Diagnostic management of post menopausal bleeding

Introduction

Abnormal uterine bleeding accounts for a significant number of gynecological referrals. The diagnostic approach depends essentially on the age – group of the patient. In most premenopausal women the cause of the abnormal bleeding is dysfunctional wherein pregnancy related complications, local abnormalities of the uterus, like fibroids and polyps, and systemic causes have been ruled out. Dysfunctional uterine bleeding is thus a diagnosis of exclusion, most commonly caused by anovulation and the diagnostic approach is geared towards finding out the cause of anovulation.


Postmenopausal bleeding (PMB) is bleeding after 1 full year without a period. The exact incidence is not known but is estimated to be around 13/1000 women at the age of 50 years to 1-2/1000 women at 80 years of age. In contrast, the risk of endometrial cancer in women with PMB rises from about 1% at 50 years to 25% at age 80. (1) Although endometrial cancer is not the most common cause of PMB, all diagnostic strategies are planned towards ruling out endometrial malignancy and other important pathological causes.

Pathology

Even though the reported risk of endometrial cancer in women with postmenopausal bleeding ranges between 1.5-28% (average 11%), and the chance of having a benign cause for the PMB as high as 70-80%, it cannot be overemphasized that all PMB should be considered to be caused by cancer unless proven otherwise. (Table 1)

table1

Polyps are much more common than cancer. More than 60% of them are symptomatic although the symptomatology is not related to the number, diameter and site of the polyps. Their importance lies in the fact that they can be removed very simply and easily at the same time as the diagnostic hysteroscopy, which is very reassuring and cures the patient of postmenopausal bleeding. (5)
Postmenopausal bleeding is also associated with other non-endometrial cancers of which the most common is cervical cancer (0.8-13%), average 5.7%, as well as small but significant risk of having ovarian (1.2%), breast or colorectal cancers (0.8%). (1,3)

Diagnostic Workup

The most important step to begin with is a thorough history and examination. One needs to rule out bleeding from the urinary and the gastrointestinal tract, which can often confuse the older patient. It is also important to look for factors that are associated with an increased risk of endometrial cancer like nulliparity, diabetes mellitus, use of unopposed estrogen. (Table 2)

table2

This meta analysis of 881 women from 3 studies suggests that the risk of endometrial cancer increases with age and the number of risk factors present. The risk was calculated as high as 87% in nulliparous, diabetic women over the age of 70 years compared to only 2.6% if none of these risk factors were present.

Cervical Assessment

It is recommended that all patients of PMB should have a Pap smear irrespective of when it was done last. About 30% of endometrial cancers can be picked up on cervical cytology. Furthermore, there is considerable risk of cervical cancer. Since Pap smear can miss significant cervical cancer, any further suspicion like post coital bleeding will warrant a colposcopic examination.

Dilatation and curettage (D&C)

A D&C is now no longer considered as the gold standard in the investigation of postmenopausal bleeding. Its use still has been condemned severely for many reasons. Since it is a blind procedure, less than half of the cavity is sampled in 60% of the cases. (7) Consequently, neoplasia is most likely to be missed with disastrous consequences both for the patient as well as the treating physician. Even when compared to outpatient sampling with Pipelle curette, D&C provided satisfactory sample in only 45.8% cases as against 84.1% with Pipelle. (8) A recent study showed that as the pathology gets worse, D&C tends to underdiagnose. 50% of patients with hyperplasia without atypia had complex atypical hyperplasia and 2/3 of patients diagnosed as complex atypical hyperplasia at initial D&C actually had endometrial cancer. (9) Even when a correct diagnosis of endometrial cancer was made, the pathology was found to be incorrect at subsequent hysterectomy. D&C could correctly diagnose only 91.6% of adenocarcinomas, 30.7% of adenoacanthomas and 37.5% of adenosquamous carcinomas.
Further, D&C is not a benign procedure. There is significant risk of perforation, haemorrhage and infection. In a meta-analysis of 12598 procedures, Grimes et al reported that perforation itself led on to unplanned major surgery -laparotomy/hysterectomy in 0.3-5/1000 patients. (10) “With modern techniques of assessing the endometrium, there is no longer a place for D&C in the management of women with postmenopausal bleeding.”

Outpatient endometrial sampling

Of the many such techniques available e.g. Vabra, Novak, Z-sampler, Permacurette, Mi-Mark Helix and Endopap, the Pipelle sampler is probably the most well tolerated. The sensitivity for detecting endometrial carcinoma ranges between 68-98% and is similar to all these devices. However, it samples only about 4.2% of the endometrial surface and if the endometrial thickness (ET) is <5 mm, the sample is likely to be inadequate in >70% cases. (11)
Many no longer consider any form of endometrial sampling without visualization of the uterine cavity as appropriate investigation for postmenopausal bleeding.

Hysteroscopy and directed biopsy

Hysteroscopy with biopsy allows direct visualization of the endometrial cavity and is now considered as the ‘Gold Standard’ for endometrial assessment. (12) Focal abnormalities are as high as 70% and likely to be missed on D&C but not on hysteroscopy. Moreover, hysteroscopy allows the endocervix to be visualized directly too and the spread of endometrial cancer to be seen thus influencing management. More uterine abnormalities are diagnosed and endometrial cancer less likely to be missed when hysteroscopy is done prior to curettage. However, hysteroscopy alone, without biopsy is unreliable in differentiating between pre-malignant and malignant lesions. (13)
The incidence of perforation and other complications range between 1-13/1000 operative hysteroscopies but are significantly lower for diagnostic hysteroscopy and the procedure is generally considered safe.
The main concern has been the possibility of neoplastic implantation into the pelvic cavity caused by hysteroscopy. Several studies in this regard are available which suggest that this risk is not common and that curettage could also be associated with this phenomenon. One study also reported that the incidence of tumour cells in the pelvic cavity was no different in those who underwent hysteroscopy and those without. (14) The risks of iatrogenic neoplastic implantation are therefore overstated. The rare occurrence of a tumour cell in the peritoneal cavity must be considered less dangerous than missing a case of endometrial cancer, although it seems advisable to perform endometrial sampling after hysteroscopy.

Ultrasound

Measurement of the endometrial thickness by transvaginal ultrasound (TVS) may have a role to play in screening for uterine cancer in women with PMB. Many authors have reported sensitivity of TVS for endometrial carcinoma to be 80-100% although one author pointed out that 3 of 15 malignant tumours were missed! (15) Important questions in this regard are the type of measurement and the cut-off level. The best evidence suggests that full double thickness measurements which include the contents of the cavity should be made using the transvaginal probe. Normal endometrial thickness varies between different ethnic groups. Therefore cut-off limits should be established at local level. Most studies, however, have used 4mm or 5 mm cut-off levels beyond which further endometrial sampling by hysteroscopy and biopsy are recommended. 96% of patients with endometrial cancer had an endometrial stripe > 5 mm. (16) Larger measurements are expected to increase sensitivity for benign pathology at the expense of specificity. Sensitivity of such measurements would also be operator dependent. 40-50% of all endometrial carcinomas develop in a hormone-independent manner from atrophic endometrium and can be focal rather than diffuse. These, as well as benign pathology like polyps, can be easily missed when inexperienced sonographers fail to visualize the whole endometrium especially in a retroverted uterus.
The advantage, however, of using TVS as a screening tool is that other local and adnexal pathology like ovarian tumours can be picked up. The downside of this is that many postmenopausal women would have unnecessary operative intervention for benign adnexal disease.
The sensitivity of detecting benign polyps by TVS (33.3%) can be improved by saline infusion sonohysterography (75%). (17) The same group found a sensitivity of 100% for hysteroscopy. Sonohysterography has the disadvantage that it is an invasive procedure, requires expertise both in performance as well as interpretation and will need additional hysteroscopy to deal with polyps or any local pathology found on examination.
An attempt to enhance sensitivity and specificity of TVS by adding Doppler blood flow studies was not very satisfactory. TVS measurements of endometrial thickness were a better discriminator between benign and malignant endometrium than any Doppler variable. More experience was associated with better intraobserver and interobserver agreement. (18)

Recommendations

    • Even though endometrial cancer is not a common cause of postmenopausal bleeding, all diagnostic strategies are geared to rule it out.
    • Transvaginal ultrasound can be used as a screening method in women with postmenopausal bleeding.
    • Endometrial thickness equal or more than 4 mm on TVS warrants endometrial sampling. (19)
    • The International Society of Gynecologic Endoscopy currently recommends hysteroscopy followed by endometrial biopsy as the ‘gold standard’. Dilatation and curettage is an outmoded procedure and is mentioned only to condemn its use in the investigation of PMB.
    • Hysteroscopic view of atrophic endometrium, which is the commonest cause of PMB, is diagnostic even if the curetted sample is ‘insufficient for analysis’.
    • Ultrasound and hysteroscopy should always precede biopsy so as not to distort the findings.
    • Little is gained from biopsy if endometrium < 4 mm since chance of malignancy rare and sample adequate in only 27% cases. (11)
    • However, those patients of PMB with thin endometrium echo complex < 4 mm in presence of other ultrasound abnormalities (e.g. presence of intracavitary fluid or lesion, myometrial mass, large uterine size and adnexal mass) should undergo diagnostic hysteroscopy and directed biopsy. (20)
    • The Canadian Society of Gynecologists and Obstetricians in their policy statement have recommended that those patients with high risk factors for endometrial cancer like nulliparity, diabetes, age more than 70 years should also undergo hysteroscopy and biopsy even with thin endometrium on ultrasound because negative sonographic findings cannot be completely reassuring.
    • Patients with recurrent or persistent bleeding after initial investigations should have repeat investigations since even hysteroscopy can miss pre-malignant endometrial hyperplasia.

References

        1. Gredmark t, Kvint S, Havel G, Mattsson LA. Histopathological findings in women with postmenopausal bleeding. Br J Obstet Gynecol 1995;102:133-136
        2. Choo YC, Mak KC, Hsu C, Wong Ts, Ma HK. Postmenopausal uterine bleeding of non-organic cause. Obstet Gynaecol 1985;66:225-228
        3. Alberico S, Conoscenti G, Veglio P, Bogatti P. A clinical and epidemiological study of 245 postmenopausal metorrhagia patients.Clin Exp Obstet Gynaecol 1989;4:113-121
        4. Nasri MN, Coast GJ. Correlation of ultrasound findings and endometrial histopathology in postmenopausal women.Br J Obstet Gynaecol1989;96:1333-1338
        5. Hassa H, Tekin B, Senses T, Kaya M. Are the site, diameter, and number of endometrial polyps related to symptomatology? Am J Obstet Gynecol 2006;194(3):718-721
        6. Feldman S, Cook EF, Harlow BL, Berkowitz RS. Predicting endometrial cancer among older women who present with abnormal vaginal bleeding. Gynecol Oncol 1995;56:376-381
        7. Stock RJ, Kanbour A. Pre-hysterectomy curettage. Obstet Gynecol 1975;45:537
        8. Ben-Baruch G, Seidman DS, Schiff E, Moran O. Outpatient endometrial sampling with the Pipelle curette. Gynecol Obstet Invest 1994;37:260-262
        9. Saygili H. Histopathological correlation of dilatation and curettage and hysterectomy specimens in patients with postmenopausal bleeding. Eur J Gynaecol Oncol 2006;27(2):182-184
        10. Grimes DA. Diagnostic dilatation and curettage: a re-appraisal. Am J ObstetGynecol 1982;142:1-6
        11. ElsandabeseeD, Greenwood P. The performance of Pipelle endometrial sampling in a dedicated postmenopausal bleeding clinic. J Obstet Gynaecol 2005;25(1):32-34
        12. Lewis BW. Hysteroscopy for the investigation of abnormal uterine bleeding. Br J Obstet Gynaecol 1990; 97:24
        13. LoverroG, Bettocchi S, VicinoM. Diagnosis of endometrial hyperplasia in women with abnormal uterine bleeding. Acta Eur Fertil1994;25;23-25
        14. Tanizawa O, Miyake A, sugimoto K. Re-evaluation of hysteroscopy in the diagnosis of uterine endometrial cancer. Acta Obstet Gynaecol Jpn1991;43:622-626
        15. Dorum A, Kristensen B, Langebrekke A. Evaluation of endometrial thickness measured by endovaginal ultrasound in women with postmenopausal bleeding. Acta Obstet Gynaecol Scand 1993;72:116-119
        16. Smith-Bindman R, Kerlikowske K, Feldstein VA. Endovaginal ultrasonography to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;280:1510
        17. Valenzano MM, Lijoi D, Mistrangelo E. The value of sonohysterography in detecting intracavitary benign abnormalities. Arch Gynaecol Obstet 2005; 272(4):265-268
        18. Alcazar Jl, Ajossa S, Floris S. Reproducibility of endometrial vascular patterns in endometrial disease as assessed by transvaginal power Doppler sonography in women with postmenopausal bleeding. J Ultrasound Med 2006; 2592);159-163
        19. Spicer JM, Siebert I, Kruger TF. Postmenopausal bleeding: a diagnostic approach for both private and public sectors. Gynecol Obstet Invest 2006;61(3):174-178
        20. Wang J, Wieslander C, Hansen G, Cass I. Thin endometrial echo complex on ultrasound does not reliably exclude type 2 endometrial cancers. Gynecol Oncol 2006;101(1):120-125

 

Dr Nirja Chawla