DOI 10.1007/s10517-015-2852-6
742
Bulletin of Experimental Biology and Medicine, Vol. 158, No. 6, April, 2015 GENERAL PATHOLOGY AND PATHOPHYSIOLOGY
Structural and Functional Basis of Chronic Pelvic Pain Syndrome during Combined Chronic Cystitis and Adenomyosis N. V. Shelkovnikova, E. L. Lushnikova*, A. K. Pichigina*, and A. I. Neimark Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 158, No. 12, pp. 704-709, December, 2014 Original article submitted February 12, 2014 Comprehensive clinical and morphological examination of 60 female patients with chronic pelvic pain syndrome after combined chronic cystitis and adenomyosis was carried out. In all patients, the complex urodynamic examination revealed various disturbances of urination and stasis-like abnormalities of circulation in vesical and uterine walls. The pathomorphological peculiarities of the urogenital disorders during combination of adenomyosis and cystitis (of the combined proliferative and erosive/destructive type) is manifested by more pronounced destructive and inflammatory changes in urothelium characterized by the formation of superficial and deep erosions as well as by association of erosive/destructive damages to the urothelium with proliferative and metaplastic changes. Combined treatment of chronic cystitides and adenomyosis eliminated the destructive and inflammatory alterations in the vesical mucosa in 70 and 93% female patients, respectively (the corresponding values after basic therapy were 60 and 77%), and pronouncedly ameliorated pain syndrome. Key Words: chronic pelvic pain syndrome; chronic cystitis; adenomyosis; pathomorphology The development of chronic pelvic pain (CPP) syndrome in women most often results from the lesions in the urogenital system. During ontogenesis, the pelvic organs are amalgamated into an integrated anatomical system with common innervation and blood/lymph circulation. The intimate juxtaposition of the organs in a small volume of pelvis minor is a formidable obstacle in differentiating and identifying the causes of CPP in female patients [1,10,11]. The development of inflammatory processes in the pelvis minor is often accompanied with mutual “pathological” influence of its organs [4,5]. In patients with CPP syndrome, the pathological process persistently recruits the nervous, endocrinic, and vascular systems [13]. *Research Institute of Regional Pathology and Pathomorphology, Siberian Division of the Russian Academy of Sciences, Novosibirsk; Altai State Medical University, Ministry of Health of the Russian Federation, Barnaul, Russia. Address for correspondence: pathol@ inbox.ru. N. V. Shelkovnikova
Among possible causes of CPP, especially important are the following: 1) inflammatory diseases in pelvic organs, 2) endometriosis, and 3) irritable bowel syndrome [7,13]. CPP can be provoked by one or several reasons. In some female patients with CPP, the specific etiological factor is unknown. Thus, the problem of combined urological and gynecological pathology and its role in the development of CPP syndrome is actual, so further studies are needed to reveal the etiological factors and pathogenesis of the disease [6,9,14,15]. There are few fragmentary studies in this field despite the modern literature pays much attention to the problems of etiology, pathogenesis, diagnostics, and the treatment of the diseases and lesions in individual pelvic organs. The peculiarities of morphological and functional changes revealed by combined endoscopic and histological examination of pelvic viscera are still unknown. This work was designed to study the structural and functional disturbances in urinary bladder and
0007-4888/15/15860742 © 2015 Springer Science+Business Media New York
N. V. Shelkovnikova, E. L. Lushnikova, et al.
uterus in patients with combined urogenital pathology (chronic cystitis and adenomyosis) aggravated by CPP syndrome, who underwent the combined therapy.
MATERIALS AND METHODS The female patients (n=60) aging 35-49 years (mean age 42.0±5.7 years) with chronic cystitis and persistent dysuria were subjected to clinical and morphological examination. The patients had associated gynecological pathology manifested by the first-second degree adenomyosis. These abnormalities were aggravated with CPP syndrome developed for a long period of 6-15 years. In the past, all patients were repeatedly treated with uroseptics and instillation. The patients were randomized into two groups. In comparison group (N=30), the patients received only basic therapy directed to cope with persistent dysuria. The antibacterial therapy was individually selected according to sensitivity of the urinal microflora to the antibacterial medications. In experimental group (N=30), the patients were subjected to complex therapy of the urological and chronic gynecological pathologies based on intravesical and vaginal antibacterial preparations as well as on hormonal, physical, and immune therapies. The patients were subjected to deep clinical examination with due account for obstetric and gynecological anamnesis and for social and marital statuses. Ultrasonography (US) of minor pelvic organs with color flow Doppler mapping (CDFM) was carried out according to Donald school of sonography employing a linear transabdominal transducer at 3.5 MHz and a transvaginal transducer at 5.5 MHz of an Aloca SSD 2000 ultrasonic scanner. The complex urodynamic examination (uroflowmetry and cystometry) was performed with a Delphis IP apparatus (Laborie). The uroflowgrams were used to calculate the following parameters: TQ, flow time (sec); TQmax, time to maximum flow rate (sec); Qmax, maximum flow rate (ml/sec); Vcomp, voided volume (ml); and T100, waiting time to the onset of urination (sec). The uroflowmetric data were compared with the normal values [2]. Urethrocystoscopy was carried out with Storz and Wolf cystoscopes. Videocystoscopy was performed with an Olympus surgical cystoscope. Cervicohysteroscopy was executed with a Storz hysteroscope and an Olympus surgical hysteroscope. Laser Doppler Flowmetry (LDF) of the urethra, vagina, uterus, and urinary bladder mucosa was performed using an LAKK-02 apparatus (Lazma) and LDF 1.18 software. LDF-grams were recorded in the monitor mode thereupon the microcirculation index (MI) and the root-mean-square deviation (RSD) was calculated. MI evaluated the flow of erythrocytes per unit time
743 across a unit of tissue weight in relative or perfusion units (PU). RSD reflected variability of microcirculation counted also in PU. To assess the level of microcirculation, we calculated the coefficient of variation (CV)=RSD×(MI×100) and microcirculation efficiency index (MEI)=AmaxLF/(AmaxHF+AmaxCF), where AmaxLF represents the active mechanism of microcirculation, AmaxHF reflects the passive mechanism of microcirculation, and AmaxCF reports the share of cardiac contractions in the microcirculatory hemodynamics. MEI reflects interaction of blood flow oscillations in various parts of frequency spectrum. In analysis of peculiarities of the blood flow and the types of its disorders, we employed the following categorization: physiological form, spastic form, stagnant form, and stasis [3]. The specimens of endometrium and urinary bladder were fixed in 10% neutral formalin for subsequent pathomorphological analysis. Then the specimens had been prepared in a Histokinette automated machine for histological examination and embedded in paraffin. During embedding, the layer orientation of the specimens on the blocks was preserved. The paraffin sections (5-7 μ) were stained with hematoxylin and eosin according to Van Gieson method. To prepare the semithin sections, the tissue specimens were fixed in 4% paraformaldehyde and 1 % OsO4 and then embedded in Epon-Araldite. These sections (1 μ) were cut in an LKB-III ultramicrotome and stained with azure II. The preparations were analyzed under a Leica DM 4000B universal microscope. The microphotos were obtained with a Leica DFC 320 digital camera and processed with a Leica Qwin 3.0 software. The data were processed with Statistica 8.0 software. When the distribution was normal or the sample variances were equal, significance was assessed with Student’s t test.
RESULTS All patients had lower abdominal pain and urinary frequency. In addition, they complained of algodismenorrhea (88.3%), painful sexual intercourse (95%), painful urination (93.3%), and urinary urgency (53.3%). In 80% patients, the score of pain syndrome attained the maximum level of 10 points according to pain questionnaire. Cystoscopy revealed pronounced hyperemia, multiple hemorrhages and ulcers. Hysteroscopy demonstrated pronounced hyperemia and edema in endometrium, the hemorrhagic bleeds, and petechial hemorrhages. The endometrial tracts and cysts contained old blood clots. Combined US and CDFM of uterine and vesical walls revealed the echogenic inclusions of about 3 mm in diameter. The pathomorphological analysis of vesical biopsy material showed that morphological alterations
744
Bulletin of Experimental Biology and Medicine, Vol. 158, No. 6, April, 2015 GENERAL PATHOLOGY AND PATHOPHYSIOLOGY
Fig. 1. Structural alterations of mucosa of urinary bladder and endometrium during combined urogenital pathology (chronic cystitis and adenomyosis). The semithin sections were stained with azure II (a, c) and with hematoxylin and eosin (b, d). a) Proliferative and dystrophic changes in urothelium, ×400; b) formation of Brunn epithelial nests and a lymphoid follicle in the lamina propria of vesical mucosa, ×200; c) focal desquamation of urothelium with fresh subepithelial bleeding, ×1000; d) numerous mitotic figures in epitheliocytes of the endometrial glands during first-second degree adenomyosis, ×400.
in patients with combined urogenital pathology were characterized with proliferative and destructive processes. These processes led to marked thickening of
urothelium with the formation of Brunn epithelial nests (Fig. 1, a, b) or pronounced destructive and inflammatory changes with the surface and deep ero-
N. V. Shelkovnikova, E. L. Lushnikova, et al.
138.1±11.8
102.0±1.2 29.9±2.2 10.0±0.6 Normal values
Note. Here and in Table 2: *p
742
Bulletin of Experimental Biology and Medicine, Vol. 158, No. 6, April, 2015 GENERAL PATHOLOGY AND PATHOPHYSIOLOGY
Structural and Functional Basis of Chronic Pelvic Pain Syndrome during Combined Chronic Cystitis and Adenomyosis N. V. Shelkovnikova, E. L. Lushnikova*, A. K. Pichigina*, and A. I. Neimark Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 158, No. 12, pp. 704-709, December, 2014 Original article submitted February 12, 2014 Comprehensive clinical and morphological examination of 60 female patients with chronic pelvic pain syndrome after combined chronic cystitis and adenomyosis was carried out. In all patients, the complex urodynamic examination revealed various disturbances of urination and stasis-like abnormalities of circulation in vesical and uterine walls. The pathomorphological peculiarities of the urogenital disorders during combination of adenomyosis and cystitis (of the combined proliferative and erosive/destructive type) is manifested by more pronounced destructive and inflammatory changes in urothelium characterized by the formation of superficial and deep erosions as well as by association of erosive/destructive damages to the urothelium with proliferative and metaplastic changes. Combined treatment of chronic cystitides and adenomyosis eliminated the destructive and inflammatory alterations in the vesical mucosa in 70 and 93% female patients, respectively (the corresponding values after basic therapy were 60 and 77%), and pronouncedly ameliorated pain syndrome. Key Words: chronic pelvic pain syndrome; chronic cystitis; adenomyosis; pathomorphology The development of chronic pelvic pain (CPP) syndrome in women most often results from the lesions in the urogenital system. During ontogenesis, the pelvic organs are amalgamated into an integrated anatomical system with common innervation and blood/lymph circulation. The intimate juxtaposition of the organs in a small volume of pelvis minor is a formidable obstacle in differentiating and identifying the causes of CPP in female patients [1,10,11]. The development of inflammatory processes in the pelvis minor is often accompanied with mutual “pathological” influence of its organs [4,5]. In patients with CPP syndrome, the pathological process persistently recruits the nervous, endocrinic, and vascular systems [13]. *Research Institute of Regional Pathology and Pathomorphology, Siberian Division of the Russian Academy of Sciences, Novosibirsk; Altai State Medical University, Ministry of Health of the Russian Federation, Barnaul, Russia. Address for correspondence: pathol@ inbox.ru. N. V. Shelkovnikova
Among possible causes of CPP, especially important are the following: 1) inflammatory diseases in pelvic organs, 2) endometriosis, and 3) irritable bowel syndrome [7,13]. CPP can be provoked by one or several reasons. In some female patients with CPP, the specific etiological factor is unknown. Thus, the problem of combined urological and gynecological pathology and its role in the development of CPP syndrome is actual, so further studies are needed to reveal the etiological factors and pathogenesis of the disease [6,9,14,15]. There are few fragmentary studies in this field despite the modern literature pays much attention to the problems of etiology, pathogenesis, diagnostics, and the treatment of the diseases and lesions in individual pelvic organs. The peculiarities of morphological and functional changes revealed by combined endoscopic and histological examination of pelvic viscera are still unknown. This work was designed to study the structural and functional disturbances in urinary bladder and
0007-4888/15/15860742 © 2015 Springer Science+Business Media New York
N. V. Shelkovnikova, E. L. Lushnikova, et al.
uterus in patients with combined urogenital pathology (chronic cystitis and adenomyosis) aggravated by CPP syndrome, who underwent the combined therapy.
MATERIALS AND METHODS The female patients (n=60) aging 35-49 years (mean age 42.0±5.7 years) with chronic cystitis and persistent dysuria were subjected to clinical and morphological examination. The patients had associated gynecological pathology manifested by the first-second degree adenomyosis. These abnormalities were aggravated with CPP syndrome developed for a long period of 6-15 years. In the past, all patients were repeatedly treated with uroseptics and instillation. The patients were randomized into two groups. In comparison group (N=30), the patients received only basic therapy directed to cope with persistent dysuria. The antibacterial therapy was individually selected according to sensitivity of the urinal microflora to the antibacterial medications. In experimental group (N=30), the patients were subjected to complex therapy of the urological and chronic gynecological pathologies based on intravesical and vaginal antibacterial preparations as well as on hormonal, physical, and immune therapies. The patients were subjected to deep clinical examination with due account for obstetric and gynecological anamnesis and for social and marital statuses. Ultrasonography (US) of minor pelvic organs with color flow Doppler mapping (CDFM) was carried out according to Donald school of sonography employing a linear transabdominal transducer at 3.5 MHz and a transvaginal transducer at 5.5 MHz of an Aloca SSD 2000 ultrasonic scanner. The complex urodynamic examination (uroflowmetry and cystometry) was performed with a Delphis IP apparatus (Laborie). The uroflowgrams were used to calculate the following parameters: TQ, flow time (sec); TQmax, time to maximum flow rate (sec); Qmax, maximum flow rate (ml/sec); Vcomp, voided volume (ml); and T100, waiting time to the onset of urination (sec). The uroflowmetric data were compared with the normal values [2]. Urethrocystoscopy was carried out with Storz and Wolf cystoscopes. Videocystoscopy was performed with an Olympus surgical cystoscope. Cervicohysteroscopy was executed with a Storz hysteroscope and an Olympus surgical hysteroscope. Laser Doppler Flowmetry (LDF) of the urethra, vagina, uterus, and urinary bladder mucosa was performed using an LAKK-02 apparatus (Lazma) and LDF 1.18 software. LDF-grams were recorded in the monitor mode thereupon the microcirculation index (MI) and the root-mean-square deviation (RSD) was calculated. MI evaluated the flow of erythrocytes per unit time
743 across a unit of tissue weight in relative or perfusion units (PU). RSD reflected variability of microcirculation counted also in PU. To assess the level of microcirculation, we calculated the coefficient of variation (CV)=RSD×(MI×100) and microcirculation efficiency index (MEI)=AmaxLF/(AmaxHF+AmaxCF), where AmaxLF represents the active mechanism of microcirculation, AmaxHF reflects the passive mechanism of microcirculation, and AmaxCF reports the share of cardiac contractions in the microcirculatory hemodynamics. MEI reflects interaction of blood flow oscillations in various parts of frequency spectrum. In analysis of peculiarities of the blood flow and the types of its disorders, we employed the following categorization: physiological form, spastic form, stagnant form, and stasis [3]. The specimens of endometrium and urinary bladder were fixed in 10% neutral formalin for subsequent pathomorphological analysis. Then the specimens had been prepared in a Histokinette automated machine for histological examination and embedded in paraffin. During embedding, the layer orientation of the specimens on the blocks was preserved. The paraffin sections (5-7 μ) were stained with hematoxylin and eosin according to Van Gieson method. To prepare the semithin sections, the tissue specimens were fixed in 4% paraformaldehyde and 1 % OsO4 and then embedded in Epon-Araldite. These sections (1 μ) were cut in an LKB-III ultramicrotome and stained with azure II. The preparations were analyzed under a Leica DM 4000B universal microscope. The microphotos were obtained with a Leica DFC 320 digital camera and processed with a Leica Qwin 3.0 software. The data were processed with Statistica 8.0 software. When the distribution was normal or the sample variances were equal, significance was assessed with Student’s t test.
RESULTS All patients had lower abdominal pain and urinary frequency. In addition, they complained of algodismenorrhea (88.3%), painful sexual intercourse (95%), painful urination (93.3%), and urinary urgency (53.3%). In 80% patients, the score of pain syndrome attained the maximum level of 10 points according to pain questionnaire. Cystoscopy revealed pronounced hyperemia, multiple hemorrhages and ulcers. Hysteroscopy demonstrated pronounced hyperemia and edema in endometrium, the hemorrhagic bleeds, and petechial hemorrhages. The endometrial tracts and cysts contained old blood clots. Combined US and CDFM of uterine and vesical walls revealed the echogenic inclusions of about 3 mm in diameter. The pathomorphological analysis of vesical biopsy material showed that morphological alterations
744
Bulletin of Experimental Biology and Medicine, Vol. 158, No. 6, April, 2015 GENERAL PATHOLOGY AND PATHOPHYSIOLOGY
Fig. 1. Structural alterations of mucosa of urinary bladder and endometrium during combined urogenital pathology (chronic cystitis and adenomyosis). The semithin sections were stained with azure II (a, c) and with hematoxylin and eosin (b, d). a) Proliferative and dystrophic changes in urothelium, ×400; b) formation of Brunn epithelial nests and a lymphoid follicle in the lamina propria of vesical mucosa, ×200; c) focal desquamation of urothelium with fresh subepithelial bleeding, ×1000; d) numerous mitotic figures in epitheliocytes of the endometrial glands during first-second degree adenomyosis, ×400.
in patients with combined urogenital pathology were characterized with proliferative and destructive processes. These processes led to marked thickening of
urothelium with the formation of Brunn epithelial nests (Fig. 1, a, b) or pronounced destructive and inflammatory changes with the surface and deep ero-
N. V. Shelkovnikova, E. L. Lushnikova, et al.
138.1±11.8
102.0±1.2 29.9±2.2 10.0±0.6 Normal values
Note. Here and in Table 2: *p
