Society of Radiologists in Ultrasound Consensus Conference Statement on Postmenopausal Bleeding

Society of Radiologists in Ultrasound Consensus Conference Statement on Postmenopausal Bleeding Peter M. Doubilet, MD, PhD Brigham and Women s Hospital Boston, Massachusetts Abbreviations HRT, hormone replacement therapy; PMB, postmenopausal bleeding; SIS, saline infusion sonohysterography; SRU, Society of Radiologists in Ultrasound; TVS, transvaginal sonography U nscheduled vaginal bleeding in postmenopausal women (i.e., any bleeding other than that occurring at the expected time in the cycle of a woman receiving sequential hormone replacement therapy [HRT]) is a worrisome symptom, because it may be the presenting symptom of endometrial cancer. (Henceforth, the term postmenopausal bleeding [PMB] will be used to refer to unscheduled bleeding.) The frequency of endometrial cancer in women with PMB has been found to be approximately 7%, 1,2 although the range of risk estimates in the literature is quite wide. In view of the relationship between PMB and endometrial carcinoma, it is a central tenet of gynecologic practice that diagnostic evaluation should be undertaken in any women with PMB. 3,4 Although the need for diagnostic evaluation is clear-cut, the appropriate choice of a test (or tests) is anything but straightforward. In fact, the decision concerning the optimal testing algorithm has become considerably more complex over the last decade, because the range of available tests has expanded to include office biopsy, dilation and curettage, hysteroscopy, transvaginal sonography (TVS), and saline infusion sonohysterography (SIS). There has been no consensus about which of these tests should be performed initially in a woman with PMB or about what (if any) follow-up tests should be performed depending on the result of the initial test. The Society of Radiologists in Ultrasound (SRU) should be commended for assembling a multispecialty group of experts to develop a consensus recommendation for the diagnostic evaluation of PMB. As with any consensus panel, however, the reliability of its recommendations is constrained by the quality and statistical power of existing studies. Here I examine how closely the panel came to achieving its stated goals and where the consensus conference statement leaves the practitioner who treats patients with PMB. I. To what extent does the consensus panel statement succeed in answering the specific questions posed by the SRU? Question 1: What are the relative effectiveness and cost-effectiveness of using TVS versus office biopsy as the initial examination for the woman with PMB? The panel s ability to answer this question is limited, because there has been no large-scale randomized controlled trial comparing the effectiveness of these tests and no full-fledged costeffectiveness analysis. The panelists state that, in their opinion, either TVS or office biopsy can be used as the initial test in the evaluation of a woman with PMB, thus 2001 by the American Institute of Ultrasound in Medicine J Ultrasound Med 20:1037 1042, 2001 0278-4297/01/$3.50

Society of Radiologists in Ultrasound Consensus Statement on Postmenopausal Bleeding implying that they think that neither of the two tests has a demonstrated advantage over the other. Their discussion of this point, however, is somewhat inconsistent. In their literature review, they state that TVS has similar (or slightly lower) false-negative rates for cancer detection (i.e., has similar or slightly higher sensitivity) than office biopsy. They corroborate this by indicating that office biopsy has a sensitivity of more than 85 percent, whereas that of TVS approaches 95%. Their literature review also indicates that TVS has an extremely high negative predictive value ( a very thin endometrial lining almost never harbors carcinoma ) and that it has a higher rate of diagnostic findings than does office biopsy. In view of the above statements about TVS, it is puzzling that Some of the panelists thought that in women considered to be at high risk for endometrial cancer (office biopsy) may be preferred as the first step. (Technical note: Bayes rule shows that the comparison of 2 tests predictive values is unaffected by the prevalence of disease; that is, if test A has as good or better predictive values than test B in a low-risk population, then test A will also equal or outperform test B in a high-risk population, and vice versa.) A reliable comparison of TVS and office biopsy would require a randomized controlled trial, and because these two tests are reasonably close in sensitivity and specificity, the study population would have to be large to achieve adequate statistical power. Even with a randomized controlled trial, however, a comparison of TVS and office biopsy would be far from straightforward. For example, the sensitivity and specificity of TVS depend on factors such as patient body habitus, uterine orientation, and the presence of fibroids. Transvaginal sonography might prove to have greater sensitivity and specificity than office biopsy in a thin woman with an anteverted uterus that contains no fibroids but to be less accurate (or have an unacceptably high rate of nondiagnostic results) in an obese woman with a retroverted fibroid uterus. The panelists are even more limited in their attempt to compare the cost-effectiveness of these tests. The closest they come is to quote a single study that compares the costs of 2 diagnostic algorithms for PMB, one beginning with TVS and the other beginning with office biopsy. 5 That study is not, and does not purport to be, a cost-effectiveness analysis. To justify the term cost-effectiveness analysis, an analysis should consider all dollars spent (for both diagnostic and therapeutic procedures) and should assess outcomes using a comprehensive measure, such as life expectancy or quality-adjusted life expectancy, that permits comparison with other medical practices. 6 In fact, a cost-effectiveness analysis of strategies to evaluate PMB has been carried out; it assessed the monetary cost and life expectancy associated with various diagnostic approaches. 7 That analysis, however, predated the common use of TVS and SIS in patients with PMB and did not consider these diagnostic tests. Thus, the panelists have given a tentative answer to the effectiveness part of question 1, concluding that TVS and office biopsy are roughly equivalent to one another in effectiveness, and they were not able to provide an answer to the cost-effectiveness part of the question. Question 2: What are the sonographic standards for evaluating a woman with PMB? The panelists give a full and clear answer to this question. They do a service both by stating what sonographic feature should be assessed, maximal doublelayer endometrial thickness (excluding fluid in the cavity) on a transvaginal sonogram, and by excluding other sonographic features (e.g., Doppler indices and endometrial echo texture) that have been studied by a number of authors. 8 10 Question 3: What are the abnormal sonographic findings in a woman with PMB? As with question 1, the panel s ability to provide a definitive answer to this question is limited by available data. There has been disagreement about whether the criterion for abnormality in endometrial thickness should be 4 mm or greater, greater than 4 mm, 5 mm or greater, or greater than 5 mm, and the panelists recommend greater than 5 mm. Their argument for choosing this threshold, however, is far from bulletproof. In arguing for a criterion of greater than 5 mm, the panelists rely heavily on a published meta-analysis performed by a team headed by Rebecca Smith-Bindman, 11 a member of the panel. Although this meta-analysis was performed well, it (like many such analyses) has to combine the results of studies with varying methods (e.g., different patient populations, testing techniques, and means of ascertaining the true diagnosis), which can 1038 J Ultrasound Med 20:1037 1042, 2001

Doubilet lead to anomalous or unreliable conclusions. In particular, Table 3 in the article by Smith- Bindman et al 11 suggests that, in women not receiving HRT, the sensitivity of TVS for endometrial disease is lower using a cutoff of 4 mm than it is using 5 mm (86% versus 95%), and that the negative likelihood ratio of TVS in these patients is higher for 4 than for 5 mm (0.20 versus 0.05). These are mathematically impossible results, because sensitivity and the negative likelihood ratio must be better (i.e., higher sensitivity and lower negative likelihood ratio) for a cutoff of 4 than for 5 mm. These inconsistencies in the findings of Smith-Bindman et al comparing the 4- and 5- mm cutoffs raise serious questions about the panel s decision to advocate a 5-mm cutoff for endometrial thickness on TVS. Another shortcoming of the panelists response to question 3, also resulting from limitations in the existing literature, is the lack of clarity about what represents a focal endometrial abnormality on TVS. For example, if the TVS shows an area of the endometrium that measures 3 mm in thickness, and the rest of the endometrium measures 2 mm, does this constitute a focal abnormality? Question 4: When should SIS or hysteroscopy be used in the evaluation of PMB? The panelists failed to achieve consensus on most aspects of this question; therefore, the algorithms they provide contain decision points that present minority opinions or leave the choice to physician preference. For example, in a woman who has had an office biopsy that yields an inadequate pathologic diagnosis followed by TVS showing an abnormal (or incompletely visualized) endometrium, algorithm 1 leaves the decision between SIS and hysteroscopy or dilation and curettage to physician preference. When the initial diagnostic test is TVS (algorithm 2), several subsequent choices, such as the decision between SIS and office biopsy, are left to physician preference. No consensus was reached about whether all women with PMB should undergo SIS; although the majority of panelists thought that SIS is unnecessary if TVS shows a thin endometrium, a minority held to the view that these women should undergo SIS. The panelists response to question 4 provides some guidance to practitioners but not the consensus sought by the SRU. Question 5. Should the diagnostic approach be modified for patients taking HRT medications, tamoxifen, or other selective estrogen receptor modulators? The panelists present an answer to this question, recommending that TVS in women receiving sequential HRT regimens should be performed 4 to 5 days after completion of cyclic bleeding, that TVS can be performed at any time in women receiving continuous HRT regimens, and that the 5-mm threshold should be used for women taking tamoxifen or other selective estrogen receptor modulators. Their discussion in response to this question, however, is somewhat problematic. In particular, in the first paragraph they state that sensitivity is not affected by HRT, and in the second paragraph they state that there is a higher rate of false-positive sonographic findings (i.e., specificity is lower) in women receiving HRT (both paragraphs quoting the analysis by Smith-Bindman et al 11 ). Only the second of these statements is an accurate representation of the analysis by Smith-Bindman et al, which finds that, for a given endometrial thickness cutoff, sensitivity is generally higher and specificity is generally lower in women receiving HRT compared with those not receiving HRT. II. To what extent does the consensus conference statement help the practitioner who treats patients with PMB? The consensus conference statement will provide several important benefits to medical practitioners, including the following: 1. It helps spread the message that sonography can play an important role in the evaluation of PMB. Until fairly recently, sonography played little role in the evaluation of PMB. Instead, conventional teaching was that any women with unscheduled PMB should undergo endometrial sampling. Although numerous publications supporting the value of ultrasound in the workup of PMB have appeared in the literature over the past 5 to 10 years, including scientific studies, 12 21 review articles, 22 and editorials, 23 none of these has the power to change clinical practice as much as a document sponsored and publicized by a major medical society such as the SRU. 2. It standardizes the sonographic technique for evaluating the endometrium. Studies have appeared in the sonography literature touting J Ultrasound Med 20:1037 1042, 2001 1039

Society of Radiologists in Ultrasound Consensus Statement on Postmenopausal Bleeding the diagnostic value of a number of sonographic features of the endometrium. These include both single-layer 12 and double-layer 13 21 endometrial thickness, the Doppler pulsatility index of the uterine artery, 8 and endometrial echotexture. 9,10 There is now general agreement that only one of these parameters is the critical sonographic feature in women with PMB: the width of the thickest portion of the endometrium, using the double-thickness measurement from a sagittal transvaginal image, excluding fluid that may be present in the endometrial cavity. The panelists have performed an important service by stating this clearly. 3. It specifies how and when TVS should be used in women with PMB who are receiving HRT. The important point, stated clearly in the consensus conference statement, is that women receiving sequential HRT should be scanned 4 to 5 days after completion of cyclic bleeding. 4. It reassures practitioners that a variety of diagnostic approaches to the evaluation of PMB are acceptable. Practitioners who routinely use office biopsy as the initial diagnostic test in women with PMB will be reassured that their approach is considered acceptable by a panel of experts. The same holds for those who prefer TVS as the initial diagnostic test. Similarly, those whose preferred test for evaluating focal lesions is hysteroscopy, as well as those who use SIS to assess focal lesions, can take comfort in the fact that their choice is deemed acceptable by the consensus panel. There are also a number of ways in which the consensus panel report is not particularly helpful to medical practitioners, including the following: 1. It does not resolve, in a convincing manner, the debate about whether to use 4 or 5 mm as the positivity criterion for endometrial thickness in a woman with PMB. As discussed above in the commentary on the response to question 3, the panel s recommended choice of 5 mm is not adequately justified or supported. Further clinical trials will be needed to determine which of 4 or 5 mm is the appropriate positivity criterion. 2. It does not select between TVS and office biopsy as the best initial test in women with PMB. Those practitioners who would like to see a definitive diagnostic algorithm for the evaluation of PMB will be disappointed. The consensus panel did not select TVS or office biopsy as their recommended initial test, leaving this (and a number of other choices) to physician preference. 3. It does not achieve consensus about whether all women with PMB should undergo SIS. Although the majority of the panelists thought that SIS is unnecessary if TVS shows a thin endometrium, a minority thought otherwise. 4. It provides little information about the costeffectiveness of diagnostic strategies for the evaluation of PMB. The practitioner or health plan intending to select a diagnostic strategy based on cost-effectiveness (that is, based on a balance of effectiveness and monetary cost) will not be helped by the consensus conference statement. As noted earlier, this is not the panel s fault but is due to the fact that no one has published a fullfledged cost-effectiveness analysis of the evaluation of PMB. III. Where does this leave the practitioner who treats patients with PMB? Given the current literature on PMB, including the SRU consensus conference statement, the following guidelines should apply in treating patients with PMB: 1. Any woman with PMB (i.e., bleeding other than that occurring at the expected time in the cycle of sequential HRT) should undergo diagnostic evaluation to determine the cause of bleeding. 2. Either office biopsy or TVS is an acceptable initial test. If TVS is used, the critical feature is the maximal double-thickness width of the endometrium, measured on a sagittal image and excluding any fluid that may be present in the endometrial cavity. Until there is definitive information concerning the choice between 4 and 5 mm as the appropriate positivity criterion for endometrial thickness, I would recommend using 4 mm, because that will miss fewer cancers (i.e., have higher sensitivity) than 5 mm. 3. Unless the initial test provides a definitive diagnosis, further testing must be carried out. In particular, the following guidelines should be considered: (A) If the initial test is TVS, it is generally agreed that an endometrial thickness of 4 mm or less virtually excludes significant disease (especially cancer), so that no further testing need be performed unless the patient s clinical condition changes. If the endometrial thickness is greater than 4 mm or the endometrium is inadequately visualized, office biopsy or SIS 1040 J Ultrasound Med 20:1037 1042, 2001

Doubilet should be performed, followed, if needed, by further testing to achieve a diagnosis (e.g., hysteroscopy if SIS shows a focal endometrial lesion). (B) If the initial test is office biopsy, unless the biopsy provides a specific pathologic diagnosis, TVS should be performed. Subsequent testing, if any, will depend on the result of the TVS (as outlined above). References 1. Lidor A, Ismajovic E, Confino E, David MP. Histopathological findings in 226 women with postmenopausal uterine bleeding. Acta Obstet Gynecol Scand 1986; 65:41 43. 2. Choo YC, Mak KC, Hsu C, Wong TS, Ma HK. Postmenopausal uterine bleeding of nonorganic cause. Obstet Gynecol 1985; 66:225 228. 3. American College of Obstetricians and Gynecologists. Carcinoma of the Endometrium. Washington, DC: American College of Obstetricians and Gynecologists; 1991. Technical Bulletin 162. 4. American College of Obstetricians and Gynecologists. Hormone Replacement Therapy. Washington, DC: American College of Obstetricians and Gynecologists; 1992. Technical Bulletin 166. 5. Weber AM, Belinson JL, Bradley LD, Piedmonte MR. Vaginal ultrasonography versus endometrial biopsy in women with postmenopausal bleeding. Am J Obstet Gynecol 1997; 177:924 929. 6. Doubilet PM, Weinstein MC, McNeil BJ. Use and misuse of the term cost effective in medicine. N Engl J Med 1986; 314:253-256. 7. Feldman S, Berkowitz RS, Tosteson AN. Cost-effectiveness of strategies to evaluate postmenopausal bleeding. Obstet Gynecol 1993; 81:968 975. 8. Bourne TH, Campbell S, Whitehead MI, Royston P, Steer CV, Collins WP. Detection of endometrial cancer in postmenopausal women by transvaginal ultrasonography and colour flow imaging. BMJ 1990; 301:369. 9. Hulka CA, Hall DA, McCarthy K, Simeone JF. Endometrial polyps, hyperplasia, and carcinoma in postmenopausal women: differentiation with endovaginal sonography. Radiology 1994; 191: 755 758. 10. Sheth S, Hamper UM, Kurman RJ. Thickened endometrium in the postmenopausal woman: sonographic-pathologic correlation. Radiology 1993; 187:135 139. 11. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998; 280:1510 1517. 12. Osmers R, Volksen M, Schauer A. Vaginosonography for early detection of endometrial carcinoma? Lancet 1990; 335:1569 1571. 13. Goldstein SR, Nachtigall M, Snyder JR, Nachtigall L. Endometrial assessment by vaginal ultrasonography before endometrial sampling in patients with postmenopausal bleeding. Am J Obstet Gynecol 1990; 163:119 123. 14. Nasri MN, Shepherd JH, Setchell ME, Lowe DG, Chard T. Sonographic depiction of postmenopausal endometrium with transabdominal and transvaginal scanning. Ultrasound Obstet Gynecol 1991; 1:279 283. 15. Varner RE, Sparks JM, Cameron CD, Roberts LL, Soong SJ. Transvaginal sonography of the endometrium in postmenopausal women. Obstet Gynecol 1991; 78:195 199. 16. Granberg S, Wikland M, Karlsson B, Norstrom A, Friberg LG. Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality. Am J Obstet Gynecol 1991; 164:47 52. 17. Karlsson B, Granberg S, Wikland M, Ryd W, Norstrom A. Endovaginal scanning of the endometrium compared to cytology and histology in women with postmenopausal bleeding. Gynecol Oncol 1993; 50:173 178. 18. Dorum A, Kristensen B, Langebrekke B, Sornes T, Skaar O. Evaluation of endometrial thickness measured by endovaginal ultrasound in women with postmenopausal bleeding. Acta Obstet Gynecol Scand 1993; 72:116 119. 19. Cacciatore B, Ramsay T, Lehtovirta P, Ylostalo P. Transvaginal sonography and hysteroscopy in postmenopausal bleeding. Acta Obstet Gynecol Scand 1994; 73:413 416. J Ultrasound Med 20:1037 1042, 2001 1041

Society of Radiologists in Ultrasound Consensus Statement on Postmenopausal Bleeding 20. Conoscenti G, Meir YJ, Fischer-Tamaro L, et al. Endometrial assessment by transvaginal sonography and histological findings after D & C in women with postmenopausal bleeding. Ultrasound Obstet Gynecol 1995; 6:108 115. 21. Karlsson B, Granberg S, Wikland M, et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: a Nordic multicenter study. Am J Obstet Gynecol 1995; 172: 1488 1494. 22. Doubilet PM. Postmenopausal vaginal bleeding. In: Bluth EI, Arger PH, Benson CB, Ralls PW, Siegel MJ (eds). Ultrasound: A Practical Approach to Clinical Problems. New York, NY: Thieme Medical Publishers; 2000:237 244. 23. Bourne TH. Evaluating the endometrium of postmenopausal women with transvaginal ultrasonography. Ultrasound Obstet Gynecol 1995; 6:75 80. 1042 J Ultrasound Med 20:1037 1042, 2001