Adenomyosis: Why we need to reassess our understanding of this condition

in myometrial hypertrophy and fibro - sis, impairing normal uterine contractility patterns. This abnormal contractility may alter sperm transport and embryo implanta - tion, and animal models that target pathways leading to fibrosis may improve endometrial receptivity.14,15 Further research is needed to elucidate specific molecular pathways and their complex interplay in this disease. Diagnosis The gold standard for diagnosis of adeno - myosis is histopathology from hysterectomy specimens, but specific definitions vary. Pub- lished criteria include endometrial glands within the myometrial layer greater than 0.5 to 1 low power field from the basal layer of the endometrium, endometrial glands extending deeper than 25% of the myome - trial thickness, or endometrial glands a cer - tain distance (ranging from 1-3 mm) from the basalis layer of the endometrium. 16 Vari- ous methods of non -hysterectomy tissue sampling have been proposed for diagnosis, including needle, hysteroscopic, or laparo - scopic sampling, but the sensitivity of these

is poor. 17 Limiting the diagnosis of adenomyosis to specimen pathology relies on invasive methods and clearly we cannot con- firm the diagnosis by hysterectomy in patients with a desire for future fertility. It is for this reason that the prevalence of the disease is widely unknown. The alternative to pathologic diagnosis is to identify radiologic changes that are associ- ated with adenomyosis via either transvaginal ultrasound (TVUS) or MRI. Features sug - gestive of adenomyosis on MRI overlap with TVUS features, including uterine enlarge - ment, anteroposterior myometrial asymme - try, T1- or T2-intense myometrial cysts or foci, and a thickened JZ. 18 A JZ thicker than 12 mm has been thought to be predictive of adenomyosis, whereas a thickness of less than 8 mm is predictive of its absence, although the JZ may vary in thickness with the men - strual cycle.19,20 A 2021 systematic review and meta-analysis comparing MRI diagnosis with histopathologic findings reported a pooled sensitivity and specificity of 60% and 96%, respectively.21 The reported range for sensi - tivity and specificity is wide: 70% to 93% for sensitivity and 67% to 93% for specificity.22-24 Key TVUS features associated with ade- nomyosis were defined in 2015 in a consensus statement released by the Morphological Uterus FIGURE 2 3D depiction of adenomyosis11 3-dimensional depiction of adenomyosis using novel tissue-clearing methods with light-sheet microscopy. Red object shows direct invasion of endometrial glands into the myometrium. Yellow objects show ectopic endometrial glands in the myometrium. Reproduced with permission from Yamaguchi M, et al. Three-dimensional understanding of the morphological complexity of the human uterine endometrium. iScience. 2021;24:102258. doi: 10.1016/j. isci.2021.10225811 38 OBG Management | August 2023 | Vol. 35 No. 8 mdedge.com/obgyn Adenomyosis: Why we need to reassess our understanding Sonographic Assessment (MUSA) group. 25 These include a globally enlarged uterus, anteroposterior myometrial asymmetry, myo- metrial cysts, fan-shaped shadowing, mixed myometrial echogenicity, translesional vas - cularity, echogenic subendometrial lines and buds, and a thickened, irregular or discontinu- ous JZ (FIGURES 3 AND 4 ).25 The accuracy of ultrasonographic diagnosis of adenomyosis using these features has been investigated in multiple systematic reviews and meta-analy- ses, most recently by Liu and colleagues who found a pooled sensitivity of TVUS of 81% and pooled specificity of 87%.23 The range for ultra- sonographic sensitivity and specificity is wide, however, ranging from 33% to 84% for sensitiv- ity and 64% to 100% for specificity. 22 Consen- sus is lacking as to which TVUS features are most predictive of adenomyosis, but in general, the combination of multiple MUSA criteria (particularly myometrial cysts and irregular JZ on 3D imaging) appears to be more accurate than any one feature alone.23 The presence of fibroids may decrease the sensitivity of TVUS, and one study suggested elastography may increase the accuracy of TVUS. 24,26 Moreover, given that most radiologists receive limited train- ing on the MUSA criteria, it behooves gynecolo- gists to become familiar with these sonographic features to be able to identify adenomyosis in our patients. Adenomyosis also may be suspected based on hysteroscopic findings, although a normal hysteroscopy cannot rule out the disease and data are lacking to sup - port these markers as diagnostic. Visual findings can include a “strawberry” pat - tern, mucosal elevation, cystic hemorrhagic lesions, localized vascularity, or endometrial defects.27 Hysteroscopy may be effective in FIGURE 3 Adenomyosis on ultrasound Ultrasound findings associated with adenomyosis, as defined by the Morphological Uterus Sonographic Assessment consensus. Findings include (A) asymmetrical myometrial thickening; (B) myometrial cysts; (C) hyperechoic myometrial islands; (D) fan-shaped shadowing; (E) echogenic subendometrial lines and buds; (F) translesional vascularity; (G) irregular junctional zone; (H) interrupted junctional zone; (I) enlarged uterus (not shown); and (J) heterogenous myometrial echotexture (not shown). Adapted with permission from Van den Bosch T, et al. Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol. 2015;46:284-298. doi: 10.1002/uog.1480625 A E C G B F D H mdedge.com/obgyn Vol. 35 No. 8 | August 2023 | OBG Management 39 the treatment of localized lesions, although that discussion is beyond the scope of this review. Clinical presentation While many women who are later diagnosed with adenomyosis are asymptomatic, the disease can present with heavy menstrual bleeding and dysmenorrhea, which occur in 50% and 30% of patients, respectively.28 Other symptoms include dyspareunia and infer - tility. Symptoms were previously reported to develop between the ages of 40 and 50 years; however, this is biased by diagnosis at the time of hysterectomy and the fact that younger patients are less likely to undergo definitive surgery. When using imaging crite- ria for diagnosis, adenomyosis might be more responsible for dysmenorrhea and chronic pelvic pain in younger patients than previ - ously appreciated.1,29 In a recent study review- ing TVUS in 270 adolescents for any reason, adenomyosis was present in 5% of cases and this increased up to 44% in the presence of endometriosis.30 Adenomyosis often co-exists and shares similar clinical presentations with other gynecologic pathologies such as endome - triosis and fibroids, making diagnosis on symptomatology alone challenging. Con - current adenomyosis has been found in up to 73% and 57% of patients with suspected or diagnosed endometriosis and fibroids, respectively.31,32 Accumulating evidence sug - gests that pelvic pain previously attributed to endometriosis may in fact be a result of adenomyosis; for example, persistent pelvic pain after optimal resection of endometrio - sis may be confounded by the presence of adenomyosis.29 In one study of 155 patients with complete resection of deep infiltrating endometriosis, persistent pelvic pain was significantly associated with the presence of adenomyosis on imaging.33 Adenomyosis is increasingly being rec - ognized at the time of infertility evalu - ation with an estimated prevalence of FIGURE 4 Ultrasound indications of adenomyosis25 Ultrasound images showing (A) myometrial cysts (arrows); (B) hyperechogenic islands (surrounded by dotted lines); and (C) echogenic spots (arrows). Adapted with permission from Van den Bosch T, et al. Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol. 2015;46:284-298. doi: 10.1002/uog.1480625 A C B 40 OBG Management | August 2023 | Vol. 35 No. 8 mdedge.com/obgyn Adenomyosis: Why we need to reassess our understanding 30% in women with infertility. 3 Among women with infertility, adenomyosis has been associated with a lower clinical pregnancy rate, higher miscarriage rate, and lower live birth rate, as well as obstetric complications such as abnormal placentation.34-36 A study of 37 baboons found the histologic diagnosis of adenomyosis alone at necropsy was asso - ciated with a 20-fold increased risk of life - long infertility (odds ratio [OR], 20.1; 95% CI, 2.1-921), whereas presence of endometriosis was associated with a nonsignificant 3-fold risk of lifelong infertility (OR, 3.6; 95% CI, 0.9-15.8).37 In women with endometriosis and infertility, co-existing adenomyosis portends worse fertility outcomes. In a retrospective study of 244 women who underwent endo - metriosis surgery, more than five features of adenomyosis on imaging was associated with higher rates of infertility, in vitro fer - tilization treatments, and a higher number of in vitro fertilization cycles. 31 Moreover, in women who underwent surgery for deep infiltrating endometriosis, the presence of adenomyosis on imaging was associated with a 68% reduction in likelihood of preg - nancy after surgery. 38

As we begin to learn about adenomyosis, our misconceptions become more evident. The notion that it largely affects women at the end of their reproductive lives is biased by using histopathology at hysterectomy as the gold standard for diagnosis. Lack of defini - tive histologic or imaging criteria and biopsy techniques add to the diagnostic challenge. This in turn leads to inaccurate estimates of incidence and prevalence, as we assume patients’ symptoms must be attributable to what we can see at the time of surgery (for example, Stage I or II endometriosis), rather than what we cannot see. We now know that adenomyosis is present in women of all ages, including adolescents, and can significantly contribute to reduced fertility and quality of life. We owe it to our patients to consider this condition in the differential diagnosis of dys - menorrhea, heavy menstrual bleeding, dys - pareunia, and infertility. CASE Resolved The patient underwent targeted hysteroscopic resection of adenomyosis ( FIGURE 5 ) and con- ceived spontaneously the following year. ●

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