Clinicopathological features of different subtypes in adenomyosis: Focus on early lesions

Adenomyosis is a common uterine disorder characterized by the presence of endometrial glands and stromas within the myometrium [ 1 ]. Symptoms are non-specific and are related to an enlarged uterus, menorrhagia, abnormal uterine bleeding, pelvic pain, or infertility; a third of patients can be asymptomatic [ 2 – 5 ]. Effective management of adenomyosis requires a lifelong plan as the disease has a negative impact on quality of life in terms of menstrual symptoms, fertility, and has a high risk of miscarriage, obstetric complications and poor pregnancy outcomes [ 1 ]. Furthermore, adenomyosis often coexists with other gynecological conditions, such as endometriosis and uterine fibroids, that share several symptoms [ 1 ] and its treatment is still challenging [ 3 ]. Traditionally, adenomyosis has been a histological diagnosis at hysterectomy [ 3 ]. Adenomyosis has always been considered the classic condition discovered in multiparous women over 40 years old who have menorrhagia and dysmenorrhea [ 1 , 6 ]. Nowadays, advances in modern imaging technology, including transvaginal ultrasound and magnetic resonance imaging (MRI), have made it possible to diagnose different phenotypes (diffuse or localized) of adenomyosis [ 7 ]. The detection of the "question mark" sign by transvaginal ultrasound is effective for the diagnosis of adenomyosis [ 8 ]. In young girls in their 10s to 20s with a history of chronic pelvic pain, the prevalence of adenomyosis reached 46.0% [ 9 ]. Diffuse adenomyosis may also develop in younger nulligravid women (early 20 years) than previously thought [ 7 ]. Thus, adenomyosis is not a disease of the elderly. To date there is no unified classification system, but several image-based classifications of adenomyosis have been proposed [ 10 – 14 ]. The history of the classification of adenomyosis is summarized in ref. [ 11 ]. Just 100 years ago, Sampson divided adenomyosis into several groups according to the origin or pathogenesis [ 3 , 15 ]. This theory, in turn, led to Kishi’s classification criteria in 2012 [ 10 ]. The authors divided adenomyosis into at least three groups: adenomyosis resulting from invagination of the endometrial basalis into the myometrium; adenomyosis caused by endometriosis infiltration from outside the uterus; and adenomyosis possibly arising from Müllerian remnants [ 10 ]. There are many other types of adenomyosis, including intrinsic adenomyosis, extrinsic adenomyosis, adenomyosis externa and focal adenomyosis located in the outer myometrium (FAOM) [ 7 , 11 , 16 ]. The two types of adenomyosis, intrinsic and extrinsic, can be more clearly distinguished histopathologically. Intrinsic and extrinsic adenomyosis occur in the inner and outer layers of the uterus, respectively. It has been suggested that these two types of adenomyosis have different clinicopathological characteristics and pathogenesis [ 10 ]. However, it is unclear whether there are already differences in clinicopathological features in early-stage adenomyosis. Long-term prospective cohort studies of asymptomatic young women are needed to detect early lesions of adenomyosis, but such clinical trials are actually difficult. Therefore, we classified histologically diagnosed adenomyosis into intrinsic, extrinsic and other types, and further focused on the early lesions of intrinsic and extrinsic adenomyosis. The purpose of this study is to identify the clinicopathological features associated with intrinsic and extrinsic adenomyosis, especially in early-stage patients.

During the period of this study, 230 patients were diagnosed with adenomyosis by MRI. Of the 230, 197 underwent surgery. Of these, 189 patients were histologically confirmed to have adenomyosis. This study revealed that the diagnostic sensitivity of adenomyosis by MRI was as high as 95.9%. The remaining 33 women were under active surveillance for adenomyosis management and were not included in this study. This study examined the clinicopathological features of 189 patients with histologically confirmed adenomyosis. This cohort of patients included 74 women with intrinsic adenomyosis (20 for A1 and 54 for A2), 78 extrinsic adenomyosis (43 for B1 and 35 for B2), and 37 other types of adenomyosis. First, clinicopathological variables were compared in the three groups. Clinicopathological characteristics of the three groups are presented in Table 1 . Of the 60 patients with adenomyosis coexisting with DIE and/or SUP, 7 had DIE only, 3 had SUP only, and 50 had both DIE and SUP. Therefore, the clinicopathological variables were grouped as "coexistence of DIE and/or SUP". Deep endometriosis infiltrated rectum and uterosacral ligaments (n = 30, 52.6%), rectum and sigmoid colon (n = 19, 33.3%), only the sigmoid colon (n = 3, 5.3%), and rarely ureters (n = 6, 10.5%), bladder (n = 5, 8.7%), small bowel (n = 2, 3.5%), cecum (n = 1, 1.7%), and others (n = 5, 8.8%). The following five variables, including coexistence of OMA (P < 0.001), coexistence of DIE and/or SUP (<0.001), the thickest wall [either] (<0.001), the thickest wall [sum] (0.039) and the thickest lesion (<0.001), were significantly different among the 3 groups (by Kruskal-Wallis test). The prevalence of OMA was significantly higher in the extrinsic group (50/78, 64.1%) compared to the intrinsic (4/74, 5.4%) and other (9/37, 24.3%) groups (P < 0.001 by Kruskal-Wallis test and post hoc analysis with Bonferroni correction). The prevalence of DIE and/or SUP was also highest in the extrinsic group (50/78, 64.1%) among the three groups. Not surprisingly, among the three groups, uterine myometrium and adenomyosis lesions were the thickest in the other group (by Kruskal-Wallis test), but there was no significant difference between the intrinsic and extrinsic groups (by Kruskal-Wallis test and post hoc analysis with Bonferroni correction). For the other variables, there were no statistical differences between the three groups (P> 0.05 by Kruskal-Wallis test). Except for the Range, the numbers in parentheses indicate percentages. a vs. b, P <0.001; b vs. c, P <0.001; a vs. c, P = 0.003. d vs. e, P <0.001; e vs. f, P <0.001; d vs. f, P = 0.153. g vs. h, P = 0.475; h vs i, P = 0.008; g vs. i, P = 0.025. j vs. k, P = 0.076; k vs. l, P = 0.031; j vs. l, P = 0.626. m vs. n, P = 0.209; n vs. o, P <0.000; m vs. o, P <0.001. In addition, clinicopathological variables were analyzed in patients with early-stage adenomyosis, groups A1 and B1. The number of induced abortion (P = 0.017), the prevalence of OMA (P <0.001) and DIE and/or SUP (P <0.001) were significantly different between the two groups ( Table 2 ). The A1 group has experienced significantly more induced abortions than the B1 group (45.0% vs. 14.0%, P = 0.017). Compared to the A1 group, the B1 group coexisted significantly more with OMA (51.2% vs. 5.0%, P <0.001) and DIE and/or SUP (51.2% vs. 0%, P 0.05). Except for the Range, the numbers in parentheses indicate percentages. Univariate analysis identified three variables as predictors of the early stage extrinsic adenomyosis: coexistence of DIE and/or SUP, coexistence of OMA, and no previous history of induced abortion (P <0.001, <0.001, and 0.017) ( Table 3 ). On multivariable analysis, coexistence of DIE and/or SUP and coexistence of OMA were independent predictors.

There are at least two types of adenomyosis, where the intrinsic type is closely associated with a history of induced abortion, while the extrinsic type is strongly associated with endometriosis.

A single-center prospective cohort (DoG-NaMe) study was conducted by collecting data from patients admitted to the D epartment o f G ynecology, Na ra Me dical University Hospital, Kashihara, Japan. The DoG-NaMe study consists of an endometriosis cohort, an adenomyosis cohort, and an ovarian cancer cohort. We performed an observational cross-sectional study using data from the adenomyosis cohort study from April 2008 to March 2018. We used data from patients who met all three selection criteria: 1) patients undergoing surgery with removal of lesions for histological evaluation; 2) patients with pathological confirmation of adenomyosis; and 3) patients who underwent magnetic resonance imaging (MRI) examinations prior to surgery. The criteria for exclusion were: 1) age below 20 years; 2) active surveillance only; 3) women coexisting with malignancies; and 4) incomplete data. Patients with preoperative use of hormone therapy were not excluded from the study. Many patients with suspected adenomyosis on transvaginal ultrasonography were referred to this university hospital for surgery from a nearby clinic. These patients were recruited for this study. MRI is mandated by this protocol as a requirement for surgery or surveillance. MRI protocol included T1w and T2w sequences using a 3T system (Magnetom Verio, Siemens Healthcare, Erlangen, Germany). MRI and blood tests were performed within a month of surgery. Information on demographic data, medical history, and clinicopathological characteristics was collected from a database containing comprehensive medical records and pathology reports. Patients’ medical records were anonymous. Clinicopathological variables include age at surgery, gravidity, parity, number of caesarean sections, number of induced abortion, BMI, severity of symptoms such as pelvic pain, menorrhagia, and infertility, coexistence of ovarian endometrioma (OMA), deep infiltrating endometriosis (DIE) and/or superficial peritoneal endometriosis (SUP), coexistence of submucosal, intramural, or sub-serosal fibroids, maximum length from cervix to uterine fundus, the length of the thickest wall [either], the length of the thickest wall [sum], the length of the thickest lesion, anteflexed or midline/retroflexed, hemoglobin levels, CA125 levels, and preoperative hormone therapy with combined oral contraceptives (low-dose estrogen-progestin combinations), dienogest, or gonadotropin-releasing hormone (GnRH) agonists. We investigated the prevalence of OMA, SUP, DIE, and uterine fibroids. Ethical approval was obtained from the Nara Medical University Ethics Committee (2012–541) and informed written consent was obtained from all participants. We used a simplified classification system based on the affected area and the locoregional extension of adenomyosis lesions [ 11 ]. Patients with adenomyosis were categorized into intrinsic, extrinsic, and other types. The intrinsic type (denoted as group A) is defined as adenomyosis that occurs in the uterine inner layer without affecting the outer structures of the myometrium. The extrinsic type (denoted as group B) is defined as adenomyosis that occurs in the uterine outer layer without affecting the inner structures. The extent of adenomyosis lesion is further categorized into three volumes (<1/3, 2/3 of uterine wall). A1, A2 and A3 are defined as "the lesion is confined to the inner 1/3 of the uterine myometrium", "the lesion is confined to the inner 2/3 of the uterine myometrium", and "the lesion extends beyond the inner 2/3 of the myometrium and part of the lesion reaches the uterine serosa." B1, B2, and B3 are defined as "the lesion is confined to the outer 1/3 of the uterine myometrium", "the lesion is confined to the inner 2/3 of the uterine myometrium", and "the lesion extends beyond the outer 2/3 of the myometrium and part of the lesion reaches the uterine endometrium." If the lesion extends to the entire myometrium, A3 and B3 are indistinguishable by MRI and pathology. If either of the two gynecologists diagnosed the patient as neither type A nor type B, she was classified as "unclassifiable". Patients were classified as "other type" when the two gynecologists agreed that they did not belong to either type A or type B. In this paper, we adopted the classification of "other type". When adenomyosis coexists with uterine fibroids, it is necessary to define the type and extension of adenomyosis. For example, in patients with intrinsic adenomyosis, if the adenomyosis lesion is 30 mm in thickness and a fibroid 70 mm in diameter is localized outside the lesion, this case was classified as "A1". The thickest wall [either] was measured at the thickest length of either the anterior or posterior wall of the uterus. The thickest wall [sum] was measured at the thickest length of the sum of the anterior and posterior walls of the uterus. The thickest lesion was measured at the thickest adenomyosis lesion infiltrating the uterine myometrium. Pelvic pain is defined as pain that required the use of painkillers and affected daily life (the loss or reduction of daily activities). Visual Analog Scale (VAS) scores can be evaluated in four levels: painless (score, 0), mild (score, 1–3), moderate (score, 4–7), and severe (score, 8–10). Patients with a score of 8–10 points were determined to have pelvic pain. Heavy menstrual bleeding was defined when one or more of the following are true: use one or more sanitary napkins or tampons within one hour over several hours; use of dual sanitary protective equipment to control menstruation; awake at midnight to change sanitary protection; bleeding lasting more than 1 week; excretion of blood coagulation over one quarter of the napkin area; and limitation of daily activities due to anemia symptoms such as severe menstruation, fatigue, shortness of breath. This is an excerpt from the Mayo Clinic homepage [ 17 ]. There were 2 types of patients in the infertility group: Patients who failed to achieve a clinical pregnancy following ≥12 months of regular unprotected sexual intercourse [ 18 ] and those who have already been treated at fertility hospitals. Blood samples were obtained from all study participants to determine serum CA125 levels at least 4 weeks prior to surgery. The blood samples were centrifuged at 1500×g for 10 minutes at 4°C, and the serum was stored at −20°C until used for measurements. Serum CA125 concentrations were determined using an electrochemiluminescence Elecsys immunoassay (ECLIA) (Roche Diagnostics, Salzburg, Austria). Statistical analyses were performed using SPSS Statistics version 25 (IBM Japan). The data were presented as mean and standard deviation (SD) or median and range. Data distribution was verified by the Shapiro-Wilk test. t-test was conducted for mean comparison for the groups. Pearson’s chi-squared test (χ2) was applied to categorize variables. Data were analyzed using the Kruskal-Wallis test followed by post hoc analysis with Bonferroni correction to evaluate differences among the 3 groups. The nonparametric Mann-Whitney U-test was used for statistical analysis of the findings, due to the abnormal distribution of the data obtained for A1 and B1 groups. Multivariate logistic regression analysis was performed on the significant factors (P<0.05) from univariate analysis using a Cox proportional hazards model to identify independent predictors of extrinsic adenomyosis. P-values of <0.05 were considered to indicate statistically significant differences.

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