PonJola Coney
History of present illness
A 39-year-old gravida 0 woman is seen who is anxious because her menses have gotten“much heavier”and she is worried. Up until six months ago her cycles were monthly, lastingfive to six days and requiring four tofive sanitary pad changes per day.
However, over the last six months her cycles now last seven to nine days and seem twice as heavy, requiring nine to ten pad changes per day, and often with golf ball-sized clots noted. She also reports several episodes of light bleeding between cycles.
She is unmarried, not sexually active, uses no contraception, but is very anxious to maintain fertility and is thinking about
“freezing her eggs.”
Her medical history is notable for obesity and her only surgical history is a repair of a diaphragmatic hernia as a neonate. She reports menarche at age eight, and denies any sexually transmitted infections, abnormal cervical screens, or vasomotor symptoms. She is on no medications other than a multivitamin. She is employed as a pharmacy technician and does not smoke or drink alcohol. She has no known family history of cancers.
Physical examination
General appearance: A pleasant, anxious-appearing woman Vital signs:
All within normal limits BMI: 42 kg/m2
HEENT: Normal
Neck: Normal thyroid exam Chest: Clear bilaterally
Cardiac: Regular rate and rhythm
Abdomen: Obese. No masses or tenderness appreciated.
Surgical scars noted
Pelvic: Revealed normal external genitalia, normal vagina, and a nulliparous cervix. The bimanual examination was limited due to the patient’s habitus. No obvious
abnormalities were appreciated Laboratory studies:
Hb: 10.7 g/dL (normal 14–18 g/dL) Ht: 31.3% (normal 36–48%) Urine pregnancy test: Negative
Imaging: Pelvic ultrasound was performed. Endovaginal ultrasound of the pelvis showed an anteverted uterus with normal shape and contour measuring 6.9 × 5.5 cm, and an endometrial stripe measuring 2.2 cm
How would you manage this patient?
Office endometrial sampling was obtained to aid in diagnosing the etiology of the patient’s abnormal uterine bleeding with associated anemia. Pathology was consistent with complex hyperplasia with atypia (Figs 63.1and63.2).
Due to the patient’s strong desire for childbearing, she was started on medroxyprogesterone acetate (MPA) 30 mg daily for the next 6 months. A follow-up dilation and curettage done in the operating room after her six months of treatment revealed benign endometrial tissue only. She is currently con- sidering her fertility options and consulting a Reproductive Endocrine and Infertility specialist.
Endometrial hyperplasia
The most common presenting symptom of endometrial abnormalities is abnormal uterine bleeding and, specifically, endometrial hyperplasia is an entity preceded by abnormal uterine bleeding more than 80% of the time. Bleeding irregularities identified in the clinical history often prompt endometrial assessment with tissue sampling for histology (an endometrial biopsy), as was the case in this patient.
Hyperplasia is a microscopic diagnosis found when endometrial tissue reveals an increased proliferation (or overgrowth) of cells which can then result in a greater
A
B
B
Fig. 63.1 Benign, small endometrial glands [A] adjacent to [B] crowded glands with complex contours. 100× H&E. (Courtesy of Department of Pathology, Medical College of Virginia Hospitals.)
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
gland-to-stroma ratio than what is observed in the normal endometrium (Fig. 63.1). Microscopically, cells may initially resemble normal cells but are increased per unit volume.
Nuclear atypia indicates the presence of nuclear enlargement and poses a higher cumulative risk of developing endometrial carcinoma. Women with conditions of prolonged unopposed estrogen stimulation, nulliparity, a BMI greater than 30 kg/m2, and irregular menstruation are at greater risk for developing hyperplasia [1,2,3].
There are currently two recommended diagnostic classifica- tions for endometrial hyperplasia: (1) The revised 1994 World Health Organization (WHO) hyperplasia system, and (2) the Endometrial Intraepithelial Neoplasia (EIN) Classification System. The WHO hyperplasia system is based on morphologic features of architectural complexity and nuclear atypia. This system recognizes cytological atypia as the defining feature for distinguishing genuine simple and complex endometrial hyperplasias from those that have higher potential to be precancerous – simple and complex atypical endometrial hyperplasias. Simple hyperplasia refers to diffuse and variably sized glands with a normal ratio of glands to stroma. Complex hyperplasia consists of architecturally irregular glands, and an increased gland-to-stroma ratio. When nuclear enlargement with evenly dispersed or clumped chromatin is present, atypical hyperplasia (simple or complex) is diagnosed.
The EIN classification system was proposed in 2000 to develop pathologic criteria for the categories of benign, pre- malignant, and malignant disease in an effort to predict clinical outcomes of endometrial hyperplasia. Benign “endometrial hyperplasia” (EH) replaces simple and complex hyperplasia while“endometrial intraepithelial neoplasia”(EIN) represents the immediate precursor of endometrioid adenocarcinoma with a 45-fold increased cancer risk. The foundation of this system is its reproducibility and its ability to detect precursors
for disease progression to carcinoma more accurately than the WHO system; however, to date, the WHO classification remains more widely used. Both classification systems attempt to capture the differences in severity across the spectrum of endometrial hyperplasia [2,3] and in both, atypia remains the defining feature in differentiating precancerous from purely hyperplastic lesions.
While solid data representing the clinical course of endo- metrial hyperplasia is lacking, endometrial hyperplasia with atypia poses a real risk of progression to carcinoma. The long-term risk of women developing cancer when diagnosed with hyperplasia (without atypia) is less than 5%, but the risk among women with atypical hyperplasia approaches 30%. The presence of atypical cells is understood to increase the risk of progressing to cancer, but there is generally poor reproduci- bility in histologic assessments by pathologists and no biomarkers have been identified to aid in this process. The often incomplete sampling of the entire uterine cavity further compromises diagnostic abilities when office techniques of endometrial sampling are incorporated. While the incidence of endometrial hyperplasia is most common in postmenopau- sal women, the risk for women aged 35–44 is 6.2% and thus, incorporates the reproductive years [1,2,3,4].
Treatment protocols for hyperplasias have not been standardized, but nonsurgical management with progestin therapy (as opposed to hysterectomy) remains appropriate in hyperplasias without atypia given the overall low risk of progression to carcinoma, particularly in the patient who desires fertility preservation. There are no randomized con- trolled trials and therefore no standard hormonal doses or regimens have been developed. Published results to date have investigated continuous treatment with MPA (10–30 mg/
day), megestrol (100–320 mg/day), or cyclic administration with norethisterone (NET) (15 mg/day for 10 days/month).
Higher doses (up to 600 mg/day) may be used in cases with atypia present and even in early endometrial carcinoma. The levonorgestrel-releasing intrauterine device (LNG-IUD), (Mirena®) holds great promise as it releases a daily local uterine dose of 20μg of levonorgestrel, but randomized controlled trials are lacking to determine whether the LNG- IUD is safe and effective for treating atypical endometrial hyperplasia. Side effects of these regimens are generally well tolerated, but may include irregular vaginal bleeding, mood changes, headaches, edema, weight gain, or more concerning thromboembolic events [5,6,7].
Published studies show regression outcomes up to 90% for oral treatment and up to 92% for the LNG-IUD for simple and complex or benign hyperplasia. The progesterone concentra- tions in the uterine mucosa when delivered through an intra- uterine device placed directly into the uterine cavity are reported to exceed that of the oral treatment and are associated with higher patient satisfaction resulting in greater patient compliance. Treatment regimens are generally continued for a minimum of 3 months up to 24 months, and repeated for failures or recurrences [5,6,7]. Endometrial sampling is generally repeated following medical therapy. The choice of
Fig.63.2 Complex atypical endometrial hypoplasia. The endometrium shows significant cytologic atypia (large nuclei, vesicular chromatin, prominent nucleoli) within the crowded glands. 200× H&E. (Courtesy of Department of Pathology, Medical College of Virginia Hospitals.)
Case 63: Irregular bleeding in a 39-year-old nulliparous woman desiring fertility
sampling technique (office procedures vs. operative) tends to represent the preference and experience of the physician.
In a large retrospective study, women were followed for a minimum offive years after their initial successful progestin treatment demonstrated regression, to the time of future relapse. Relapse rates for simple/complex hyperplasia versus atypical hyperplasia were 28% and 50% respectively [8].
Relapse rates for women treated with LNG-IUD for simple/
complex hyperplasia versus atypical hyperplasia were 13% and 27% respectively. Relapses also occurred sooner with oral therapy than with intrauterine therapy, but the treatment interval is generally shorter for oral therapy [8]. From a prac- tical standpoint, atypical hyperplasia poses a higher chance of relapse versus simple/complex hyperplasia (without atypia), and future clinical surveillance and management options should be mindful of this when caring for the patient who desires fertility preservation.
Infertility treatment, particularly the use of ovulation induction drugs and assisted reproduction following conserva- tive progestin treatment of endometrial hyperplasias, has not been shown to increase the risk of recurrence of the disease.
Furthermore, a resulting pregnancy seems to have an advanta- geous effect on patient outcomes [9,10]. In one retrospective study of 36 patients who received conservative treatment for endometrial cancer or atypical complex endometrial hyperpla- sia, 26 went on to receive infertility treatment. Eighteen of these patients (69%) conceived and 16 of these patients went on to deliver healthy babies. Three of the 16 women who delivered babies experienced a recurrence, while 7 women who did not accomplish pregnancy experienced a recurrence.
In addition, 7 (70%) of the 10 women who did not undergo any infertility treatments experienced recurrence. Overall, while the data is limited by small numbers, 38.5% of women who underwent infertility therapy had a recurrence of their endometrial pathology versus 70% of women who had a recur- rence despite not pursuing infertility treatments. The time to
recurrence was not significantly different among the groups, averaging 13–23 months [10].
Considering the gap in knowledge that remains regarding the risks of progression for any endometrial hyperplasia diag- nosis, the decision to choose conservative hormonal manage- ment rests with the physician and patient after a review of both risks and benefits. The objective of conservative hormonal management is to induce endometrial regression and avoid hysterectomy. Endometrial hyperplasia when treated in a timely fashion allows for future fertility options in women who may desire such, as was the case in this patient.
Key teaching points
Endometrial hyperplasia is preceded by abnormal uterine bleeding in more than 80% of the time.
Two classification systems (World Health Organization [WHO] and Endometrial Intraepithelial Neoplasia [EIN]) exist for classifying endometrial hyperplasia. The presence of atypia is the defining feature in differentiating lesions more likely to be precancerous.
Conservative management using progestin for endometrial hyperplasia is a valid management option to preserve fertility, but requires close follow-up surveillance.
Pregnancy is feasible after medical management of endometrial hyperplasia with good outcomes noted in small studies. Limited existing data suggests that ovarian stimulation or ovulation induction and assisted
reproductive techniques do not increase the overall risk of recurrence of hyperplasia.
Considering our current knowledge gaps regarding predicting the risk of progression to cancer, as well as difficulties with histologic reproducibility for any hyperplasia diagnosis, choosing conservative treatment with hormonal management rests with the physician and patient after appropriate counseling.
References
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Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia.
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5. Ozdegirmenci O, Kayikcioglu F, Bozkurt U et al. Comparison of the efficacy of three progestins in the treatment of simple endometrial hyperplasia without atypia.Gynecol Obstet Invest2011;72:10–14.
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