Endometrial and Endocervical Micro Echogenic Foci

Article Endometrial and Endocervical Micro Echogenic Foci Sonographic Appearance With Clinical and Histologic Correlation Curtis Duffield, BS, Eugenio O. Gerscovich, MD, Marijo A. Gillen, MD, PhD, John P. McGahan, MD, Alexander Truskinovsky, MD Objective. The purpose of this research was to determine the clinical and histologic importance of small echogenic foci seen in the endometrium/endocervix on pelvic sonography. Methods. A retrospective study was performed on 62 women, aged 28 to 81 years, who had echogenic foci of the endometrium and endocervix. Patients medical records were accessed to review pertinent obstetric and gynecologic information. Additionally, histopathologic slides from patients who underwent diagnostic procedures (endometrial biopsy or dilation and curettage) or hysterectomy were reviewed. Results. The clinical information for the 62 women included the following: mean age, 49 years; history of exogenous hormonal use, 84%; prior abortion (therapeutic or spontaneous), 57%; prior dilation and curettage, 56%; prior cesarean delivery, 28%; and sexually transmitted disease, 36%. The initial finding of echogenic foci was followed by ultrasound examinations in 18 patients for a mean interval of 16 months. Of the 18 patients, the foci remained unchanged in 13 women and disappeared or became less prominent in the other 5. Histopathlogic results were available in 28 women, and microcalcifications were found in 15 of them. The etiology most common was microcalcification but also included crystals, debris from laminaria, and ossified tissues. Clinical follow-up in 62 patients showed that this condition was mostly benign (endometrioid carcinoma developed in 1 patient). Conclusions. Histopathologic studies showed microcalcifications, which are the most common cause of echogenic foci. The foci were stable with time and seemed to be an incidental finding associated mostly with benign conditions. The etiologic factors for echogenic foci may be numerous. Key words: echogenic foci; endocervix; endometrium; microcalcifications; sonography. Abbreviations D&C, dilation and curettage; EMB, endometrial biopsy; IUD, intrauterine device Received December 2, 2004, from the School of Medicine (C.D.) and Departments of Radiology (E.O.G., M.O.G., J.P.M.) and Pathology (A.T.), University of California, Davis, Sacramento, California USA. Revision requested December 15, 2004. Revised manuscript accepted for publication January 25, 2005. Address correspondence to Eugenio O. Gerscovich, MD, Department of Radiology, University of California, Davis, 4860 Y St, Suite 3100, Sacramento, CA 95817 USA. E-mail: eugenio.gerscovich@ucdmc.ucdavis.edu In our practice, we occasionally observe small echogenic foci in the endometrium and endocervical canal during pelvic sonography. To our knowledge, very few studies in the literature have described the appearance, etiology, and importance of these foci. This study was performed to determine their clinical and histologic importance by correlating the obstetric and gynecologic history of each patient with her sonographic examination findings and histopathologic data. 2005 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2005; 24:583 590 0278-4297/05/$3.50

Endometrial and Endocervical Micro Echogenic Foci Materials and Methods We performed a retrospective study with approval by the Human Subjects Review Committee of our institution. Case studies were collected at random from January 2000 to December 2003 during routine pelvic (transabdominal and endovaginal) ultrasound examinations that showed micro echogenic foci in the endometrium and endocervical canal. We are uncertain whether we retrieved the results of all patients who showed this finding. We define micro echogenic foci as areas of high echogenicity measuring between 1 and 3 mm, with or without shadowing, that may be in clusters or isolated. Sixty-two women, aged 28 to 81 years, with a mean age of 49 years, who had echogenic foci were included in the study. All sonograms were reevaluated with special attention to this finding by one of the authors (E.O.G.), and, subsequently, the patients charts (electronic medical records and paper charts) were accessed to review pertinent obstetric and gynecologic information. The reasons for obtaining the ultrasound examinations were varied and included abnormal vaginal bleeding in 29 (48%) of 62 patients, pelvic pain in 16 (26%) of 62, an enlarged uterus or a pelvic mass in 7 (11%) of 62, and other etiologies in 9 (15%) of 62. The clinical information that was reviewed included the following patient information: age, reason for ultrasound examination, age at menarche, hormone use (birth control and hormone replacement therapy), history of sexually transmitted diseases and pelvic inflammatory disease, gravida/parity, use of an intrauterine device (IUD), height, weight, Papanicolaou test history, and number of cesarean deliveries, dilation and curettage (D&C) procedures, and abortions (therapeutic or spontaneous). Not all of the above listed information was available for every patient. The ultrasound examinations were performed with Sequoia and 128XP10 sonography units (Acuson, Siemens Medical Solutions, Mountain View, CA). The transabdominal examinations were performed with the use of a vector transducer with a frequency of 3 to 4 MHz; the endovaginal examinations were performed with the use of an endocavitary transducer with a frequency of 6 to 10 MHz. Histopathologic slides from those patients who underwent diagnostic procedures such as endometrial biopsy (EMB), D&C, and hysterectomy were reevaluated by one of the authors (A.T.) after the original formal interpretation. This author is a dedicated gynecologic pathologist with 2 years of subspecialty training. Special attention was paid to identifying calcifications or other potential etiologies of echogenic regions seen on sonography. The initial review consisted of examining slides stained with hematoxylineosin. Subsequently, the specimens were restudied and, when necessary, additionally stained for calcium with alizarin red and von Kossa stains. Results The clinical information of the patients included in this study is summarized in Tables 1 4 and includes general information (Table 1), patients menstrual status and gravida/parity (Table 2), obstetric and gynecologic interventions (Table 3), and history of hormone therapy, sexually transmitted diseases, and Papanicolaou tests (Table 4). The results of ultrasound examinations were collected from 62 women who had small hyperechoic foci in the endometrium (47 [76%] of 62) or endocervical canal (12 [19%] of 62) or in a combination of endometrium/endocervix (2 [3%] of 62) or endometrium/myometrium (1 [2%]). The echogenic foci measured a few millimeters each, were mostly nonshadowing, and often appeared in small clusters (Figures 1 and 2). Eighteen women had follow-up ultrasound examinations with a mean interval period of 16 months and a range of 2 to 44 months. In 13 of the women, no changes were observed in the appearance or number of echogenic foci. In 1 patient, the hyperechoic foci became less prominent, and in 4 patients, the foci disappeared. Of the 4 patients whose foci disappeared, 2 women had endometrial/endocervical biopsies between the 2 ultrasound examinations. Another patient whose foci disappeared had echogenic foci on the initial study and at a 5-month follow-up. This patient subsequently became pregnant, and the echogenic foci could still be observed in the endometrium adjacent to the gestational sac (Figure 3). The pregnancy ended with a spontaneous abortion. A subsequent ultrasound examination 1 year later showed no echogenic foci. No clinical follow-up was obtained for the last patient, whose echogenic foci disappeared. Of the 62 patients with echogenic foci, we found pathology studies for 28. Twenty-three of the tis- 584 J Ultrasound Med 2005; 24:583 590

Duffield et al sue samples were obtained by EMB; the other 5 were obtained by D&C. On the original pathology reports, however, only 2 of the 28 women had results that could explain the sonographic findings, both having microcalcifications. We subsequently asked the pathology department to review all 28 specimens, with special attention paid to findings that could result in echogenic foci, and microcalcifications were found in 15 (54%, including the initial 2 of 28) (Figure 4). Of these 28 patients, 10 were premenopausal (with calcifications in 50%), 4 were perimenopausal (with calcifications in 50%), and 14 were postmenopausal (with calcifications in 64.3%). The morphologic characteristics of the calcifications were varied and included psammomatous (laminated), spherical, amorphous, and fractured crystals. One of the 15 women had fragments of apparent plant material (likely due to laminariadesiccated seaweed used for cervical dilation to induce labor) with focal embedded birefringent crystals of uncertain composition that was confirmed to be a calcium salt on von Kossa staining. Two other women had unusual calcifications composed of calcium salts, 1 within retained old blood and the other within a probable ossified tissue fragment. Follow-up pathologic specimens were obtained (primarily because of dysfunctional uterine bleeding) in 10 of the 28 women, with a mean follow-up interval of 1.4 months (range, 2 36 months): 6 were obtained by EMB, 2 by D&C, and 2 by hysterectomy. These were reevaluated by the pathology department. Six of the 10 women with follow-up specimens had calcifications on initial pathologic studies, and 3 of the 6 continued to show them. In 2 of the 6, the calcifications disappeared, but in 1 of these patients, a third biopsy showed calcifications. In the other patient who originally had calcifications, none were identified on follow-up, but needle-shaped eosinophilic crystals were seen, plus an endometrioid type of endometrial carcinoma. Four of the 10 women with follow-up pathologic studies did not have any calcifications on the initial study, but calcifications developed in 1 of these 4. Of the initial 28 women for whom tissue samples were obtained, the pathology results showed benign tissue in 27; there was insufficient tissue for diagnosis in 1. The types of benign endometrium were atrophic (n = 8), proliferative (n = 8), inactive (n = 6), not otherwise specified (n = 3), focal complex hyperplasia (n = 1), and Table 1. Clinical Information for the 62 Patients in This Study Parameter Mean Range Age at sonography, y (62 of 62 women) 49 28 81 Menarche, y (43 of 62 women) 13 9 17 Body mass index, kg/m 2 (50 of 62 women) 28 16 45 Table 2. Obstetric History Parameter No. of Women % Menstrual status at time of sonography (56 of 62 women), n (%) Of menstrual age 28 50 Perimenopausal 6 11 Postmenopausal 22 39 Mean Range Gravida (47 of 62 women) 3.2 0 9 Parity (51 of 62 women) 2.1 0 7 Table 3. History of Obstetric and Gynecologic Interventions Parameter No. of Women % Abortions (TAB or SAB) (47 of 62 women) At least 1 TAB or SAB 27 57 Type of abortion TABs only 7 SABs only 7 Both TABs and SABs 7 Unknown (either TABs or SABs) 6 No. of abortions 1 TAB/SAB 12 2 TABs/SABs 9 3 TABs/SABs 4 >3 TABs/SABs 2 No history of abortions 20 43 D&C (41 of 62 women) No. of women with 1 18 44 1 D&C 11 2 D&Cs 5 3 D&Cs 2 None 23 56 Cesarean delivery (46 of 62 women) Number of women with 1 13 28 1 prior cesarean delivery 8 2 prior cesarean deliveries 3 3 prior cesarean deliveries 2 None 33 72 IUD (25 of 62 women) Yes 1 4 No 24 96 SAB indicates spontaneous abortion; and TAB, therapeutic abortion. J Ultrasound Med 2005; 24:583 590 585

Endometrial and Endocervical Micro Echogenic Foci Table 4. Gynecologic History Parameter No. of Women % Hormonal history (44 of 62 women) HRT or hormonal contraception 37 84 HRT only 22 Hormonal contraception only 13 Both HRT and hormonal contraception 2 No hormone use 7 16 Sexually transmitted diseases (39 of 62 women) Any sexually transmitted disease 14* 36 Trichomonas vaginalis 5 Chlamydia trachomatis 4 Condylomata acuminata (HPV) 4 Herpes simplex virus 3 Neisseria gonorrhoeae 1 None 25 64 Papanicolaou tests (34 of 62 women) All normal Papanicolaou stains 22 65 History of abnormal stain(s) 12 35 History of cryotherapy for abnormal stains 2 History of cone biopsy for abnormal stains 2 HPV indicates human papillomavirus; and HRT, hormone replacement therapy. *The total of the individual diseases does not add up to 14 because some women had more than one disease. secretory (n = 1). Five of the patients with a benign endometrium also had endometrial polyps. All of the patients with polyps showed calcifications that were in the polyps themselves, and all of these patients were perimenopausal or postmenopausal. For the 10 patients who received follow-up pathologic studies, the initial benign results remained benign for all but 1, and this included the woman who initially had insufficient tissue for diagnosis; however, the woman with focal complex hyperplasia on initial pathologic studies had a focal well-differentiated endometrioid type of endometrial carcinoma on follow-up 1 year later, as mentioned above. Discussion To our knowledge, very few studies in the literature have discussed the presence and importance of micro echogenic foci in the endometrium and endocervix. We launched our study with the purpose of discovering the importance of micro echogenic foci in the endometrium and endocervix. One case report discussed a patient with endometrial calcifications who had a diagnosis of Asherman syndrome, 1 which is a condition with intrauterine synechiae that can obliterate the endometrial cavity and produce secondary amenorrhea. 2 The authors commented that Asherman syndrome and the associated hemorrhage, inflammation, and tissue destruction may have had a causal role in endometrial calcification. Valicenti and Priester 3 illustrated the case of a woman who had been taking oral contraceptives for 3 years in whom psammoma bodies developed in the endometrial stroma. Also present in the endometrium were amorphous calcified structures but no cellular dysplasia. 3 A similar case was reported of a 28-year-old woman, previously treated with clomiphene, who underwent a D&C for an infertility evaluation and was found Figure 1. Sonograms of endometrial echogenic foci in a 69-year-old patient. A, Sagittal view. B, Coronal view. Arrows indicate endometrium. A B 586 J Ultrasound Med 2005; 24:583 590

Duffield et al to have multiple psammoma bodies in the lower endometrium. 4 These studies showed that psammoma bodies may be seen in benign conditions and may be related to the use of exogenous hormones. Our data showed a high percentage (84%) of hormone replacement therapy or hormone contraception use among the women in our study. Only 7 (16%) of the 44 women for whom we obtained information about hormone use had not used any form of exogenous hormone therapy; however, without a control population, we are unable to confirm a causal relationship between hormone use and microcalcifications. Another case report and review of the literature commented on a possible causal relationship of endometrial calcifications and recurrent pregnancy loss. 5 In our study, 1 patient had endometrial calcifications on an early obstetric ultrasound examination that eventually resulted in fetal death; however, many of the remaining patients in our study had multiple successful pregnancies, with a mean gravida-parity ratio of 3.2:2.1. It should be noted that the temporal relationship between calcifications and pregnancies could not be established with certainty. Endometrial ossifications are a different type of endometrial echogenicity and cause of fertility problems. These are larger and coarser than the microcalcifications seen in our study, and many studies over the past 10 years have reported on this condition. 6 9 The theories to explain these ossifications include retention of fetal bones after miscarriage or therapeutic abortion and osseous metaplasia from chronic inflammation and tissue damage after repeated spontaneous or therapeutic abortions. These studies indicated that endometrial ossification and retention of fetal bone have a negative effect on fertility. A study on echogenic foci within the inner myometrium showed a relationship with prior uterine instrumentation. 10 Myometrial echogenic foci were observed in 35 of 80 patients who had undergone a prior D&C or endocervical biopsy and in only 2 of 174 patients who had not had either procedure. The authors speculated that the myometrial echogenic foci were likely the result of direct mechanical injury resulting in dystrophic calcification. Although the echogenic foci in our study were located in the endometrium/endocervical canal and not in the myometrium, we also found a high percentage of women who had prior interventional procedures and abortions. Of the 52 women for whom we obtained information on D&Cs, cesarean deliveries, or abortions, 40 (77%) had a history for at least 1 of the 3. Of the 41 women for whom we obtained information on D&C history, 44% had undergone a D&C. More than half of the women (57%) had at least 1 therapeutic or spontaneous abortion. There were equal numbers of therapeutic and spontaneous abortions, suggesting that both may play a role in calcification formation. Compared with D&Cs and abortions, a smaller but substantial percentage of women had a cesarean delivery (28%). One woman in Figure 2. Sonograms of endocervical echogenic foci in a 48-year-old patient. A, Sagittal view. B, Coronal view. Arrows indicate endocervix. A B J Ultrasound Med 2005; 24:583 590 587

Endometrial and Endocervical Micro Echogenic Foci A B Figure 3. Sagittal sonograms of a 34-year-old patient with a history of genital infections and multiple therapeutic and spontaneous abortions. A, Echogenic foci (arrow) in the endometrium (arrowheads). B, Sonogram 2 years later of the same patient with an early pregnancy (arrowheads) and persistent echogenic foci in the endometrium (arrow). our study had a history of IUD use (IUD information was obtained for 25 women). Burks et al 10 suggested that one of the patients in their study who had echogenic foci in the endocervical canal without a history of instrumentation previously had an IUD, which may have been responsible for the foci. Overall, we found that echogenic foci were seen in a variety of patients. There was a wide age variance, with premenopausal, perimenopausal, and postmenopausal women represented. The mean age at menarche (13 years) was similar to Figure 4. Microphotograph of a specimen of endometrium showing numerous microcalcifications (arrows) within a benign polyp on a background of atrophic endometrium. the mean age and range at menarche in American girls, which is 12.5 to 13 years, with 1% to 2% of healthy girls not having menstruated by the age of 16 years. 11 The mean body mass index for the women in our study was 28 kg/m 2, which is above the healthy body mass index range of 18.5 to 24.9 kg/m 2 ; however, only 33% of adults in the United States fall within this range, and more than 50% have indices that exceed 25.0 kg/m 2, so our study group is likely similar to the general public. 12 Sexually transmitted diseases were reported in 14 (36%) of 39 women. In 1996, the incidence estimate was 12 million to 15 million new cases per year in the United States. 13 Papanicolaou test histories were available for 34 of 62 women. Of those, 22 (65%) had stains that were normal, whereas 12 (35%) had abnormal Papanicolaou stains. Sirovich and Welch 14 reported that 20% of American women have had at least 1 abnormal Papanicolaou stain. Therefore, our patients had slightly more abnormal Papanicolaou stains than the typical American woman; however, of the 12 women with abnormal Papanicolaou stains, most had resolution without intervention. Our data showed that the echogenic foci seen on ultrasound examinations mostly remained constant with time. Thirteen (72%) of 18 women had similar findings over a mean period of 16 months. In the other 5 women, the echogenic foci disappeared in 4 and became less prominent in 1. Of the 4 women whose foci disappeared, 2 had endometrial and endocervical biopsies between the 2 ultrasound examinations, which 588 J Ultrasound Med 2005; 24:583 590

Duffield et al may explain the disappearance. One woman became pregnant and had a spontaneous abortion and on subsequent examinations did not show any echogenic foci. No notable history was obtained on the fourth woman whose foci disappeared. We suggest that interventions such as endometrial and endocervical biopsies may be responsible for the removal of microcalcifications. As mentioned previously, however, a large percentage of women in this study had a history of interventional procedures, IUDs, and abortions, which may have had an etiologic role in the microcalcifications; therefore, we conclude that interventions may contribute to both the pathogenesis and removal of microcalcifications. All of the original and follow-up pathologic results reported benign endometrial tissue, except for 1 woman in whom well-differentiated endometrioid carcinoma developed. Of the 5 endometrial polyp fragments identified, all had associated calcifications; 4 of the polyps were in postmenopausal patients, and 1 was in a perimenopausal patient. Interestingly, a literature review revealed that, for up to 50% of patients, the rare finding of psammoma bodies (microcalcifications) on cervical vaginal stains has been associated with benign conditions. The other 50% of the patients had malignant tumors, most of which originated from the ovary. 15 Pathologic studies combined the results of endometrial and endocervical findings because of the availability of both tissues after hysterectomy and in most of the biopsy specimens. It is of note that only 2 of the original pathology reports mentioned calcifications in the endometrial specimens, whereas 15 of 28 cases were found after review. This discrepancy may be related to the fact that the calcifications were rather subtle and, to be identified, required a search with special attention to their presence; therefore, the original pathologists may have failed to look specifically for the calcifications. Furthermore, the original pathologists may have seen the calcifications and simply not mentioned them in their reports, possibly not considering this finding to be of clinical relevance. Because the pathology results were positive for possible echogenic material in only 15 of the 28 cases, it is possible that there is a high percentage of false-negative results with an EMB or a D&C. This is a reasonable consideration because the purpose of the tissue studies was clinical (abnormal bleeding and pelvic pain) and not a search for echogenic material. Additional calcifications or other echogenic material might have been prevalent if the studies had been repeated or more thorough samples had been taken. For example, of the 10 women with follow-up pathologic studies, 4 did not have calcifications on the initial study, and 1 (25%) of the 4 showed calcifications on follow-up. Some limitations of this study include the relatively small number of patients and the lack of a control group, that is, patients with clinical histories without microcalcifications on sonography. In addition, follow-up in our study was for only a few years. An extended follow-up would be necessary to ensure that the calcifications have no long-term deleterious results. In summary, we observed echogenic foci of the endometrium and endocervical canal in 62 women. Endometrial microcalcifications are the most common cause of the echogenic foci seen on our ultrasound examinations. They appear to be stable or to regress with time and are associated mostly with benign endometrial conditions. The clinical histories for these patients varied, but a large percentage (96%) indicated hormone use, IUD use, interventions such as D&Cs, cesarean deliveries, therapeutic or spontaneous abortions, and infections. Micro echogenic foci seem to be a concomitant finding and not a marker for disease. Because standard pathologic results may not comment on calcifications of endometrial and endocervical specimens, it may be necessary to request that the pathologist look for them or for other possible echogenic material if in question. References 1. Untawale VG, Gabriel JB Jr, Chuahan PM. Calcific endometritis. Am J Obstet Gynecol 1982; 144: 482 483. 2. Stenchever MA. Comprehensive Gynecology. 4th ed. St Louis, MO: CV Mosby Co; 2001:1099 1123. 3. Valicenti JF Jr, Priester SK. Psammoma bodies of benign endometrial origin in cervicovaginal cytology. Acta Cytol 1977; 21:550 552. 4. Herbold DR, Magrane DM. Calcifications of the benign endometrium. Arch Pathol Lab Med 1986; 110:666 669. J Ultrasound Med 2005; 24:583 590 589

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