Clinical prognostic value of imaging and immuno-hormonal markers in uterine leiomyoma.

Uterine leiomyoma (UL), a prevalent benign neoplasm of the female reproductive system, affects a substantial proportion of women of reproductive age. Epidemiological and geographical data suggest an incidence ranging between 25% and 70%, depending on population and diagnostic criteria ( 1 ). The true prevalence remains difficult to determine due to the frequent asymptomatic nature of the disease. Despite their benign character, ULs are a major cause of reproductive dysfunction, including infertility, recurrent miscarriage, menorrhagia, and chronic pelvic pain ( 2 , 3 ). Histologically, UL represents a monoclonal proliferation of smooth muscle cells originating from the myometrium and surrounded by a pseudocapsule ( 4 , 5 ). The growth of these tumors is hormone-dependent, primarily regulated by estrogen and progesterone ( 6 ). Biochemical markers are well noted for obstetrics and gynecologic pathologies like gestational, miscarriage, and hypertension ( 7 - 9 ). Clinically, symptoms vary from asymptomatic presentation to severe uterine bleeding, anemia, dysuria, dyspareunia, and subfertility. Approximately 25% of affected women require active medical or surgical management due to symptomatic disease. In contemporary gynecology, preserving and restoring reproductive potential is a leading clinical priority. Uterine fibroids represent the second most common gynecological disorder after inflammatory diseases of the genital tract, accounting for up to 40% of gynecological cases with no recent decline in incidence. Alarmingly, the prevalence of leiomyomas has been increasing among younger women, reflecting both environmental and endocrine factors ( 10 ). Global estimates indicate that 25–35% of women of reproductive age and up to 80% of women over 30 years develop fibroids during their lifetime ( 11 ). Recent studies have underscored the significance of immune-endocrine interactions in the development and progression of ULs, ovarian chronic process ( 12 - 14 ). Hysterectomy for UL remains one of the most common gynecological procedures worldwide, second only to cesarean section in many countries, including Canada. The immune system plays a pivotal role in maintaining antitumor surveillance, and dysregulation of both innate and adaptive immunity contributes to fibroid growth interleukin-8 (IL-8), which are implicated in leukocyte recruitment and chronic inflammation within the myometrium ( 15 ). This imbalance is characterized by altered Th1/Th2 cytokine ratios, increased monocyte and neutrophil activity, and modified natural killer (NK) cell function. NK cells, key effectors of antitumor immunity, exhibit dual behavior in leiomyoma tissue ( 16 ). They secrete interferon-γ (IFN-γ), a cytotoxic cytokine promoting apoptosis, as well as anti-inflammatory mediators such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which can suppress immune activation. Studies demonstrate increased numbers of CD56⁺ NK cells and subpopulations expressing CD158a⁺ and CD158i⁺ receptors in leiomyoma tissue ( 17 ). Interestingly, smaller tumors tend to show elevated levels of CD56⁺IFN-γ⁺ lymphocytes, while larger masses exhibit enhanced expression of TGF-β1-secreting NK cells, suggesting an immunosuppressive shift during tumor progression ( 18 , 19 ). Additionally, monocyte chemoattractant protein-1 (MCP-1), Ki67, and cytokine levels ( 20 ). Elevated concentrations of α 2 -macroglobulin (α 2 -MG) and soluble p55-TNF receptor reflect systemic immune modulation associated with fibroid growth and vascular remodeling. These immune mediators may serve as potential prognostic markers, linking inflammation, angiogenesis, and hormone-dependent proliferation ( 21 ). The clinical management of UL continues to pose a major therapeutic challenge. Hysterectomy remains the standard intervention for extensive or symptomatic cases; however, it irreversibly compromises reproductive potential and may negatively affect psychological well-being ( 22 , 23 ). Consequently, there is a growing emphasis on organ-preserving and fertility-sparing treatments. Minimally invasive modalities such as uterine artery embolization (UAE) and focused ultrasound surgery (FUS) have emerged as effective alternatives, offering reduced morbidity and preservation of uterine integrity ( 24 ). In parallel, selective estrogen receptor modulators (SERMs) and progesterone receptor modulators (PRMs) have demonstrated efficacy in decreasing fibroid volume and symptom severity. Advanced imaging techniques, including magnetic resonance imaging (MRI)-based perfusion and diffusion mapping, allow non-invasive assessment of tumor vascularity and may complement immuno-hormonal profiling in predicting disease progression ( 25 ). Despite extensive research, the prognostic integration of imaging biomarkers with immunological and hormonal profiles remains limited in chronic autoimmune, oncologic, and precancerous process ( 26 ). Understanding the interplay between vascular endothelial growth factor (VEGF), fibroblast growth factor-1 (FGF-1), TGF-β, and various immune cell subsets could substantially enhance diagnostic precision and inform individualized therapy. Therefore, the present study aims to assess the clinical and prognostic value of imaging and immuno-hormonal markers in UL among women of reproductive age, emphasizing their role in early detection, disease stratification, and treatment optimization. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2233/rc ).

A total of 61 women aged 20–49 years with clinically and radiologically confirmed UL were included in the study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Institutional Review Board of Bukhara State Medical Institute (No. 571, dated April 22, 2024). Informed consent was obtained from all subjects involved in the study. The majority of patients were 40–49 years old (approximately 75%). Most participants resided in urban areas of the Bukhara region and identified as Uzbek (88.3%). Obstetric history revealed a higher prevalence of leiomyoma in multiparous women (≥4 pregnancies, 45.8%), with spontaneous miscarriage (14.2%), comorbid gynecological conditions included cervical erosion (28.8%), ectropion (47.5%), prior cervical electrocoagulation (23.7%), and chronic pelvic inflammatory disease (62.5%). Endometrial hyperplasia occurred in 17.5%, acyclic uterine bleeding requiring curettage in 39.2%, and benign ovarian cysts in 9.2%. Morphological studies were performed at the Bukhara Regional Pathology Center. Among the specimens examined, 49.2% had UL alone, 22.5% leiomyoma with adenomyosis, and 28.3% leiomyoma with proliferative processes. Intramural (46.7%) and subserous-intramural (38.4%) locations predominated. Multiple nodules were identified in 64.2% of patients, while 35.8% had a solitary large node. Histological classification distinguished simple and proliferating leiomyomas. Peripheral blood samples were analyzed at the Institute of Immunology and Human Genomics, Tashkent. Concentrations of cytokines and growth factors (IL-6, TNF-α, TGF-β2, IGF-I, FGF, VEGF) were determined using ELISA (Vector-Best, Novosibirsk). Pelvic MRI was performed using a 1.5-T Siemens Magnetom Avanto system (Siemens Healthcare, Erlangen, Germany) with a phased-array body coil. Scans were obtained during the follicular phase (days 5–10) to minimize hormonal variability. Sequences: axial and sagittal T1-weighted spin-echo [repetition time/echo time (TR/TE) =500/12 ms]. Axial, sagittal, and coronal T2-weighted fast spin-echo (TR/TE =4,000/90 ms). Fat-suppressed T2-weighted for tissue contrast. Diffusion-weighted imaging (DWI) (b =0, 400, 800 s/mm²) for cellular density and apparent diffusion coefficient (ADC) mapping. Dynamic contrast-enhanced (DCE)-MRI after IV gadobutrol 0.1 mmol/kg to assess vascularity. Image analysis: two experienced radiologists (>10 years) independently evaluated all scans, blinded to laboratory data. Parameters included number, size, and location of leiomyomas; T2-signal intensity (hypo-/iso-/hyperintense); ADC values; and contrast-enhancement pattern (homogeneous, heterogeneous, or peripheral). Data were processed using Microsoft Excel 2012. Descriptive statistics included mean (M), standard deviation (SD), and frequency (%). Group comparisons were performed using Student’s t-test, χ² test, and Z test. Correlation analysis applied Pearson’s (r) and Spearman’s (Rs) coefficients, with interpretation based on Chaddock’s scale. A P value <0.05 was considered statistically significant.

A total of 61 women diagnosed with UL, aged 20–49 years, were included in the clinical study and divided into a control group (n=30) and an experimental group (n=31). The majority of patients were in the 40–49-year age group, representing the largest proportion of the study population (41 patients, 67.2%) ( Figure 1A ). Analysis of the place of residence showed that cases of UL were more frequently observed among women living in urban areas of the Bukhara region compared with those residing in rural areas ( Figure 1A ). Patients with UL most commonly presented with the following complaints ( Figure 1B ). Menstrual cycle disorders were observed in 36 patients (59.0%), hyperpolymenorrhea in 31 patients (50.8%), pelvic pain and algomenorrhea in 22 patients (36.1%), and dyspareunia in 17 patients (27.9%). Infertility was diagnosed in 14 patients (23.0%) of the study population. Among infertile women, primary infertility was identified in 7 patients (50.0%), whereas secondary infertility was observed in 7 patients (50.0%) ( Figure 1B ). Analysis of myoma node localization showed that intramural and subserous-intramural nodes were the most common. According to the International Federation of Gynecology and Obstetrics (FIGO) classification, types IV, V, and VI were the predominant forms ( Figure 1C ). Comparative clinical and morphological characteristics of patients with uterine leiomyoma in control (n=30) and experimental (n=31) groups. (A) Age distribution and place of residence of patients. (B) Frequency of main clinical manifestations, including hyperpolymenorrhea, pelvic pain with algomenorrhea, menstrual cycle disorders, dyspareunia, and infertility (primary, secondary, total). (C) Distribution of leiomyoma types according to FIGO classification (types 0–VIII) in both study groups. (D) Parity structure of examined patients depending on the number of previous pregnancies. Error bars represent SEM; statistical differences were considered significant at P<0.05. SEM, standard error of the mean. The condition was most frequently observed in women with four or more pregnancies, followed by those with two to three deliveries ( Figure 1D ). Multiple leiomyoma nodes were observed more frequently than solitary nodes. Most tumors were located in the middle third of the uterine body, followed by the upper and lower thirds. Regarding uterine wall localization, nodes were most detected in the anterior wall, followed by the posterior and lateral walls. As shown in Figure 2A , the tumor markers CA-125 and CA-19-9 were significantly elevated in the experimental group compared with the control group. CA-125 levels increased from approximately 3 U/mL in the control group to about 20 U/mL in the experimental group, while CA-19-9 concentrations increased from roughly 3 U/mL to approximately 12 U/mL (P<0.0001). Hormonal analysis ( Figure 2B ) demonstrated significant differences between groups. Progesterone levels were higher in the experimental group than in controls, while estradiol concentrations were markedly elevated in the experimental group, reaching approximately 60 pg/mL, compared with about 37 pg/mL in the control group (P<0.001–0.0001). Evaluation of inflammatory and angiogenic cytokines ( Figure 2C ) revealed significantly increased levels of IL-6, TNF-α, TGF-β2, FGF, IGF, and VEGF in the experimental group compared with the control group (P<0.0001). The most pronounced elevations were observed for TGF-β2 and VEGF, indicating enhanced inflammatory activity and angiogenesis associated with UL. Findings demonstrate that UL is associated with increased tumor markers, hormonal imbalance, and elevated inflammatory and angiogenic cytokines. Serum concentrations of tumor markers, sex hormones, and cytokine-growth factors in women with uterine leiomyoma (Exp gr) and healthy controls (Cont gr). (A) Tumor markers CA-125 and CA-19-9 were significantly elevated in the experimental group compared with controls. (B) Sex hormones progesterone and estradiol were markedly increased in women with leiomyoma, confirming a hyperestrogenic-hyperprogestogenic background. (C) Cytokine and growth factor analysis showed pronounced rises in IL-6, TNF-α, TGF-β 2 , FGF, and VEGF, accompanied by a compensatory decline in IGF, indicating activation of inflammatory and angiogenic pathways in tumor progression. ***, P<0.001; ****, P<0.0001. CA-125, cancer antigen 125; CA-19-9, cancer antigen 19-9; Cont gr, control group; Exp gr, experimental group; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL-6, interleukin-6; TGF-β2, transforming growth factor beta-2; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor. Radiological findings are illustrated in Figure 3 . MRI of the pelvis demonstrates characteristic structural features of ULs in women of reproductive age. The images illustrate variability in localization, vascularization, and internal architecture of the myomatous nodes. Leiomyomas appear as well-defined masses within the uterine wall with heterogeneous signal intensity reflecting differences in tissue composition, including smooth muscle proliferation and connective tissue elements. The MRI scans also demonstrate differences in nodular size, intramural or subserosal localization, and vascular supply, highlighting the heterogeneity of leiomyoma morphology. These imaging findings were used to assess the number, localization, and structural characteristics of the myomatous nodes prior to surgical management. MRI findings in women with uterine leiomyoma demonstrate variations in localization, vascularity, and structural composition of the myomatous nodes. (A) Intramural and subserosal leiomyomas of the anterior uterine wall showing well-defined, hypointense lesions on T1-weighted and hyperintense signals on T2-weighted images with moderate contrast enhancement—indicative of viable vascularized tissue. (B) Submucosal leiomyomas with high T2 signal intensity and early post-contrast enhancement consistent with hyperperfusion and active cellular proliferation. (C) Multiple leiomyomatous nodes with mixed signal intensity on T2-weighted images and heterogeneous enhancement, reflecting degenerative and fibrotic transformation zones. (D) Leiomyomas with cystic and necrotic changes presenting as heterogeneous hyperintense regions on T2-weighted sequences with peripheral enhancement, indicating secondary degeneration and reduced perfusion. MRI, magnetic resonance imaging. Figure 4 shows the morphological parameters of UL in women of reproductive age. Representative macroscopic and histological features of UL obtained from surgical specimens are presented. Macroscopically, the excised myomatous nodes appear as well-circumscribed, firm, round formations with a whorled cut surface, typical of benign smooth muscle tumors of the uterus. Microscopic examination demonstrates interlacing bundles of smooth muscle cells with elongated nuclei and minimal cellular atypia, surrounded by variable amounts of connective tissue stroma. In some cases, structural variations such as fibrotic changes, hyalinization, or vascular alterations are observed, reflecting differences in tumor development and growth patterns. These findings confirm the benign smooth muscle origin of the myomatous nodes and correspond with the imaging characteristics observed on MRI. Macroscopic and microscopic characteristics of uterine leiomyoma in women of reproductive age. (A) Macroscopic view: excised leiomyoma nodules showing spherical morphology with smooth external surfaces and well-defined fibrous capsules. On section, the tumors display a whitish, whorled appearance with alternating dense and edematous areas, characteristic of smooth muscle proliferation and fibrosis. (B) Histological section of leiomyoma (H&E, ×100–200): compact bundles of spindle-shaped smooth muscle cells arranged in intersecting fascicles with areas of focal hyalinosis and collagenization. The nuclei are elongated and uniform, without significant atypia or mitotic figures—confirming benign nature. (C) Myometrial hypertrophy and adenomyosis features (H&E, ×200): infiltration of endometrial glands and stroma into the myometrium, with associated fibro-muscular hyperplasia and vascular congestion, indicating secondary reactive changes surrounding the myomatous node. (D) Leiomyoma with degenerative changes (H&E, ×200–400): irregular arrangement of muscle bundles with hyaline and cystic degeneration, edematous stroma, and focal necrotic foci, reflecting progressive vascular insufficiency and remodeling. H&E, hematoxylin and eosin.

This study provides a comprehensive analysis of the clinical, hormonal, angiogenic, and morphological features of UL in women of reproductive age, integrating data from epidemiologic, imaging, biochemical, and histopathological perspectives. The results confirm that UL represents a multifactorial disease driven by a hormonal-angiogenic-inflammatory triad, modulated by metabolic and reproductive risk factors ( 9 , 26 ). Clinical and epidemiological features as shown in Figure 1A , the majority of affected women were aged 40–49 years, reflecting the typical reproductive-age vulnerability ( 27 ). Hyperpolymenorrhea, pelvic pain with algomenorrhea, menstrual irregularities, dyspareunia, and infertility were the most frequent manifestations Figure 1B ( 28 ). According to the FIGO classification, the majority of women were categorized as type IV, representing the dominant anatomical variant of UL ( Figure 1C ) ( 29 ). The highest proportion of pregnancies was observed in women with parity ≥4 ( Figure 1D ) ( 30 ). A predominance of multiparity and a history of two or more spontaneous or induced abortions were observed among patients, suggesting that reproductive trauma and repeated endometrial remodeling may contribute to myometrial transformation and fibroid development. Table 1 further demonstrates a predominance of organ-preserving surgical approaches in the experimental group, reflecting a shift toward fertility-sparing strategies. Comorbidities were frequent ( Table 2 ), led by post-hemorrhagic anemia (35.8%), neuro-functional disorders (26.7%), and cardiovascular pathology (20.8%), suggesting that systemic metabolic and vascular factors contribute to UL pathogenesis. The multivariate statistical analysis ( Tables 3,4 ) revealed several highly significant predictors of leiomyoma development. The strongest associations were observed for VEGF >95.1 pg/mL [odds ratio (OR) ~38.5], ≥2 induced abortions (OR ~8.8), overweight (OR ~8.2), and estradiol >40.5 pg/mL (OR ~8.3). Moderate risk was attributed to elevated FGF-1 >81.4 pg/mL (OR ~5.5), previous gynecologic surgery, pelvic inflammatory disease, early menopause, and hereditary predisposition (OR ~2–3). Conversely, frequent respiratory infections and urinary tract inflammation were not associated or were slightly protective (OR <1). Collectively, these findings delineate a metabolic-angiogenic risk profile in which estrogenic stimulation, angiogenic activation, and chronic inflammation act synergistically. Tumor markers CA-125 and CA-19-9 were significantly elevated, reflecting benign proliferative or inflammatory processes rather than malignant transformation Figure 2A ( 31 - 33 ). Hormonal and cytokine growth factor milieu serum profiling ( Figure 2B,2C ) showed pronounced elevations of progesterone and estradiol, confirming a hyperestrogenic-hyperprogestogenic background that favors smooth-muscle proliferation. In parallel, pro-inflammatory and angiogenic mediators-IL-6, TNF-α, TGF-β 2 , FGF, and VEGF-were markedly increased, whereas IGF-I was reduced, indicating suppression of reparative growth signaling. These patterns implicate RTK/MAPK, PI3K-AKT-mTOR, and TGF-β/SMAD pathways in myometrial hyperplasia, ECM remodeling, and vascular expansion ( 34 ). Their elevation mirrors the systemic inflammatory and metabolic stress associated with leiomyoma and should be interpreted contextually rather than diagnostically. Radiologic and morphologic correlations MRI demonstrated characteristic structural heterogeneity corresponding to perfusion and degeneration stages. Active intramural/subserosal lesions exhibited hyperintense T2 and strong contrast enhancement, denoting viable angiogenic tissue. Submucosal nodes showed hyperperfusion, consistent with cellular proliferation. Mixed-signal multiple nodes represented transitional fibrotic or degenerative forms, whereas cystic-necrotic leiomyomas displayed peripheral enhancement and reduced diffusion, reflecting ischemic remodeling ( Figure 3A-3D ) ( 35 , 36 ). Macroscopic and microscopic analysis ( Figure 4 ) confirmed these imaging patterns. The tumors displayed whorled fibrous surfaces, bundled spindle-cell proliferation, and focal hyalinosis, with occasional adenomyosis-like infiltration and degenerative necrosis. These features align with chronic hypoxia and vascular dysregulation, paralleling biochemical evidence of VEGF and TGF-β 2 overexpression. Integrated pathophysiologic interpretation. Correlation analysis revealed close interdependence between inflammation, hematologic stress, and metabolic imbalance. Taken together, these findings depict UL as a benign proliferative disorder driven by dysregulated angiogenesis and chronic inflammatory signaling superimposed on an estrogen-dominant endocrine milieu. Post-surgical dynamics and clinical implications following myomectomy or hysterectomy, VEGF levels decreased 1.6-fold, whereas IGF-I and FGF increased, indicating partial normalization of vascular and reparative processes ( 37 ). For follow-up, a compact immuno-hormonal-oncomarker panel-comprising VEGF, TGF-β 2 , IL-6, TNF-α, estradiol, IGF-I, and CA-125, 19-9-can enhance risk stratification and recurrence monitoring. Limitations and perspectives Limitations include a single-center design, cross-sectional biomarker evaluation, and limited confounder adjustment [e.g., parity, body mass index (BMI), metabolic profile]. Future studies should employ longitudinal sampling, multivariable regression, and imaging-biomarker integration to validate predictive thresholds and explore therapeutic modulation of angiogenic pathways. ARI, acute respiratory infection. IGF-1, insulin-like growth factor 1; TGF-β1, transforming growth factor beta 1; VEGF, vascular endothelial growth factor. This table presents the results of the logistic regression and contingency analysis evaluating clinical, hormonal, and immunological predictors of uterine leiomyoma. CI, confidence intervals; OR, odds ratios; RR, relative risks; Se, sensitivity; Sp, specificity; VEGF, vascular endothelial growth factor. Overall, this investigation demonstrates that UL evolves through a coordinated cascade of hormonal stimulation, vascular proliferation, and inflammatory remodeling. Elevated VEGF, TGF-β2, IL-6, TNF-α, and estradiol, together with characteristic MRI and histological features, define its biological signature. Targeted metabolic and reproductive interventions, combined with biomarker-based surveillance, may offer improved prevention and management of leiomyoma in women of reproductive age. UL in women of reproductive age develops through an integrated hormonal angiogenic inflammatory mechanism, in which VEGF, TGF-β2, IL-6, and TNF-α act as leading mediators against a background of estrogen excess, metabolic dysregulation, and chronic inflammatory load ( 38 ). The most significant clinical predictors of tumor formation include ≥2 induced abortions, overweight, and elevated VEGF (>95 pg/mL), each conferring markedly increased odds of leiomyoma development. Among biochemical markers, pronounced elevations of CA-125, CA-19-9. These markers, though non-specific, reflect systemic inflammatory and metabolic comorbidity rather than malignant transformation, emphasizing the need for contextual interpretation in gynecologic diagnostics. Following organ-preserving or radical surgery, VEGF levels decreased 1.6-fold, while IGF-I and FGF levels increased, indicating partial restoration of vascular and immune homeostasis.

Preventive strategies should focus on metabolic correction, reproductive counseling, management of chronic inflammation, and early immune-biochemical screening in at-risk women to reduce recurrence and preserve fertility.

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