Uterine Adenomyosis: Classification, Diagnosis, Symptoms, and Treatment

Adenomyosis is a benign condition of the uterus historically diagnosed based on histologic examination after hysterectomy (removal of the uterus). By visualizing ectopic endometrial glands and stroma at a minimum depth of 2.5 mm below the endomyometrial junction with hypertrophic and hyperplastic myometrium. Visualization of this condition is done by techniques such as ultrasound or MRI.

The prevalence of adenomyosis ranges from 5 to 70%. Up to 40 years of age, the disease affects 2 out of 10 women, while between 40 and 50 years of age, the incidence increases to 8 out of 10 women. However, the incidence of adenomyosis is difficult to establish due to the lack of a uniform definition and diagnostic criteria based on non-invasive diagnostic techniques. There are neither pathognomonic clinical features of adenomyosis nor laparoscopic criteria that can be applied to diagnose this disease.

Adenomyosis may be accompanied by other estrogen-dependent benign diseases such as endometriosis (70%), uterine myoma (50%), and endometrial hyperplasia (35%).

The pathogenesis is still unclear, but several theories have been put forward:

• Spontaneous or induced microtrauma of the endomyometrial zone.
• Increased pathologic invasion of the endometrium into the myometrium.
• Stem cell metaplasia in myometrium.
• Infiltration of endometrial cells by retrograde menstrual flow into the uterine wall on the serosal side.
• Induction of adenomyotic lesions by aberrant local steroid and pituitary hormones.
• Abnormal uterine development in response to genetic and epigenetic modifications.
• Expression of messenger RNA (mRNA) and long non-coding RNA (lncRNA) in foci of adenomyosis is a new area of research.

Classification of uterine adenomyosis

Attempts have been made to classify adenomyosis into subtypes according to the results of histological examination and imaging techniques, but none of the proposed systems has been accepted in practice. The simplest classification distinguishes diffuse and focal adenomyosis according to its distribution in the myometrium.

Diffuse adenomyosis is defined by the presence of multiple foci in the myometrium ( <25% of the lesion surface is surrounded by normal myometrium), while focal adenomyosis appears as isolated nodules of hypertrophic myometrium and ectopic endometrium.

However, the pathogenesis of adenomyosis remains unclear, and the relationship between the extent of disease and clinical manifestation is still unclear, making it difficult to define a standardized treatment.

Russian literature distinguishes a classification, taking into account the depth of the lesion:

• 1 – the lesion site is located in the structure of the submucosal layer;
• 2 – the pathologic process affects less than half of the thickness of the myometrium;
• 3 – the entire muscle layer of the uterus is involved;
• 4 – the lesion extends beyond the uterus.

3D Models of Uterine Adenomyosis:

Grade 1 adenomyosis

Grade 2 adenomyosis

Grade 3 adenomyosis

Fourth-degree adenomyosis

According to the classification of Bird et al, adenomyotic lesions are classified according to the depth of invasion reflected in the affected uterine layer and the degree of involvement measured by the number of endometrial glands observed in the low power microscope field.

Grade one is subbasal/subendometrial adenomyosis (adenomyosis in one field of view below the “basal” endometrium, but without further invasion).

Grade two represents infiltration of adenomyosis into the middle of the myometrium, and grade three represents infiltration of adenomyosis beyond the middle of the myometrium.

The authors also demonstrated a direct correlation between the severity of dysmenorrhea and the depth of penetration. Thus, 4.3% of women with grade I adenomyosis reported dysmenorrhea, compared with 42.4% of women with grade II and 83.3% of women with grade III.

Another histopathologic feature that has been described in people with profound adenomyosis is hemosiderin deposition that surrounds the adenomyotic lesions. This is caused by bleeding from ectopic endometrial foci and suggests that hemosiderin deposition may reflect the extent and severity of adenomyosis, but the significance of this finding remains unclear.

Levgur et al. described the depth of adenomyosis as a percentage of lesion to myometrial thickness, so that:

• superficial – less than 40% of myometrial thickness;
  
• intermediate – 40-80% of thickness;
  
• deep – exceeding 80% of the thickness.

They also noted the presence of dysmenorrhea in 77.8% of patients with deep lesions compared to 12.5% with intermediate lesions. Superficial myometrial foci were not associated with dysmenorrhea or menorrhagia.

Hulka et al. introduced a new category of focal adenomyosis, they defined the term “adenomyoma”, in addition to previous classifications. Rassmussen et al. proposed a histologic classification based on endomyometrial biopsies by transcervical endometrial resection (TCRE). The study is performed by taking a biopsy of ≥5 mm depth of myometrium.

Internal adenomyosis involves myometrial invasion without contact with the basal endometrium ≥2 mm.

The serrated connecting zone is a myometrial invasion >3 mm with adherence to the basal endometrium.

Linear connective zone corresponds to absence or myometrial lesions ≤3 mm in contact with the basal endometrium.

Classification of uterine adenomyosis

Diagnosis of uterine adenomyosis

The criteria proposed by MUSA based on transvaginal ultrasound findings are used for clinical diagnosis. Although MUSA has provided uniform guidelines for recognizing and identifying signs of adenomyotic lesions, this has not created a classification of adenomyosis. Given that ultrasound is a subjective method of evaluation, this makes it difficult to standardize and create a classification.

According to the MUSA classification, all signs of adenomyosis can be divided into direct and indirect signs. Direct signs indicate the presence of ectopic endometrial tissue in the myometrium. Indirect signs are those that are secondary to the presence of endometrial tissue in the myometrium, such as muscular hypertrophy (globular uterus) or artifacts (e.g., shadowing).

Direct signs of adenomyosis

1. Myometrial cysts

According to the MUSA classificatio, myometrial cysts are defined as rounded masses in the myometrium. The contents of the cysts may be anechogenic, low-level echogenicity, frosted glass, or mixed echogenicity. The cysts may be surrounded by a hyperechogenic rim. Myometrial cyst size has no minimum or maximum size, and a hyperechogenic rim is not a necessary feature. Experts recommend the use of color Doppler ult rasonography to identify blood vessels, which helps in the differential diagnosis with myometrial cysts.

2. Hyperechogenic islets

Hyperechogenic islets have been defined as hyperechogenic areas in the myometrium, and they may be regular, irregular, or poorly defined. However, hyperechogenic islets should not have any association with the endometrium. The minimum distance from the endometrium has not been precisely defined because it may be individually arbitrary. The minimum diameter and number of hyperechogenic islets has also not been determined.

3. Echogenic subendometrial lines and buds

Experts note that evaluation of these features is difficult due to the lack of 3D ultrasound images, difficulty in recognizing the endometrium-myometrium boundary, and an invisible connective zone. The definition of this feature in the MUSA consensus statement was as follows: “Hyperechogenic subendometrial lines or boutons disrupting the connective zone may be observed. Hyperechogenic subendometrial lines are (almost) perpendicular to the endometrial cavity and are in conjunction with the endometrium. However, experts note that any form of invasion of endometrial tissue into the myometrium can be a sign of adenomyosis, even if it doesn’t have the appearance of lines or bouts.”

Indirect signs of adenomyosis

1. Globular uterus

A globular uterus is diagnosed when the serous layer diverges from the cervix in at least two directions (anterior, posterior, or lateral) instead of following a path parallel to the endometrium. In this case, the measured diameters (length, width, depth) of the uterus are approximately equal, resulting in a typical spherical shape. There was consensus that this sign may be a false positive in the presence of myoma or intracavitary anomaly.

2. Asymmetric thickening of the myometrium

The ratio between anterior and posterior wall thickness is calculated. A ratio of about 1 indicates that the myometrial walls are symmetrical, while a ratio above or below 1 indicates asymmetry, although this assessment is subjective. Also an indirect sign is a difference in endometrial wall thickness of more than 5 mm. It is worth remembering that uterine asymmetry may be associated with temporary uterine contractions or the presence of uterine myoma.

3. Fan shading

This shading is defined by the presence of hyperechogenic linear bands, sometimes alternating with linear hypoechogenic bands. Fan-shaped shadowing is best evaluated in grayscale mode. Diagnostic problems may arise from other lesions that cause shadowing, such as myoma or cesarean scar fibrosis.

4. Through vascularization

Circumferential vascularization is characterized by the presence of blood vessels perpendicular to the uterine/serosal cavity crossing the lesion. Such vascularization is likely to be present in diffuse adenomyosis, but circumferential vascularization, which is usually seen around the myoma, may also be present in the presence of adenomyosis. Vessels within the mass may be present in myoma; end-to-end vascularity, that is, vessels crossing the lesion, is not characteristic of myoma. This feature is suitable for distinguishing adenomyosis from myoma.

5. Irregular connecting zone

There are several problems with defining this criterion. First, it is difficult to evaluate the connecting zone without 3D imaging. According to the MUSA statement, the connecting zone may be irregular due to cystic areas, hyperechogenic dots, and hyperechogenic lines. The magnitude of connective zone irregularity is expressed as the difference between the maximum and minimum thickness of the connective zone. Second, the degree of irregularity is defined as a subjective assessment of the percentage of the connecting zone that is irregular (< 50% or ≥50%). The connective zone should be evaluated by 3D ultrasound in the sagittal, transverse, and coronal planes, and determination of connective zone thickness is not a mandatory diagnostic criterion.

6. Interrupted connecting zone

An interrupted connecting zone is defined when a portion of the connecting zone cannot be visualized in either 2D or 3D ultrasound in any plane. An uninterrupted connecting zone means that the connecting zone is clearly visible in all planes on 2D ultrasound or in all planes on 3D ultrasound.

Magnetic resonance imaging of the pelvic organs

A pooled analysis of studies showed that the sensitivity of MRI in the diagnosis of adenomyosis is about 78% and the specificity is 93%. Although transvaginal ultrasound has also been reported to have similar sensitivity and specificity, the ultrasound findings are too heterogeneous to be combined. Thus, MRI-based systems provide greater objectivity and consistency in the classification of adenomyosis. MRI can distinguish the zonal anatomy of the uterus and visualize the transitional zone (Junctional Zone – JZ), allowing the diagnosis of lesions in any part of the endometrium and myometrium. The most comprehensive of the recent classifications is the system proposed by Kobayashi et al. which includes five components and grades them as follows:

The final score is then reported as four letters with corresponding numbers according to the MRI results.

Hysteroscopy

In patients with abnormal uterine bleeding, hysteroscopy can be a valuable diagnostic method that, on the one hand, provides direct visualization of the uterine cavity and, on the other hand, allows taking material for histological examination. Although visual inspection does not allow a diagnosis, a number of features have been established that may indicate the presence of adenomyosis: marked hypervascularization on the endometrial surface, irregular endometrium with small holes, the so-called “strawberry endometrial pattern” and fibrotic and/or hemorrhagic cystic lesions. More detailed information can be obtained during histologic examination after taking a biopsy with a diathermy loop resectoscope.

Clinical picture

In one third of cases, adenomyosis is asymptomatic. The most common clinical symptoms are menorrhagia (up to 50% of patients), dysmenorrhea, metrorrhagia, abnormal uterine bleeding, chronic pelvic pain, dyspareunia and infertility. The exact mechanism of the relationship between adenomyosis and infertility is still unclear. So far, a number of factors have been proposed that focus on four putative pathways:

1. Intracavitary abnormalities and increased uterine peristalsis cause abnormal sperm migration. Intracavitary anatomic distortions caused by uterine hyperperistalsis and inflammation can alter the axis of the uterine cavity and potentially impair sperm migration and embryo transport. Abnormal myometrial contraction waves lead to abnormal sperm transport through the uterine cavity and may also result in increased intrauterine pressure.
   
2. Abnormal endometrial steroid metabolism, enhanced inflammatory response and increased intrauterine oxidative environment, leads to altered endometrial function and susceptibility.
   
3. Implantation impairment can result from inflammation, lack of adequate expression of adhesion molecules (integrins), and decreased expression of implantation markers.
   
4. The occurrence of chronic endometritis due to intrauterine microbial infection may be associated with negative fertility outcome in women with adenomyosis.

It is important to note that endometriosis occurs in 54-90% of cases in patients with adenomyosis. Therefore, it cannot be stated that the cause of infertility is related to adenomyosis rather than concurrent endometriosis, as endometriosis is a well-known disease causing infertility.

Treatment of uterine adenomyosis

Drug therapy

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat pain associated with endometriosis, but there are only a few randomized trials showing the use of NSAIDs in endometriosis, and none in adenomyosis. NSAIDs can have negative effects on fertility. The drugs can suppress ovulation, but there is some evidence that NSAIDs can be used as co-treatment in IVF treatment.

Combined oral contraceptives are used in the treatment of adenomyosis to reduce menstrual bleeding by decidualization and subsequent atrophy of the endometrium. In patients with dysmenorrhea and menorrhagia, the use of oral contraceptives reduces the risk of symptoms. Oral contraceptive therapy provides satisfactory long-term pain control in two-thirds of women with symptomatic endometriosis or adenomyosis. However, there is no published information on the effect of oral contraceptive therapy on subsequent fertility improvement.

Gonadotropin-releasing hormone analogs have been used to induce a permanent hypoestrogenic state in women with histologically confirmed adenomyosis. However, there is not much data on their effect on future fertility. Published studies have shown no improvement in fertility after treatment with gonadotropin-releasing hormone analogs combined with conservative microsurgery.

Progestins have antiproliferative and anti-inflammatory effects on adenomyosis. They have been found to be partially effective in controlling pain symptoms associated with adenomyosis. Progestins reduce uterine volume and decrease the risk of abnormal uterine bleeding, but their effects on fertility have not been adequately investigated.

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Surgical treatment

Endomyometrial resection is effective and indicated in patients with lesions limited to the endomyometrial junction and is a treatment option for recurrent abnormal uterine bleeding. However, in patients who wish to become pregnant, endomyometrial resection is contraindicated. Destruction of the endometrium together with the transition zone can cause serious complications such as termination of pregnancy, preterm labor, and placentation abnormalities in women planning pregnancy.

Embolization has also been described as an effective treatment for symptoms resulting from adenomyosis. A dangerous complication of embolization is the development of premature ovarian failure. This can affect both hormone production and oocyte reserve, leading to premature and iatrogenic amenorrhea and infertility. Endometrial receptivity is reduced after this surgery, so embolization is also contraindicated in women planning pregnancy, but is effective in premenopausal women.

High-intensity focused ultrasound (HIFU) utilizes the thermal effect of the ultrasound beam to induce coagulation necrosis in the targeted adenomyotic lesion. The lesion must be clearly visible on ultrasound or MRI to accurately guide the ultrasound. This means that this method will not be effective for diffuse form of adenomyosis. The rehabilitation period after this procedure is shorter for pregnancy planning than after surgical treatment, but the exact time has not been established.

The classic surgical method of removing a significant amount of myometrium with adenomyotic lesions may result in decreased uterine myometrial capacity and scarring.

Electrocoagulation is also applied to focal or diffuse masses. However, the main disadvantage of electrocoagulation is the lack of precision compared to surgical excision, as well as the lack of complete control over the course of the operation.

Hysterectomy is the definitive treatment for patients with no reproductive plans.