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Endometrial Carcinoma-

Ultrasound Evaluation of the Endometrium

 

Markedly enlarged, thickened and inhomogeneous endometrium in a patient with endometrial carcinoma

Normal post-menstrual endometrium

Findings:

The scan on the left demonstrates a markedly enlarged, thickened and heterogeneous endometrium that proved to be endometrial carcinoma. Contrast this to the normal post-menstrual endometrium in the adjacent scan.

Discussion:

During the past decade ultrasound has played an increasing role in the evaluation of the endometrium in patients with infertility, pelvic pain and abnormal uterine bleeding. Previously, and still today, in many centers, invasive endometrial biopsy, curettage of the endometrium and hysteroscopy were and are the main methods of evaluation of these patients. While these techniques clearly have a role in the diagnostic armamentarium, they have been replaced by diagnostic ultrasound as the initial step in the investigation of the patient with abnormal uterine bleeding.

Prior to embarking upon a discussion of the techniques utilized in performing and interpreting the sonographic evaluation of the endometrium it is necessary to review the normal anatomy and physiology of the endometrium. Thanks to the early work of Fleischer et al, Forrest et al and Jones et al, we now have a better understanding of the sonographic appearances of the endometrium and uterus throughout the reproductive menstrual cycle. Much of this discussion is taken from these authors early work. The sonographic appearance of the endometrium will depend upon whether the patient is of reproductive age or post-menopausal and if of reproductive age, at what point in the menstrual cycle they are examined. The normal endometrium consists of two layers: the functional and basal layers. The uterine or endometrial cavity is the apposition of the inner aspects of the functional layers. At the junction of the basal layer and the myometrium, frequently a poorly echogenic layer is identified. This layer is inner myometrium containing a vascular network of capillaries and veins around the muscle fibers of the inner third of the myometrium. Thus at various times in the reproductive cycle one may identify the following structures: the myometrium, the "halo" of the inner myometrium, the basal endometrial layer, the functional endometrial layer and the reflection from the interface of the uterine cavity or inner functional layers.

The normal reproductive cycle consists of the menstrual, post-menstrual, proliferative and secretory phases. The basal layer, containing vessels that elongate to supply nutrients to the functional layer, remains relatively constant throughout the menstrual cycle. It is the functional layer which thickens in the first half of the cycle and will ultimately be shed during menstruation. In the post-menstrual and early proliferative phases the functional layer is thin between 1 and 4 mm and is homogeneous and poorly echogenic sonographically. The vessels and glands within this layer are straight and perpendicular to the endometrial basalis. At the proliferative phase of the menstrual cycle "three lines" may often be identified; the line representing the interface between the myometrium and basal layer (or the basal layer alone), the central uterine cavity reflection from the interface of the inner functional endometrium and the interface of the myometrium and basal layer on the opposite side of the uterine cavity. The separation of these lines and conspicuity will depend upon the thickness and echogenicity of the functional layer.

Proliferative endometrium. Three lines representing the basal endometrium (red arrows) and central endometrial cavity echo (yellow arrow)

Secretory endometrium demarcated between the two arrows. The basal endometrium is no longer seen.

With the transition from the proliferative to the secretory phase the endometrium will become more echogenic. In the periovulatory period the arteries supplying the functional layer become more tortuous. The glands in the functional layer lengthen, also become more tortuous and contain increasing amounts of mucous and glycogen. In addition to the above, interstitial fluid increases (stromal edema). The increased echogenicity in the secretory phase is thus a combination of increased reflectivity of the tortuous and elongated vessels and glands, interstitial fluid and glandular mucous and glycogen. The endometrium will be echogenic and become iso-echogenic with the basal layer, thus the three line will no longer be present. It is of interest that in the secretory phase there may be enhanced through-transmission of sound. This may in part be due to the increased interstitial fluid.

During the secretory phase the functional layer is echogenic and thick, approximately 4-6 mm. It should be remembered that secretory endometrium is thicker than early proliferative endometrium. There is little difference between late proliferative and mid-secretory endometrium. Thus while echogenicity may be a helpful discriminating factor in determining the menstrual phase in up to 80% of patients in some reports, the thickness has less utility in this regard. There has been some interest in identifying infertility patients with "luteal phase defects" using ultrasound. Probably the only useful sign would be absence a combination of the normal thickening and echogenicity seen in the secretory phase of the reproductive cycle.

The Sonographic Examination

The pivotal role of ultrasound in the evaluation of the endometrium is due to a combination of improvements in ultrasound image technology and the development and use of the endovaginal (transvaginal) ultrasound transducers. Virtually all examiners who evaluate the gynecologic patient should have the capability to perform transvaginal sonography. That having been said, it is the editor's belief that all patients should also be examined with the use of conventional transabdominal technique. Even with extended field of view transducers, adnexal or high-pelvic masses may be missed using only the transvaginal technique.

The patient is initially examined with a full urinary bladder allowing visualization of the the uterus in its entirety as well as the adnexa. Scans should be performed in both sagittal and transverse planes of section. The bladder should then be emptied and after preparation of the transvaginal transducer it should be inserted into the vaginal introitus. Sagittal or long axis views as well as semi-coronal or short axis views should be obtained. The two most common pitfalls in transvaginal imaging are:1) not having the urinary bladder completely emptied and 2) failure to adequately elevate the patient's pelvis from the underlying table. thus making angulation and manipulation of the transducer difficult. The endometrium should be measured in the long-axis or sagittal plane. The measurement is of the thickest echogenic area from one basal endometrial interface across the endometrial canal to the other basal endometrium. Care should be taken not to include the hypoechoic myometrium in this measurement.

Double (bi-layer) Measurement of the Endometrium

The measurement of the endometrium should be in a sagittal plane of section and should include only the echogenic endometrium on either side of the endometrial canal.

Endometrial Measurements and Pathology

Abnormal uterine bleeding, particularly in the post-menopausal patient, may be a relatively frequent reason for gynecologic visits and may be challenging to explain. The incidence of this complaint may increase with the increasing number of patients on hormonal replacement therapy. In a study by Whitehead et al as many as 24% of patients experienced irregular breakthrough bleeding for the initial 16 months. Another, equally common explanation for abnormal uterine bleeding in the post-menopausal patient is endometrial atrophy. The thin and atrophic post-menopausal endometrium is prone to superficial punctate ulceration and bleeding. Endometrial measurements of 2-3 mm may be seen in this group. Other explanations for abnormal uterine bleeding in the post-menopausal patient include endometrial hyperplasia, polyps and endometrial carcinoma. As ultrasound is often becoming the first line test in these patients, a frequently asked question is what findings or measurements are predictive of pathology, specifically endometrial carcinoma. Endometrial carcinoma is the fourth most common cancer in women and the most common gynecologic malignancy with approximately 37,000 new cases each year in the United States. It is felt to be increasing in incidence, possibly due to increased longevity as well as exogenous estrogen. 80% of cases occur in postmenopausal women, with bleeding as the initial symptom in 90% of cases. While explanations other than carcinoma are frequently found, it is this diagnosis that is most worrisome to clinicians.

Measurement of the endometrium in a patient in the secretory phase of the menstrual cycle. Only the echogenic endometrium is measured (line). The surrounding sonolucent halo (arrows) should not be included in the measurement.

In the pre-menopausal patient the endometrium should be evaluated in the immediate post-menstrual stage. It is at this time when the endometrium will be the thinnest. As was mentioned above, the late proliferative and secretory endometria are the thickest of the reproductive cycle. There is considerable debate as to the upper limits of the normal bilayer endometrium. Obviously, as in all medical tests one tries to reach a compromise between a test that will pick up all pathology, but have large numbers of false positive examinations and a test that has few false positive examinations and misses significant pathology. Virtually all examiners would agree that a bilayer endometrium that is 4 mm or less is unlikely to be associated with pathologic changes and will likely not yield satisfactory tissue at the time of biopsy. At the other end of the extreme an endometrium that measures more than 15 mm should be sampled for the possibility of carcinoma. Most reports of endometrial carcinoma have demonstrated an endometrium in excess of 20 mm. There have been a handful of reports of endometrial carcinoma in patients with endometria as thin as 4-5 mm. It is the editors practice that in the absence of clinical symptomatology eg bleeding an endometrium that is < 5 mm can be assumed to be normal. If the patient is on hormonal replacement therapy a measurement < 8 mm can also assumed to be normal if there is no symptomatology. In the presence of abnormal uterine bleeding measurements of 5-8 mm should prompt endometrial sampling, unless otherwise explained.

In a recent cost analysis of vaginal ultrasound and endometrial biopsy for postmenopausal bleeding Weber et al summarized nicely the literature statistics on the accuracy of ultrasound evaluation of the endometrium. They correctly remind us of two facts: there is still controversy as to the "best" cutoff value of endometrial thickness for the detection of endometrial cancer and that while the risk of endometrial cancer is low when the endometrial thickness is less than or equal to 4 mm; it is not zero. Their summary of the literature revealed that the false-negative rate for a threshold of less than or equal to 4 mm is 0.8% (this means that 6 of 763 women with postmenopausal bleeding and an endometrial thickness of less than or equal to 4 mm on transvaginal ultrasound had endometrial cancer). From the opposite perspective, as the endometrial thickness increases, the accuracy of a positive prediction for diagnosing endometrial cancer will increase from 6.6% at 5-10 mm to 62% when the endometrium is > than 20 mm.

A recent study by O'Connell et al evaluated the accuracy of the triage of postmenopausal patients with abnormal uterine bleeding using transvaginal sonography, sonohysterography, endometrial biopsy and surgical hysteroscopy. 100 patients participated in the study in which all three procedures wereperformed in each patient. The mean age for women in the study was 59.7 years. 72% of women in the study were taking either cyclic or continuous hormonal replacement therapy. The pathologic diagnoses included: submucosal fibroids (8), proliferative endometrium (23), polyp(33), hyperplasia (4), atrophy (31) and cancer (5). Benign findings (atrophic and proliferative changes) occurred in 52%. Women diagnosed with either endometrial cancer or atrophy were significantly older than the mean age of the study group. The mean endometrial stripe thickness for all women examined was 7.6 mm. Patients diagnosed with endometrial atrophy demonstrated a significantly thinner endometrium (4.4 mm) than the mean for al patients. Those diagnosed with either submucosal leiomyomas or adenocarcinoma had significantly thicker mean endometrial stripes. There were 9 patients in this study with an endometrial stripe thickness < 5 mm and significant endometrial pathology including: one patient with endometrial carcinoma (4.7 mm stripe), six patients with endometrial polyps and two with submucosal fibroids. The combination of endometrial biopsy and transvaginal sonohysterography had a 95% positive correlation with surgical pathologic findings. This combination had a sensitivity of 94%, specificity of 96%, positive predictive accuracy of 96% and negative predictive accuracy of 94%. There were only 5 patients in whom the sonographic report did not correlate with the surgical findings. This included one intramural myoma mistakenly interpreted for a submucosal myoma, two echogenic areas within the endometrium mistaken for small polyps and two small cornual polyps not seen at sonohysterography. (All 5 patients were in the early part of the study). A disproportionate number of false-positive and false-negative results were seen in the 8 patients taking tamoxifen. Neither endometrial biopsy (positive correlation of 64% and sensitivity of 23%) or endometrial stripe thickness (positive correlation of 64% and sensitivity of 79%), alone were very reliable tests. Sonohysterography alone had a high positive correlation of 92%. Lastly, the authors found that using a triage of endometrial biopsy followed by sonohysterography in these patients had a cost savings of $ 636 per patient.

As the absolute endometrial thickness may not always be the best discriminator for carcinoma, other sonographic observations have occasionally been helpful. Most patients with either a proliferative endometrium or endometrial hyperplasia will have an echogenic sonographic appearance. Carcinoma usually has an inhomogeneous appearance. Unfortunately, there can be considerable overlap between the appearance of benign and malignant lesions. Additionally, most endometrial lesions that are predominantly cystic will be benign, such as endometrial polyps. However, in a study by Atri et al, although cystic endometrial changes were present in the majority of patients with benign disease, cystic changes were also present in 24% of patients with endometrial malignancy.

Color Doppler imaging demonstrating tumoral and peritumoral flow in an endometrial carcinoma
Low resistance flow within an endometrial carcinoma

Several investigators have been interested in the utility of Doppler ultrasound to discriminate benign from malignant endometrial disease. In 90% of patients with either normal, atrophic or hyperplastic endometria no arterial blood flow was seen in a study by Kurjak et al. In 90% of endometrial carcinomas intratumoral or peritumoral blood flow was seen with a low mean resistive index in his study. While this appears promising, not all investigators have had similar experiences. Sheth et al found considerable overlap between blood velocities in benign and malignant lesions. Endometrial polyps were the most common cause of endometrial thickening in their series and 74% of them had prominent arterial flow with low-resistance, high diastolic velocity flow pattern that is commonly associated with malignancy.

Once the diagnosis of endometrial carcinoma is considered, staging is an important next step. Ultrasound may have a role in assessing the depth of invasion of the neoplasm. In addition to color Doppler imaging of tumor vascularity; sonographic evidence of myometrial invasion can be demonstrated. In those patients in whom the sonolucent "halo" surrounding the basal layer is interrupted, penetration of the carcinoma can be suggested.

Endometrial hyperplasia is a common cause of abnormal uterine bleeding and in some centers accounts for up to 20% of all presenting complaints in gynecologic patients. The diagnosis can only be definitively made pathologically and is seen in up to 10% of all diagnostic curettages. Endometrial hyperplasia represents a spectrum of endometrial changes ranging from cystically dilated glands to cellular atypia. While carcinoma can develop in these patients it is uncommon. It is felt that less than a third of patients with endometrial carcinomas are preceded by one of the types of endometrial hyperplasia. The cystic from of endometrial hyperplasia is the most common and benign form of endometrial hyperplasia. Sonographically, thickening of the endometrium, occasionally cystic, is the most common finding. Thickening can be non-specific, however.

In addition to the differential diagnostic possibilities mentioned above, one should also consider the diagnosis of a first trimester hydatidiform mole. Remember that in patients with an early molar pregnancy the predominant findings may be echogenic tissue with small cystic areas. This may simulate the appearance either of cystic hyperplasia or an endometrial polyp.

1st Trimester Hydatidiform Mole with echogenic tissue and multiple cystic spaces

References:

Bernard JP, Lecuru F, Darles C, Robin P et al. Saline contrast sonohysterography as first-line investigation for women with uterine bleeding. Ultrasound Obstet. Gynecol. 10:121-125, 1997

Holbert TR. Transvaginal ultrasonographic measurement of endometrial thickness in postmenopausal women receiving estrogen replacement therapy. Am J Obstet Gynecol 176:1334-9, 1997

Dubinsky TJ, Parvey HR, Maklad N. The role of transvaginal sonography and endometrial biopsy in the evaluation of peri-and postmenopausal bleeding. Amer J Roentgenol 169:145-149, 1997

Goldstein SR, Zeltser BS, Horan CK, Snyder JR, Schwartz LB. Ultrasonography-based triage for perimenopausal patients with abnormal uterine bleeding. Am J Obstet Gynecol 177:102-8, 1997

Laughead MK, Stones LM. Clinical utility of saline solution infusion sonohysterography in a primary care obstetric-gynecologic practice. Amer J Obstet Gynecol 176:1313-8, 1997

Lev-Toaff AS, Toaff ME, Liu JB, Merton DA, Goldberg BB. Value of sonohysterography in the diagnosis and management of abnormal uterine bleeding. Radiology 201:179-184, 1996

Teefey SA, Stahl JA, Middleton WD, Huettner PC et al. Local staging of endometrial carcinoma: Comparison of transvaginal and intraoperative sonography and gross visual inspection. Amer J Roentgenol 166:547-552, 1996

Dijkhuizen FPHLJ, Brolmann HAM, Potters AE, Bongers MY, Heintz APM. The accuracy of transvaginal ultrasonography in the diagnosis of endometrial abnormalities. Obstet Gynecol 87:345-9, 1996

Cullinan JA, Fleischer AC, Kepple DM, Arnold AL. Sonohysterography: A technique for endometrial evaluation. Radiographic 15:501-514, 1995

Levine D, Gosink BB, Johnson LA. Change in endometrial thickness in postmenopausal women undergoing hormone replacement therapy. Radiology 197:603-608, 1995

Sheth S, Hamper UM, McColum ME, Caskey CI, Rosenshein NB, Kurman RJ. Endometrial blood flow analysis in postmenopausal women: Can it help differentiate benign from malignant causes of endometrial thickening? Radiology 195:661-665, 1995

Karlsson B, Granberg S, Wikland M, Ylostalo P et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding- A Nordic multicenter study. Am J Obstet Gynecol 172:1488-94, 1995

Emanuel MH, Verdel MJ, Wamsteker K, Lammes FB. A prospective comparison of transvaginal ultrasonography and diagnostic hysteroscopy in the evaluation of patients with abnormal uterine bleeding: Clinical implications. Am J Obstet Gynecol 172:547-52, 1995

Tongsong T, Pongnarisorn C, Mahanuphap P. Use of vaginosonographic measurements of endometrial thickness in the identification of abnormal endometrium in peri- and postmenopausal bleeding. J Clin Ultrasound 22:479-482, 1994

Atri M, Nazarnia S, Aldis AE, Reinhold C, Bret PM, Kintzen G. Transvaginal US appearance of endometrial abnormalities. Radiographics 14:483-492, 1994

Hulka CA, Hall DA, McCarthy K, Simeone J. Endometrial polyps, hyperplasia, and carcinoma in postmenopausal women: Differentiation with endovaginal sonography. Radiology 191:755-758, 1994

Goldstein SR. Use of ultrasonography for triage of perimenopausal patients with unexplained uterine bleeding. Am J Obstet Gynecol 170:565-570, 1994

Zalud I, Conway C, Schulman H, Trinca D. Endometrial and myometrial thickness and uterine blood flow in postmenopausal women: The influence of hormonal replacement therapy and age. J Ultrasound Med 12:737-741, 1993

Kurjak A, Shalan H, Sosic A, Benic S, Zudenigo D et al. Endometrial carcinoma in postmenopausal women: Evaluation by transvaginal color Doppler ultrasonography. Am J Obstet Gynecol 169:1597-,1993

Mogavero G, Sheth S, Hamper U. Endovaginal sonography of the nongravid uterus. Radiographics 13:969-981, 1993

Goldschmit R, Katz Z, Blickstein I, Caspi B, Dgani R. The accuracy of endometrial pipelle sampling with and without sonographic measurement of endometrial thickness. Obstet Gynecol 82:727-30, 1993

Grunfeld L, Walker B, Sandler B, Hoffman G, Navot D. High-resolution ultrasonography of the endometrium: A noninvasive test for endometrial adequacy. Obstet Gynecol 78:200, 1991

Nasri MN, Shepard JH, Setchell ME, Lowe DG, Chard T. Sonographic depiction of postmenopausal enodmetrium with transabdominal and transvaginal scanning. Ultrasound Obstet. Gynecol 1:279-283, 1991

Lin MC, Gosink BB, Wolf SI, Feldesman MR et al. Endometrial thickness after menopause: Effect of hormone replacement. Radiology 180:427-432, 1991

Forrest TS, Elyaderani MK, Muilenburg MI, Bewtra C, Kable WT, Sullivan P. Cyclic endometrial changes: US assesment with histologic correlation. Radiology 167:233-237, 1988

Fleischer AC, Kalemeris GC, Entman SS. Sonographic depiction of the endometrium during normal cycles. Ultrasound in Med and Biology 12:271-277, 1986

Fleischer AC, Kalemeris GC, Machin JE, Entman SS, James AE. Sonographic depiction of normal and abnormal endometrium with histopathologic correlation. J Ultrasound Med 5:445-452, 1986

Malpani A, Singer J, Wolverson MK, Merenda G. Endometrial hyperplasia: Value of endometrial thickness in ultrasonographic diagnosis and clinical significance. J Clin Ultrasound 18:173-177, 1990

Osmers R, Volksen M, Schauer A. Vaginosonography for early detection of endometrial carcinoma? Lancet 335:1569-1571, 1990

Varner RE, Sparks JM, Cameron CD, Roberts LL, Soong SJ. Transvaginal sonography of the endometrium in postmenopausal women. Obstet Gynecol 78:195-9, 1991

Weber AM, Belinson JL, Bradley LD, Piedmonte MR. Vaginal ultrasonography versus endometrial biopsy in women with postmenopausal bleeding. Am J Obstet Gynecol 177:924-9, 1997

O'Connell LO, Fries MH, Zeringue E, Brehm W. Triage of Abnormal Postmenopausal Bleeding: A comparison of endometrial biopsy and transvaginal sonohysterography versus fractional curettage with hysteroscopy. Am J Obstet Gynecol 178:956-61, 1998

 

 

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Peter W. Callen, M.D.
Professor of Radiology, Obstetrics, Gynecology and Reproductive Science
University of California Medical Center, San Francisco, California