea score [43]. Hemorrhagic lesions that can be dis- criminated from cysts without hemorrhage in T1-weighted MRI were more frequently found in intrinsic or extrinsic adenomyosis when compared to isolated adenomyosis in the middle myometrium [ 27 •]. Yet, the number of cases was relatively small and involved a selected group of women. Bourdon et al. found no association between infer - tility and the presence of bright spots on T2 [38]. Several investigators have correlated MRI-based sig- nal intensity (T2 hyperintense foci or T1 lesion signal) to the success of high-intensity focused ultrasound (HIFU) therapy [44– 47]. These studies suggest that the relative amounts of glands and stroma in the adenomyotic mass can impact the results of hyperthermic treatment—at least based on the imaging outcomes. Volumetric Relationships: Lesion Size and Disease Extent Bird et al. studied the association between depth of adeno- myosis involvement and symptoms. They found no relation- ship with recorded bleeding symptoms, but they demon- strated that the number of “islets” of adenomyotic glandular tissue per low powered field was proportional to the subjec- tively determined volume of menses [13]. Similar findings were described by Sammour et al. and Rasmussen et al., who also reported no relationship between depth of myometrial involvement and the symptom of HMB [15, 26]. However, Rasmusen et al. reported that symptom improvement after Table 2 (continued) Author, year Criteria Classification Mild: 50% F ocal: plane of largest diameter of largest lesion Size Diffuse: myometrial thickness Exacoustos et al. [34] Score 1: single myometrial wall involvement with thickness ≤ 20 mm Diffuse outer Score 2: double m yometrial wall involvement with thickness ≥ 20 mm or Single m yometrial wall involvement with thickness ≥ 20– ≤ 30 mm Score 3: sing le myometrial wall involvement with thickness ≥ 30 mm or double my ometrial wall involvement with thickness ≥ 20– ≤ 30 mm Score 4: Double m yometrial wall involvement with thickness ≥ 30 mm or whole uterus in volved with global enlargement Diffuse inner Score 1: JZmax ≥ 6- ≤ 8 mm or diffuse infiltration of t he JZ ≤ 20 mm in length Scor e 2: JZmax ≥ 8 mm or diffuse infiltration of t he JZ ≤ 20 mm in length or ≤ 50% of the uter us Score 3: diffuse infiltration of the JZ ≥ 50% ≤ 80% of the uter us Score 4: diffuse infiltration of the JZ ≥ 80% of the uter us Score 1: One focal intramyometrial lesion < 10 mm Focal outer Scor e 2: ≥ 2 intram yometrial lesions 20 mm Scor e 4: ≥ 2 intram yometrial lesions > 20 mm or ≥ 3 focal intr amyometrial lesions Score 1: One focal lesion in JZ or cystic areas ≤ 10 mm Focal inner Scor e 2: ≥ 2 focal lesions of t he JZ ≤ 10 mm or one focal intr amyometrial lesion of 10–20 mm Score 3: ≥ 2 focal lesions of t he JZ 10–20 mm or one focal lesion of the JZ of > 20 mm Score 4: ≥ 2 focal lesions of t he JZ > 20 mm or ≥ 3 focal lesions of t he JZ 5Current Obstetrics and Gynecology Reports (2022) 11:1–11 1 3 Table 3 Studies correlating adenomyosis features to clinical outcomes. MRI, magnetic resonance imaging; TVUS, transvaginal ultrasound; 2D, two dimensional; 3D, three dimensional; GnRHa, gonado tropin releasing hormone agonist; HMB, heavy menstrual bleeding; JZ, junctional zone; CPP, chronic pelvic pain First author, year Study design N, population characteristics Mode of diagnosis Classification feature Clinical outcomes Limitations Iwasawa et al. [41] Retrospective cohort 136 embryo transfers in 52 infertile women with adenomyosis, undergoing in vitro fertilization (fresh and frozen) MRI + T VUS • Advanced (invades the full thickness of the uterine myometrium) • Extrinsic (localized on the serosal side) • intrinsic (localized on the endometrial side) • Adenomyoma (not present in this population) • Fertility outcomes • Pregnancy complications • Obstetric outcomes Retrospective, endometriosis as confounder, phenotype groups unevenly distributed, some received GnRHa- treatment Bourdon et al. [49] Same as Bourdon 2020 Same as Bourdon 2020 MRI • Internal vs. external adenomyosis • JZ thickness • HMB • Dysmenorrhea • Non-cyclic CPP • Dyspareunia Bourdon et al. [38] Retrospective observational, cross-sectional cohort 248 women with adenomyosis out of nonpregnant women between 18 and 42 years of age who underwent surgery for benign gynecological pathologies MRI • Focal: localized, ill-defined, low signal intensity mass, inhomogeneous circumscribed area located in the outer shell of the uterus, with indistinct margins separated from the JZ • Lesion size • Location (anterior/ posterior) • Infertility (none/ pri- mary/secondary) Retrospective design; Single timepoint; Male factor as confounder not assessed Exacoustos et al. [34] Prospective cohort 108, premenopausal women referred for pelvic pain assessment TVUS (2D/3D) • Adenomyosis severity score • Diffuse vs focal vs adenomyoma • HMB • Dysmenorrhea • Dyspareunia • Infertility • Miscarriage • Endometriosis Relatively low n, selection bias (pelvic pain) Tamura et al. [39] Retrospective, multicenter, questionnaire-based cohort 262 pregnant women with adenomyosis, without fibroids/ endometriosis MRI and/or TVUS • Focal/diffuse, lesion size, location (anterior/ posterior) • Pregnancy and obstetric complications Recall bias, selection bias Li et al. [50] Prospective case–control; consecutive cohort 578 (298 with adenomyosis, 280 matched controls) MRI or TVUS • Uterine size • Lower urinary tract symptoms Orazov et al. [52] Prospective translational 90 (60 adenomyosis + pain; 30 adenomy osis without pain but HMB) TVUS + MRI + His tology • VEGF expression in adenomyosis and eutopic tissues • Dysmenorrhea No adjustment for confounders 6 Current Obstetrics and Gynecology Reports (2022) 11:1–11 1 3 Table 3 (continued) First author, year Study design N, population characteristics Mode of diagnosis Classification feature Clinical outcomes Limitations Naftalin et al. [40] Prospective observational consecutive cohort 718 premenopausal women, 157 with adenomyosis TVUS (2D, 3D) • Asymmetrical myometrial thickening • Parallel shadowing • Linear striations • Myometrial cysts Hyperechoic islands Adenomyomas • Irregular endometrial– myometrial junction • Dysmenorrhea Pinzauti et al. [7] Prospective observational consecutive cohort 156 women, 18 and 30 years, regular menstrual cycle, nul- ligravid, no endometriosis or fibroids TVUS (2D, 3D) • MUSA criteria • Diffuse vs focal adenomyosis (focal not present in population) • Dysmenorrhea • HMB • Dyspareunia • CPP Only diffuse adenomyosis found in this cohort Wang et al. [51] Prospective translational 80; (40 adenomyosis + dy smen- orrhea; 20 no adeno dysmen- orrhea, 20 controls) TVUS + his tology/hyster- ectomy • CD65 expression in adenomyosis tissue • Dysmenorrhea Hysterectomy specimen Li et al. [8] Retrospective cohort; con- secutive 734 with adenomyosis (97% premenopausal) Histology/Hysterectomy specimen • Uterine size (TVUS based) • Diffuse/focal (histology diagnosis) • HMB • Dysmenorrhea • Metrorrhagia • Time from symptom onset to diagnosis • CPP Retrospective, hysterectomy Naftalin et al. [48] Prospective observational consecutive cohort 714 premenopausal women, 100 with adenomyosis TVUS (2D, 3D) • Number of TVUS features for adenomyosis found • Menstrual blood loss Different blood loss assessment measures in same cohort Kishi et al. [27 •] Retrospective cohort 152, surgical treatment for adenomyosis (hysterectomy or adenomyomectomy) MRI • Location: • Type I: intrinsic • Type II: extrinsic • Type III: middle only • Type IV: does not fit other category • T2/T1 high intensity spots • Dysmenorrhea • HMB • CPP Retrospective, surgical cohort with expected high symptom scores Levgur et al. [14] Retrospective cohort 111 (17 with adenomyosis alone, 19 with adenomyosis with leio- myomas, 39 with leiomyomas alone, and 36 with neither) Histology/Hysterectomy specimen • Invasion: • Deep (above 80%), intermediate (40–80%), and superficial (under 40%), • Number of adenomyotic foci • Dysmenorrhea • HMB Uterus weight under ≤ 280 g, clinical dat a were collected retrospectively from patient records, possibly underpowered 7Current Obstetrics and Gynecology Reports (2022) 11:1–11 1 3 transcervical endometrium resection was greater with mini- mal depth of involvement of the myometrium [26]. The outlier in this group of studies is the report by Levgur et al., where the symptom of HMB was 36.8% in women with deep foci and 13.3% in those with “intermediate” depth foci [14]. Sammour et al., who evaluated dyspareunia and “other pain” found a poor correlation with depth, but again, there was a correlation with the number of foci identified histopathologi- cally. A few authors reported a correlation between depth of adenomyosis involvement as well as the number or volume of foci of glandular tissue and dysmenorrhea [13, 14,  24]. Naftalin et al. and Pinzauti et al. reported a linear rela- tionship between ultrasound diagnosis of adenomyosis and dysmenorrhea and HMB symptom severity [7, 40, 48]. Volumetric Relationships Lesion Volume Estimated adenomyosis volume and clinical manifestations have been examined by Exacoustos et al. who showed that symp- tom severity was associated with disease severity mainly based on lesion size and %-involvement of the myometrium [34]. However, it seems that the size of an adenomyoma, defined as a subgroup of focal adenomyosis surrounded by hypertrophic myometrium, is not associated with more pain, as demonstrated in two studies [34, 48]. There have been early evaluations of the volume of adenomyosis findings and pregnancy outcomes. Tamura et al. found the rates of miscarriage and cervical insuf- ficiency were higher in the group with large lesions [39]. Uterine Volume Another feature associated with adenomyosis, and indirectly, with disease volume, is uterine volume. Li et al. showed that large uterine size was independently associated with both- ersome lower urinary tract symptoms (LUTS) and HMB, but not dysmenorrhea or chronic pelvic pain (CPP) [50]. Another group showed that smaller uteri were associated with more CPP (8). Disease duration and age were also positively associated with the uterine size, supporting the progressive nature of adenomyosis. Molecular Markers An evolving approach to evaluating the potential impact of adenomyosis is using molecular markers, not only for diagnosis but also as instruments to monitor response to therapeutic interventions. Wang showed that CD65 expres- sion was higher in women with dysmenorrhea than those without dysmenorrhea and controls [51]. The same associa- tion was also found for VEGF expression and dysmenorrhea [52]. VEGF was found in hypertrophic muscular bundles [52]. Bourdon et al. correlated MRI findings with serum cytokine profiles. They found that in women with both focal and diffuse adenomyosis, the levels of IL-23, IL-25, IL-31, and IL-33 were lower than in controls. The levels of IL-17F levels were lower in women with focal adenomyosis than in controls. TNFα levels were lower in women with focal disease compared to those with diffuse adenomyosis [53].

Adenomyosis is a disorder of increasing interest, in part because of its newfound high prevalence on ultrasonic and magnetic resonance imaging and in part because of its variable impact on clinical outcomes such as infertility, pelvic pain, abnormal uterine bleeding, and pregnancy-related disorders. It is still unclear how imaging features of adenomyosis correlate to symptoms or other adverse outcomes such as infertility or pregnancy loss. There exists an urgent need, at least for a standardized reporting system to harmonize the design and interpretation of basic science and clinical investigation as well as education and clinical care. In this review, we found various reporting or classifica- tion systems based on histopathological, MRI, or TVUS features. While most systems are designed to include the location, the extent, and the distribution pattern of adeno- myosis features (focal or diffuse), few describe more specific phenotypical patterns such as the presence, size, or types of cysts, or the location and extent of findings suggesting the presence of muscular hyperplasia. We identified studies that correlated clinical findings with phenotypical traits of adenomyosis, suggesting that a variety of features could be relevant in the design of a reporting or classification system. There have been conflicting results regarding the clini- cal significance of the disease pattern (diffuse, focal, and adenomyoma). The differences in patient populations, the low number of participants in some studies, and the differ - ent definitions of those groups are likely the reason for these incongruencies. Also, as those traits are assessed by subjec- tive pattern recognition, a high inter-rater variation is likely an important reason for these conflicting results. The clinical significance of myometrial cysts (with and with- out hemorrhage) and muscular hyperplasia remains unclear. In a study investigating treatment response of high-intensity focused ultrasound (HIFU) in different phenotypes, the absence of T2 hyperintense spots in MRI was associated with an increased chance of nonperfusion and thus treatment response [45]. As a result of these considerations, it would seem prudent to include disease patterns in a reporting system. Such an approach would allow investigators to evaluate further the relationship of such findings to clinical manifestations of adenomyosis and characterize responses to various types of medical, ablative, and surgical therapy. We found that the disease extent is likely to be linked to symptom severity. This was consistently shown in 8 Current Obstetrics and Gynecology Reports (2022) 11:1–11 1 3 histopathological, MRI-based, and ultrasound-based stud- ies. Furthermore, it was demonstrated that treatment effi - cacy depended on disease extent, which is not surprising [26,  44]. These observations, along with the spectrum of disorder phenotypes, beg for evidence-based information to assist patients and clinicians in informed decision-making. While the need for a uniform system for reporting should lead to a valuable classification of adenomyosis, it is equally apparent that such a system does not yet exist. We suggest that the research needed to obtain such information requires an accurate diagnosis and methods by which some composite of disease phenotype and molecular expressions are identi- fied and documented. Categorizing the phenotype in a stand- ardized fashion would allow for meaningful comparison of symptoms and clinical outcomes of medical and procedural interventions in patients with similar disease characteristics. It might lead to a better understanding of adenomyosis in a fash- ion sufficient to inform more tailored therapeutic approaches. Imaging modalities are now widely accepted to be reli- able tools and the first choice in diagnosing adenomyosis. Histopathology, while once the “gold standard” for diagnos- ing adenomyosis, requires extensive sections throughout the whole uterus to be reliable, which is not given in standard clinical practice [13, 54]. Furthermore, using a hysterectomy specimen introduces a selection bias that does not allow to draw conclusions on, for example, symptoms [55 •]. Therefore, a classification and reporting system needs to be based on imaging. Previous reviews suggest that both MRI and ultrasound, as currently used, may have similar sensitivity and specificity for diagnosing adenomyosis [23]. As MRI potentially provides greater accuracy in determining disease volume, distribution, location, and pattern, it seems to be best suited to develop a classification system. However, as TVUS is widely available and either the only or the first- line tool in diagnosing adenomyosis, a universally useful classification needs to be applicable for ultrasound. Assessment of molecular and genetic expressions, be they from serum, endometrial aspirates, or endometrial or myometrial biopsy specimens, may be necessary for deter - mining the impact of adenomyosis in a given patient: a cir - cumstance that may have particular importance in women with reproductive failure or who are planning to undergo embryo transfer. The place for such variables should be con- sidered in the design of any system.

In summary, there is a need for a harmonized reporting sys- tem for both ultrasound and MRI that would allow performing research, which could be used to develop a disease classifica- tion system. In both reporting and classification systems, imag- ing modalities should take into account the histopathological features of the disorder. Fortunately, initiatives involving the international radiological and gynecological communities are underway. They are designed to achieve this goal so that clini- cians, investigators, and especially patients will benefit from an increased understanding of this disorder. Author Contribution The authors contr ibuted equally to this manuscript. Funding Open access funding pro vided by University of Oslo (incl Oslo University Hospital). Availability of Data and Material (Data Transparency) All data is included in the manuscript. Code Availability No t applicable. Compliance with Ethical Standards Ethics Approval Ethical appr oval was not necessary due to the nature of this work. Consent to Participate No t applicable. Conflict of Interest Dr. T ellum reports grants from South Eastern Norwegian Health Authority, personal fees from GE Healthcare, and personal fees from Medtronic, outside the submitted work. Dr Munro reports personal fees from Hologic, AbbVie, and Myovant as well as options held with Gynesonics Inc. Human and Animal Rights and Informed Consent This article does no t contain any studies with human or animal subjects performed by any of the authors. Open Access This article is licensed under a Cr eative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// cr eat iv eco mmons. or g/ licen ses/ b y/4. 0/ .

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