Benign gynecologic diseases

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Medvediev M.V.

Types of fibroids

(The European Society of Hysteroscopy, 1993)

1. Submucos (SM): Fibroid distorting the uterine cavity.

Type 0: pedunculated without intramural extension

Type I: Sessile with intramural extension <50%

Type II: Sessile with intramural extension >50%

2. Intramural (IM): Fibroid not distorting the cavity & with <50% protrusion into serosal surface

3. Subserosal (SS): >50% protrudes out of the serosal surface

ETIOLOGY

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Townsend and co-workers have demonstrated that each of the cells comprising a leiomyoma is of identical glucose-6-phosphate dehydrogenase electrophoretic type. Their data strongly suggest that leiomyomata are unicellular in origin.

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• Estrogen
• Progesterone
• Growth hormone
• Increase of 4-hydroxylation of estradiol
• Increase aromatase enzyme

J.C.M. Tsibris, et al, analyzed 12,000 genes using the Affymetrix platform. Their analysis revealed 67 overexpressed and 78 underexpressed genes and they speculate that leiomyoma might be characterized by the loss of a contractile phenotype.

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Fertility & Sterility

80(2):279-28, 2003

Dysregulation of a number of growth factors in the myometous uterus (many of these factors regulate the process of angiogenesis)�

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• Fibroblast growth factor
• Vascular endothelial growth factor
• Heparin-binding epidermal growth factor
• Platelet-derived growth factor
• Transforming growth factor ,
• Parathyroid hormone-related protein
• Prolactin

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• Forty percent of the myomas evaluated by Bronsen F, et al demonstrated an abnormal karyotype and had a significantly lower DNA content than chromosomally normal myomas.

Uterine leiomyomas are monoclonal tumors that demonstrate nonrandom cytogenetic mutation. The most frequently reported cytogenetic abnormalities in myomas are:

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• + (12:14) (q13-15, q23-24)
• del (7) (q21)
• + (1;2) (p36, p24)

Nonhormonal Risk Factors for Uterine Leiomyoma

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• Any history of hypertension (odd ratio (OR):1.7)
• Hypertension requiring mediation (OR:2.1)
• Hypertension at age less than 35 years (OR:2.7)
• Hypertension of 5 or more years duration (OR:3.1
• Pelvic inflammatory disease (3 or more episodes OR:3.7)
• Chlamydial infection (OR:3.2)
• Use of intrauterine device with PID (OR:5.3)
• Perineal talc use (daily vs. no use:PR=2.2)

Symptomatology

Twenty to fifty percent of uterine leiomyomas are estimated to produce symptoms.

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Menorrhagia (29 - 59%)

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Pelvic pain and pressure (34%)

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Pregnancy complications

Incidence of Myoma During Pregnancy

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0,30 – 7.2%

17.3% had clinical pathological state

7.28 % requiring surgical intervention

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HL Gainey and JE Keeler

Am J Obstet Gynecol, 1949

Pregnancy Complications Due to Leiomyoma

• Abortion
• Premature labor
• Disturbances in labor

Postpartum hemorrhage

(questionable

• Ectopic pregnancy

• Premature rupture of membrane
• Dystocia secondary low segment myoma
• Increase operative deliveries
• Inversion of uterus

Effects of the Pregnancy on the Myoma

• Degeneration of myomas

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• Infection (the process is usually sterile but may be complicated by secondary infection from uterine cavity)

Causes of Uterine Degeneration

1. Vascular Insufficiency
• Rapid growth during pregnancy
• Torsion of pedunculated myoma
• Uterine artery embolization
2. Hypoestrogenic State
• Postpartum or postabortal
• GnRH – agonist or antiagonist
• Postmenopausal (perimenopausal)
3. Other Causes
• High dosage progestin therapy
• Progesterone receptor modulator

Type of Degenerative Change� Persaud & Arjoon, Obstet & Gynecol, 1970

445 Pregnancies Complicated by Leiomyoma��

• Degeneration of Myoma

Only one of four myomas evidences degeneration. Degeneration was variable in successive pregnancies. Of the cases that degenerated in the first pregnancy, 6 percent did not degenerate subsequently, whereas 10 percent that did not evidence degeneration in the first pregnancy did degenerate in later ones.

• Antepartum Course

28 percent had pain of varying degrees. In the successive pregnancies, 15 percent had pain the the first pregnancies and none subsequently, whereas 7.5 percent had no pain in the first pregnancies, but did have pain in following ones.

According to DJ Grandin, 1949

The Significance of Leiomyoma Uteri in Pregnancy

Pain occurred in 15.6 percent. In about 50 percent; however, it was of sufficient degree to require hospitalization for observation or treatment. In most cases, the acute symptoms are relieved after a few days of bed rest. Recent studies have shown that myomectomy during pregnancy carried a high fetal mortality and an increased maternal risk.

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FA Duckering

Am J Obstet Gynecol

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Changes in Myomas During Pregnancy

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Infertility (27%)

According to VC Buttram in only 2.4% of patients who had myomectomy no cause of infertility was found. Uterine leiomyomas were the sole cause of 9.1% in among black patients. In contrast, only 1.8% of white patients had infertility after attributable to leiomyoma alone. Pelvic adhesive disease requiring surgery for infertility was significantly higher in black patients (44%) other white patients (17.5%).

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Fertility & Sterility, 1981

Outcome and Resource Use �Associated with Myomectomy

Conversion to more invasive procedure occurred in 5.4% of the patients. Conversion to open myomectomies occurred in 13.3% of laparoscopies and 7.4% of hysteroscopies. Hysterectomy conversion occurred in 3.7%, 2.8% and 1.5% of the open, laparoscopic and hysteroscopic procedures respectively. The rate of additional surgeries was 8.3% in 6 months. 10.6% in 1 year, and 16.5% in 2 years.

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Subramanian S, et al

Obstet Gynecol, 2001, 98(4):583-576

Fertility Among Women with Uterine Leiomyoma

Pelvic adhesions: 36.2 percent of the 196 women had pelvic adhesions at operation. The highest incidence (58%) of adhesions were noted in women complaining of infertility. Of special interest was the incidence of pregnancy among the 52 subjects whose presenting complaints included infertility: only 5 (9.6%) conceived, and all were of the 22 women in whom the were pelvic adhesion-free at operation.

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VE Eqwuatu, J Fertility, 1989

Other Problems Associated with Uterine Leiomyoma

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• Polycythermia
• Ascites
• Impingement
• Related complications
• Sarcomatous changes

Management of Uterine Leiomyomata: What Do We Really Know?

Systematically review the literature on the surgical and non surgical management of uterine leiomyomata.

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Despite the clinical and public health importance of uterine leiomyomata, the available literature has significant limitations that prevent patients, clinicians, and policymakers from reaching conclusions about the relative risks, benefits, and costs of currently used treatments for leiomyomata. Rectifying these limitations should be a major research priority.

Myers ER et al, Obstet Gynecol 2002

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Surgical Treatment of Uterine Leiomyomas

• Hysterectomy

Laparotomy

Laparoscopic

Vaginal

• Myomectomy

Vaginal

Hysteroscopic

Laparoscopic

Laparotomy

• Myolysis

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Disseminated leiomyomatosis and diffuse endometriosis may occur following laparoscopic supracervical hysterectomy. Presumably small, even microscopic, fragments of smooth muscle or endometrium dispersed during morcellation can proliferate and ultimately result in pelvic pain and masses.

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Kung R. et al, 2000

The major indications for aggressive management of uterine myomas are as follows:

• Abnormal uterine bleeding
• Rapid growth
• Growth after menopause
• Infertility
• Recurrent pregnancy loss
• Pain or pressure symptoms
• Urinary tract symptoms or obstruction
• Possibility of ovarian neoplasia
• Iron deficiency anemia secondary to chronic blood loss

Management of Nonpregnant Patients with Uterine Leiomyomata

Complication Rate with Abdominal Myomectomy

Complication

Febrile

Hemorrhage

EBL > 1,000 mL

Unintended hysterectomy

Post op

DVT

Wound infection

Ileus

Data from LaMorte, et al

Patients

15 (12%)

26 (20%)

6 (5%)

1 (1%)

3 (2%)

1 (1%)

1 (1%)

1 (1%)

Effect of Patient Age on Conception Following Myomectomy

Pregnancy Rate in Infertile Women Following Myomectomy

Factors Influencing Pregnancy After Myomectomy

Factors Influencing Pregnancy Rates After Myomectomy�(Continued)

Effects of intramural subserosal and submucosal uterine fibroids on the outcome of assisted reproductive technology (Elder-Geva et al)�

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• The pregnancy rates per transfer were 34.1%, 16.4%, 10%, and 30.1% in the patients with subserosal fibroids, intramural fibroids, submucosal fibroids and no fibroids, respectively.

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• Pregnancy and implantation rates were significantly lower in the groups of patients with intramural and submucosal fibroids, even when there was no deformation of the uterine cavity. Pregnancy and implantation rates were not influenced by the presence of subserosal fibroids. Surgical or medical treatment should be considered in infertile patients who have intramural and/or submucosal fibroids before resorting to ART treatment.

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Some indications for the use of GnRH agonists in women with uterine leiomyomata are as follows:

• Preservation of fertility in women with large leiomyomas before attempting conception, or preoperative treatment before myomectomy

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• Treatment of anemia to allow recovery of normal hemoglobin levels before surgical management, minimizing the need for transfusion or allowing autologous blood donation

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• Treatment of women approaching menopause in an effort to avoid surgery

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• Preoperative treatment of large leiomyomas to make vaginal hysterectomy, hysteroscopic resection or ablation, or laparoscopic destruction more feasible

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• Treatment of women with medical contraindications to surgery

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• Treatment of women with personal or medical indications for delaying surgery

The prevalence of leiomyosarcomas discovered incidentally (1:2,000) and mortality rate for hysterectomy for benign disease (1.0-1.6 per 1,000 for premenopausal).

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Reiter RC et al, 1992

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Judicious patient observation and follow-up are indicated primarily for uterine leiomyomas; intervention is reserved for specific indications and symptoms.

Uterine Artery Embolization

• Following the procedure the fibroids shrunk by 39-60%.
• Complications

Endometritis

Tubo-ovarian abscess

Necrobiosis

Vaginal expulsion of submucous myoma

Amenorrhea

Death

• Recurrent Rate – 20% in 5 years
• Operation – 10% in 1 year.

Future Investigation in Treatment of Uterine Leiomyomata

• Cryomyolysis
• Laser-induced interstitial thermotherapy (LITT)

(Magnetic-resonance-guided percutaneous laser ablation)

• Mifepristone (RU-486)
• Pirfemidone (inhibits leiomyoma cell proliferation and collagen production)
• Interferone-alpha (inhibitor of basic fibroblast growth factor-stimulated cell proliferation)
• Chinese herbal medicines (Keishi-bukuryogan and Shakuyaku-kenzo-to)
• Pharmacological agents that counteract angiogenic factors
• Gene therapy
• Laparoscopic occlusion of uterine vessels
• Asoprisnil

Low-Dose Mifepristone for Uterine Leiomyomata�(5 mg and 10 mg)

Mean uterine volume shrank by 48% in the 5 mg group and 49% in the 10 mg group. Amenorrhea occurred in 60-65% of both groups. The incidence of hot flushes increased significantly over baseline in the 10 mg group but not in the 5 mg group. Simple hyperplasia occurred in 28% of all groups; with no difference between groups.

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Eisinger SH et al, Obstet Gynecol 2003

ENDOMETRIAL HYPERPLASIA

Hysteroscopy – Not satisfactory for screening test

• Studies of the efficacy of hysteroscopy as a diagnostic tool vary widely
• Sensitivity reported ranging from 60-95% compared to D&C obtained at the same time
• Specificity 50-99%

Normal Endometrium

Endometrial Polyp

Polyp and Atypical Hyperplasia

Focal Simple Hyperplasia

Grade 3 Endometrial cancer

Hysteroscopy and Positive Cytology?

• Studies have been mixed:
• Some studies suggest an increase in positive peritoneal cytology seen at staging laparotomy in patients who have had hysteroscopy
• Other studies have failed to find a difference in positive cytology in patients diagnosed via hysteroscopy as compared to office biopsy or D&C

Positive Studies:

Bradley WH, Boente MP, Brooker, D, et al.: Hysteroscopy and Cytology in Endometrial Cancer. Obstet Gynecol 2004;104:1030-3

Zerbe M, Zhang J, Bristow RE, et al.: Retrograde seeding of malignant cells during hysteroscopy in presumed early endometrial cancer. Gynecol Oncol 2000;79:55-8

Obermair A, Geramou M, Gucer F, et al.: Does hysteroscopy facilitate tumor cell dissemination. Cancer 2000;88:139-43

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Increase in positive cytology from ~2-3% to ~10%

(RR 3-4)

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Negative Studies:

Gu M, Shi W, Huang J, et al.: Association between initial diagnostic procedure and hysteroscopy and abnormal peritoneal wahisngs in patients with endometrial carcinoma. Cancer 2000;90:3:143-7

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Selvaggi L Cormio G, Ceci O, et al.: Hysteroscopy does not increase the risk of microscopic extrauterine spread in endometrial carcinoma. Int J Gynecol Cancer 2003;13:223-7

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Hysteroscopy – Not satisfactory

• Too much cost and risk to be used as a screening test.
• Useful for evaluation of abnormal uterine bleeding where office biopsy is unrevealing.
• Use in conjunction with uterine curettage
• Useful to see and resect polyps and small submucous fibroids
• Useful to perform directed biopsy of small lesions.

Endometrial Cancer:�Who Needs an Endometrial Biopsy?

• Postmenopausal bleeding
• Perimenopausal intermenstrual bleeding
• Abnormal bleeding with history of anovulation
• Postmenopausal women with endometrial cells on Pap
• Thickened endometrial stripe via sonography

Sampling of the Endometrium

• Office biopsy procedures (Pipelle, Vabra aspirator, Karman cannula) will agree with a D&C performed in the OR ~95% of the time
• Office biopsy has a 16% false negative rate when the lesion is in a polyp or the cancer covers less than 50% of the endometrium
• Guido et al. J Reprod Med. 1995;40:553
• Patients with persistent PMB after negative office biopsy should have D&C (+/- hysteroscopy)
• D&C is the gold standard sampling method
• preoperative D&C will agree with diagnosis at hysterectomy 94% of the time

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Endometrial cyclic changes�Proliferative phase

Endometrial cyclic changes�Proliferative phase

Endometrial cyclic changes�Early secretory

Endometrial cyclic changes�mid-secretory

Endometrium: Post-menopausal atrophy

Endometrial Simple Hyperlasia

Endometrial Hyperlasia - Complex

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Endometrial Hyperplasia - Atypical

Endometrial Atypical Hyperplasia

Endometrial Hyperplasia Classification and Risk of Progression to Cancer:

Combined No Atypia (n=122) 1.6%

Combined with Atypia (n=48) 23% (P=0.001)

Mean age at study entry= 40y/o Mean study F/U=13.4yrs

Treatment for Endometrial Hyperplasia without atypia:

• Progestin therapy continuous or cyclical
• Childbearing age:
• Progestin dominant OCPs or
• Depo-Provera 150mg IM q3 months or
• Provera 10mg po 10 days/month and
• May follow with ovulation induction after normal biopsy if pregnancy desired
• Peri or Postmenopausal:
• Provera 20mg po 10 days/month or
• Depo-Provera 200mg IM q2 months
• Repeat biopsy in 3-4 months

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Treatment for Atypical Endometrial Hyperplasia:

• 23% risk of progression to carcinoma (over 10 years) if untreated.
• Standard treatment when childbearing is complete is total hysterectomy (abdominal or vaginal)
• Frozen section to rule out carcinoma (up to 20% have coexisting endometrial cancer)

Treatment for Atypical Endometrial Hyperplasia:

• Conservative medical therapy can be attempted in younger patients who request preservation of fertility.
• D&C prior to initiation of medical therapy to rule out carcinoma
• Megace 40-80mg/day, Norethindrone acetate 5mg/day
• Conservative therapy may also be attempted in young patients with early, well differentiated endometrial carcinomas.
• Megace 120-200mg/day, Norethindrone acetate 5-10mg/day

Conservative/Medical Therapy:

• Objective
• Determine efficacy of conservative treatment of AH/ECA in patients <40 yrs. of age
• Methods
• Retrospective Study of pathology records of women age < 40 diagnosed with AH or ECA at Johns Hopkins Jan/90 - Jan/96

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Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol. 1997 Sep;90(3):434-40.

Conservative/Medical Therapy:

• Results
• Among 29 pts treated with progestins

16/17 (94%) w/ AH regressed

9/12 (75%) w/ ECA regressed

• Median length of treatment required for regression was 9 months.

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T.C.Randall, R.J.Kurman.

Obstet Gynecol 1997;90:434-440

Conservative/Medical Therapy:

• Results
• At a mean f/u of 40 mos all pts were alive w/o evidence of progressive dz.
• 5 of 25 women attempting pregnancies delivered healthy full term infants.

T.C.Randall, R.J.Kurman.

Obstet Gynecol 1997;90:434-440

Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Montz FJ. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women. Report of seven cases and review of the literature. Cancer. 1997 Jan 15;79(2):320-7.

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• 13 of 20 patients (62%) with well differentiated endometrial carcinoma regressed with progestins (3 later recurred).

Conservative/Medical Therapy:

Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N, Koupolovic J, Ben-Baruch G. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol. 2003 Oct;102(4):718-25.

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• 13 of 13 patients regressed with progestin therapy, 6 later recurred

• Conclusion
• Treatment of AH/ECA with progestins appears to be a safe alternative to hysterectomy in women < 40 yrs of age in whom fertility is desired.
• Perform hysterectomy after childbearing is completed.

Conservative/Medical Therapy:

Endometriosis

Endometriosis - pathologic process the occurrence of endometrial tissue in ectopic places.

Epidemiology

• The 3rd place in the structure of gynaecological pathology occupies.
• Frequency according to different authors - 7-59% in the women of reproductive age.
• In the last decade is noted the growth of the frequency of disease from 12% to 27% from all operated gynaecological patients.

Factors of the risk:

• Hereditary predisposition (43.5%).
• Reproductive age.
• Disturbance of menstrual function.
• Absence of labor or one labor in anamnesis.
• Frequent abortions and the diagnostic scraping out of uterine.
• Prolonged use of intrauterine contraceptives.
• Retrograde wave of the reduction of womb from the neck to the bottom during the menses
• Anovulation

Etiological theory:

• Embryonic.
• Metaplastic (metaplasia of the coelomic epithelium from which Mullerian system developed).
• Implantation (regurgitate through the tubes and become implanted).
• Iatrogenic dissemination.
• Lymphogenic/hematogenic..
• Genetic.
• Hormonal.
• Immune.

Classification:

1. Extra genital (bowels, perineum, nose, navel, postoperative scar, etc)
2. Genital:
3. Internal (adenomyosis). is the infiltration of myometrium by ectopic deposits of endometrium
4. External:
• cervix
• vagina
• perinea
• Retro-cervical region
• ovaries.
• Uterine pipes.
• Peritonea.

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Классификация Американского общества фертильности (r-AFS):

Classification of adenomyosis:

• The stage of the I - pathologic process is limited uterine submucous.
• The stage II - pathologic process passes to the muscular layers.
• The stage III - propagation of pathologic process to the serous cover.
• The stage IV - involvement in the pathologic process of parietal peritoneum and adjacent organs.

Classification endometriosis of the ovaries:

• Stage I - small point of endometriosis formations on the surface of ovaries, the peritoneum of recto - uterine deepening without the formation of cystic cavities.
• Stage II - the endometriosis cyst of one ovary is not more than 5-6 cm, presence of small endometriosis starts on the peritoneum. Insignificant soldering joint process in the region of the adnexa.
• Stage III - endometriosis cysts of both ovaries (more than 5-6 cm of one and small of another). Endometriosis heterotopias of small sizes on the serous cover of womb, uterine pipes and on the parietal peritoneum of small basin. Expressed soldering joint process in the region of adnexa with the involvement of bowels.
• Stage IV - bilateral endometriosis cysts of both ovaries by size is more than 6 cm, the passage of pathologic process to the adjacent organs (the bladder, sigmoid and rectum).

Endometriosis of the ovaries:

Classification of retro-cervical endometriosis:

• The stage I – endometriosis centers are located in the limits of recto-vaginal cellulose tissue.
• The stage II - germination of endometriosis into the cervix and the wall of sheath with the formation of small cysts.
• The stage III - propagation of pathologic process to the sacral- uterine bonds and the serous cover of rectum.
• The stage IV - involvement in the pathologic process the mucous membrane of rectum, the propagation of process to the peritoneum of recto-uterine space with the formation of soldering joint process in the region of the adnexa.

Clinic picture

• The painful syndrome - pulling pains in below abdomen, lumbar- sacral region, which are amplified on the eve of and during the menses, they sometimes have a picture of sharp stomachache; pain in the spin.
• The disturbance of menstrual cycle - gyperpolimenorrea,
• Dispareunia
• Infertility.
• Meteorism.
• Dysuria.

Diagnostics:

1. complaints.
2. anamnesis.
3. General and gynecological examination.
4. Instrumental examination:
1. USE.
2. Hystero-salpingography.
3. hysteroscopy.
4. Laparoscopy (диагноз окончательно выставляется на основания данных лапароскопии).
5. Laboratory examination.
1. CA-125, CA-15-3.

Treatment:

1. Conservative:
1. Nonmedicamental.
2. Medicines:
• Progestegeny: medroksiprogesterona acetate, noretinodrel, noretisteron, retroprogesteron,
• Antigonadotropic medicines: danazol.
• Anti-gestagen: mefepriston, gestrinon.
• Agonist of gonadoliberinov: diferelin, goserelin, buserelin, gitorelin.

2. Оперативное:

3. Laparoscopy – gold standard.
4. Transabdominal method.

(volume of interference it is determined by the nature of pathology).