Applied Radiology

Dr. Gerety is a senior resident and Dr. Harris is Associate Professor of Radiology and Obstetrics & Gynecology and Director of Ultrasound at Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH.

Endometriosis is a common, sometimes debilitating, and often elusive gynecologic condition characterized by the presence of ectopic foci of endometrial tissue outside the uterus, as a result of retrograde menstruation and subsequent abnormal implantation. Endo-metriosis has an estimated prevalence of 10% in women of reproductive age: the mean age of onset is 25 to 29 years. ¹ It is the third leading cause of gynecologic hospitalizations in the United States and a leading cause of hysterectomy. ^2,3 This article will review current epidemiological and pathological concepts of endometriosis and present the typical imaging findings with discussion of the accuracy and role of currently available noninvasive imaging techniques.

Introduction

Risk factors for endometriosis largely relate to the concept of endometriosis as an estrogen-dependent disease associated with reflux of menstrual effluent into the peritoneal cavity. ¹ Endometriosis, defined according to pathologic criteria, is ectopic endometrial stroma and glands beyond the myometrium. Ectopic endometrial mucosa located within the uterus is defined as adenomyosis, a subject beyond the scope of this treatise. True endometriosis is located outside the uterus and is also known as endometriosis externa.

Because endometriosis can only be definitively diagnosed surgically, usually during laparoscopy or laparotomy, most prevalence estimates are highly selective. Furthermore, there is a high percentage of mild endometriosis in asymptomatic women undergoing tubal ligation. ² Prevalence estimates vary depending upon 1) the definition and criteria used for diagnosis; and 2) the limitation that the lack of disease cannot be confirmed in those who have not been examined, undergone lapa-roscopy, or reported symptomatology. Nonetheless, it is thought to be a relatively common. Endometriosis has been detected in 4.5% to 32% (mean 18.8%) of women undergoing laparoscopic evaluation of chronic pelvic pain and in 4.5% to 33% (mean 14%) of women with infertility. ⁴

Clinical definitions require the additional criteria of symptomatology and/or infertility as a direct result of endometriotic lesions. This description, however, does not explain the frequent detection of endometrial glands and stroma in asymptomatic and fertile women, nor does it recognize the broad histologic spectrum of endometriotic lesions and their natural evolution to fibrotic, hemosiderin-stained lesions. ⁵ It has been estimated that the prevalence of asymptomatic, but pathologically confirmed, endo-metriosis in healthy women undergoing tubal ligation ranges from 6% to 43%. ² Furthermore, microscopic foci have been found in normal-appearing peritoneum in women with no gross evidence of endometriosis elsewhere. ¹ It has been speculated that meticulous sampling may detect lesions in most, if not all women; however these microscopic foci can hardly be considered disease, especially in the absence of symptoms. ⁶ Because of controversies in defining the disease, the diagnosis cannot be made by history and physical examination findings alone. Nonsurgical diagnostic techniques include hysterosalpingography, abdominal ultrasound (US), transvaginal pelvic US, and MRI. Conclusive diagnosis, however, currently requires invasive techniques such as laparoscopy or laparotomy with histologic confirmation of the surgical specimen. Therefore, clinicians should attempt to identify women at high risk for endometriosis and select those who warrant further testing. Because transvaginal sonography is well tolerated and widely available, it remains the primary screening modality for imaging the female pelvis. High-resolution MRI techniques have some limitations, but offer the potential to identify early pathological changes when interventions may be more effective. It also provides evaluation of areas unapproachable laparoscopically.

Epidemiology

Epidemiologically, endometriosis has been clearly linked to both pain and infertility, but the mechanism by which these symptoms result from the disease remains elusive.

Endometriosis in early adolescence is usually associated with partial or complete obstructive Mullerian abnormalities, such as cervical atresia or obstructed rudimentary uterine horns, which presumably induce severe retrograde menstrual flow. In postmenopausal women, symptomatic endometriosis is very rare and is typically associated with hormone replacement therapy. ⁷ Other risk factors include women with short menstrual cycles (<27 days), longer menstrual flow (>7 days), and premenstrual spotting. Smoking, exercise, and prior pregnancy are associated with decreased risk, the latter may reflect a protective effect of pregnancy. It may also reflect a decreased fertility of patients with endometriosis, because the pregnancy protective effect appears to wane with increased years since last pregnancy. ^1,6 Family history is relevant, as some studies have suggested a polygenic pattern of genetic inheritance. ⁸ Various other risk factors have been examined such as age, race, socioeconomic and marital status, reproductive history, menstrual cycle characteristics, pregnancy-related factors (such as parity, gravidity, length of preceding infertility, spontaneous or induced abortions, age at first pregnancy or birth), contraceptive use, personal habits (such as smoking, alcohol, caffeine intake, exercise, illicit drug use, number of sexual partners), and body characteristics (such as height, weight, and body mass). A prospective study even found that women with red hair are at increased risk! ⁹

Epidemiologic findings reported across studies have been contradictory and inconsistent. This is probably because most of the studies were not formal epidemiologic studies and different diagnostic and inclusion criteria were used. Different populations (those referred for infertility, pain, etc.) have been studied and often no controls were studied for confounding factors. Zreik and Olive ¹⁰ reviewed almost 100 studies and identified those risk factors for which there has been some consistency of findings based on well-designed, well-controlled analytic studies. The most significant risk factors for endometriosis were heavy menstrual flow and increased peripheral body fat, i.e., fat distributed in the subcutaneous tissues versus intra-abdominal fat. It is theorized that greater peripheral body
fat may be related to higher estrogen levels and hence increased risk for endometriosis.

Pathogenesis and pathophysiology

Most theories of the pathogenesis of endometriosis suggest either development as a consequence of: 1) dissemination of endometrium by vascular, lymphatic, uterotubal, or direct invasion; or 2) in situ metaplasia of coelom, Wolffian or Mullerian duct remnant. ¹¹ Oral and Arici ¹² point out that the second mechanism is problematic for several reasons. If peritoneal epithelium has the potential to undergo metaplasia, endometriosis would be expected to develop in men, and in women with congenital absence of the uterus there should be increasing frequency with advanced age. Cultured tissue fragments from antegrade menstruation have shown the presence of adhering, proliferating fibroblastic or epitheloid cells. ¹² This agrees with the concept that these cells are seeded during retrograde menstruation. Transtubal dissemination appears to be the most common route; vascular, lymphatic and iatrogenic (mechanical) deposition have also been observed. ^13,14 Data supporting this theory include demonstration of viable endometrial cells in peritoneal fluid and an association between menstrual outflow obstruction and endometriosis. ^15,16

There is strong evidence suggesting that endometriosis is estrogen dependent. It does not occur before menarche and is rare in women with anovulatory cycles. ¹¹ Its occurrence in postmenopausal women is associated with obesity or estrogen therapy and, though very rare, can occur in the prostatic utricle of men on high-dose estrogen treatment. ^16,17

Interestingly, the connection be-tween estrogen-containing oral contraceptive pills (OCP) and the risk of endometriosis is controversial, because some authors report a lowered risk in this group of patients, while others do not confirm this finding. ^1,18

There is no unifying explanation for infertility in women with endometriosis, but there is general agreement that women with adhesions, scarring, and distortion of the normal pelvic anatomy from endometriotic lesions have a clear cause for decreased fertility. Endometriosis can produce massive, dense adhesions among reproductive structures resulting in tubal obstruction, inaccessibility of the ovary to the fallopian tube, or even destruction of ovarian stroma. Mechanisms theorized to be responsible include inflammation, pressure, adhesions, neuronal involvement, increased prostaglandin production, and even psychological factors.

Because the fallopian tubes and ovaries are constantly bathed in peritoneal fluid, components of this fluid have been extensively studied for a causal linkage. Studies in women with endometriosis, regardless of the presence of pelvic pain, show significantly elevated levels of specific prostaglandins in peritoneal fluid. ¹⁹ Others suggest that only a specific subtype of prostaglandin is elevated during days 8 to 12 of the menstrual cycle. ²⁰

Another study demonstrated no differences between prostaglandin levels in women with endometriosis when compared with normal women, women with pelvic inflammatory disease, and other women with chronic pelvic pain. ²¹ Although the data is conflicting, it does appear that at least a subgroup of patients with endometriosis may suffer from prostaglandin exposure, either as a result of lesion activity or a degree of inflammatory response. ^22-24

Other theories suggest immunologic abnormalities in women with endometriosis, but there has been no direct link to fertility status. Immunologic factors such as the increased circulation of autoantibodies, activation of peritoneal macrophages, and/or decreased T-lymphocyte reactivity and natural killer cell activity may predate, coincide with, or result from endometriosis. The disease does appear to be systemic in some cases, accounting for the presence of endometriosis in distant sites such as lung, nose, pelvic lymph nodes, and extremities, with immunologic mediation. ¹¹

Classification of endometriosis

Endometriosis has widely variable appearances that evolve over time and the natural history of the disease is still poorly understood. ²⁵ Current classification systems are unable to predict pregnancy outcome or aid in management of pelvic pain. The American Fertility Society (Revised) staging is based on a presumed natural history of progression and assigns points based on the number of implants or adhesions and their relationship to pregnancy. ²⁶ Because the cause of infertility may be different than the mechanism by which endometriosis causes pain, there has been very poor correlation between the presence and severity of symptoms and disease stage. Further revisions of the current staging system are anticipated that will allow for recording of variables such as depth of invasion, histology, data from adjunct investigations, and preoperative physical findings. ²⁶

Clinical presentation and diagnostic approach

The most important clinical factors suggestive of endometriosis are chronic pelvic pain (including dysmenorrhea, intermenstrual pain, or dyspareunia) and infertility. Physical examination generally reveals nonspecific diffuse or focal abdominal tenderness or, rarely, a tender mass (e.g., in a post-cesarean section scar). The uterus may be retroverted or fixed with decreased mobility and increased tenderness. The adnexa can be enlarged, tender, and with limited mobility or fixed in the pelvis. Nodularity or focal tenderness may also be found in the cul-de-sac, rectovaginal septum, or over the uterosacral ligaments.

Three classes of techniques have been used to diagnose and observe women with endometriosis: 1) serum immunology, 2) radiologic imaging, and 3) laparoscopic examination. The current laboratory tests lack the necessary sensitivity and specificity to serve as reliable screening tests. There is some evidence that Ca-125 may be useful in following the course of the disease and response to therapy. ^27,28 The most useful imaging techniques in identifying patients with endo-metriosis have been US and MRI. Standard radiography, hysterosalpingography, and computed tomography (CT) are infrequently helpful in localizing and describing lesions, and the findings are most often nonspecific and rarely useful in the diagnosis of endometriosis. CT or barium enema may help visualize endometriosis within the bowel, pleura, or other rare locations, but the nonspecific findings may represent other inflammatory or neoplastic processes. Laparoscopy is invasive and has several limitations, including its ability to detect atypical, nonpigmented lesions, and areas ob-scured by pelvic adhesions.

Imaging characteristics

Though there are a broad range of US and MR appearances, it is possible to achieve a high degree of accuracy in diagnosis and differentiation of endometriosis from other adnexal masses or lesions with similar imaging characteristics, such as ovarian abscesses, neoplasm, metastasis, and ectopic pregnancy.

Because of its widespread availability, US is typically the first modality used for the evaluation of pelvic disease, but it may not differentiate two common pelvic masses from endometriomas: hemorrhagic cysts and dermoids. Ultrasound is also insensitive in the detection of peritoneal implants. The reliability of sonography depends on operator skill and experience, as well as on the nature of the endometriotic lesion, and may be enhanced with Doppler flow analysis. Three entities may be distinguished: the peritoneal implant, the endometrial cyst, and the deep nodular lesion. The sensitivity for detection of focal implants with US has been reported as low as 11%, compared with a sensitivity of 83% and a specificity of 98% for detection of endometriomas. ^29,30 Pelvic MRI is probably more accurate for the detection and identification of small endometrial implants (<3 mm) than other non-invasive imaging tests. ³¹

Ultrasonographic examination in patients with clinical suspicion of endometriosis is best performed using a transvaginal (TV) approach and a high frequency probe (5 to 10 MHz). Peritoneal implants are small (usually 2 to 3 mm) and are not seen with transvaginal US (TVUS). Typically, endometriomas are visualized on US as predominantly cystic masses with thick (and generally regular) walls, increased acoustic enhancement, and homogeneous, low-level internal echoes (figure 1). Blood flow, if present, is usually pericystic with a resistive index above 0.45. ³² Not uncommonly, septations or fluid-fluid levels are seen (figures 2 and 3). Multilocular cysts (7% of endometriomas in one series) and solid-cystic masses (10%) are seen less commonly. ³² Endometriomas are usually multiple and occur bilaterally.

Several studies have described particular features that have great relevance in discriminating endometriomas from other adnexal masses. ³³ These features include a clearly demarcated adnexal mass with diffuse, homogeneously dispersed, low-level internal echoes; and the absence of neoplastic features, such as wall nodularity or regional bright echoes. The latter are more closely associated with cystic ovarian neoplasms and dermoids. Though hemorrhagic ovarian cysts can also demonstrate diffuse low-level echoes with or without mural wall thickening, they are almost exclusively non-neoplastic (thinner walls and no mural nodules) and resolve spontaneously over several months. As a result, the usual diagnostic strategy for hemorrhagic cysts is a follow-up US exam (in 3 to 4 months) to confirm resolution and avoid unnecessary surgery. Extraperitoneal implants in the bladder or bowel may appear as nodular or polypoid soft-tissue foci with active color or power Doppler flow representing viable endometrial tissue (figure 3).

MRI has become increasingly accepted with a reported sensitivity and specificity of 90% for detecting endometriosis before surgery. Its main limitation is the detection of <3 mm peritoneal implants, although the addition of fat-saturated T1-weighted imaging (T1WI) has helped improve lesion conspicuity and differentiation between fat-containing dermoids and those lesions containing blood. ^34,35 On MR imaging, the findings highly suggestive of endometrial lesions are related to their underlying proteinaceous, hemorrhagic, or fibrous content (figure 5). Additional findings include tethering of the rectum or bowel due to adhesions and loss of a clear uterine margin. The vast majority of endometriomas appear hyperintense on T1WI and may be solid or cystic with hemorrhage in differential stages of organization-producing fluid-fluid levels (figure 4). On T2-weighted images (T2WI), large lesions appear hypointense with areas of high signal due to the presence of deoxyhemoglobin and methemoglobin. Acute hemorrhage is characterized by hypointensity on T1WI and T2WI, while older hemorrhage may be hyperintense on both T1WI and T2WI. It has been reported that multiplicity of lesions characterized by hyperintense cysts on T1WI, regardless of T2 characteristics, are particularly characteristic of endometriosis (figure 5). ³⁶ A small endometrioma may be suspected when a pelvic mass <1 cm in diameter is hyperintense on T1WI, irrespective of its appearance on T2WI, as lesions <1 cm have variable T2WI signal.

Diagnostic MRI accuracy is en-hanced with fat suppressed images. In a prospective study, suspected endometriosis was evaluated with conventional T1- and T2-weighted conventional spin-echo (CSE) MRI alone and in combination with T1-weighted fat suppression (T1FS) and gadolinium-enhanced T1FS (Gd-T1FS) spin-echo techniques. The sensitivity for the detection of endometriosis was greatest for CSE/T1FS at 86% compared with 76% for CSE and 81% for CSE/T1FS/Gd-T1FS. Specificity was greatest for CSE alone (60%). ³⁷ Large endometrial lesions were characterized by diameter >1 cm and hyperintensity on T1WI and T2WI. Small lesions were well demarcated, <1 cm, and hyperintense on T1WI or T1FS sequences. Fat saturation accurately demonstrated 30 of 33 large and 9 of 19 small endometriomas compared with 27 of 33 and 2 of 19 using CSE alone. ³⁷ Dermoids are hyperintense on T1WI, but suppress with chemical shift fat saturation. Because normal peritoneal contrast enhancement occurs next to peritoneal implants, gadolinium does not appear to provide further diagnostic information as there are numerous false positives. ³⁸

The single most important differential factor in identifying endometriosis by MRI is the detection of pigmented hemorrhagic lesions. A high-signal central lesion with low-signal rim (due to hemosiderin-rich macrophages or a fibrous wall) and internal lower signal shading (probably related to hemorrhage evolution) is almost pathognomic (figure 6). MRI may be particularly helpful in evaluating changes in size and number of endometriotic lesions following treatment, detecting nerve invasion (as in sciatic endometriosis), and in identification of incisional or abdominal wall lesions. Other clues pointing toward endometriosis are multiplicity of hemorrhagic cysts (often involving the cul-de-sac and areas noncontiguous with the ovary) with associated free fluid. Mimickers of endometriosis on MRI are normal peritoneal enhancement with gadolinium, magnetic susceptibility artifacts from air-tissue interfaces or metallic foreign bodies, and increased signal on T1WI from mucous or proteinaceous bowel contents. ³⁸ Analysis of multiple pulse sequences and imaging planes may help to distinguish endometriosis from its false-positive pitfalls. AR

References

1. Mahmood TA, Templeton A: Prevalence and genesis of endometriosis. Hum Reprod 6:544-549, 1991.

2. Moen MH, Muus KM: Endometriosis in pregnant and non-pregnant women at tubal sterilization. Hum Reprod 6:699-702, 1991.

3. Velebil P, Wingo PH, Xia Z, et al: Rate of hospitalization for gynecologic disorders among reproductive-age women in the United States. Obstet Gynecol 86:764-769, 1995.

4. El-Yahia AW: Laparoscopic evaluation of apparently normal infertile women. Aust NZ J Obstet Gynaecol 34:440-442, 1994.

5. Redwine DB: Age related evolution in color appearance of endometriosis. Fertil Steril 48:1062-1063, 1987.

6. Wheeler JM: Epidemiology of endometriosis-associated infertility. J Reprod Med 34:41-46, 1989.

7. Moen MH: Is a long period without childbirth a risk factor for developing endometriosis? Hum Reprod 6:1404-1407, 1991.

8. Zreik TG, Olive DL: Epidemiology of endometriosis. Obstet Gynecol Clin N Am 24:235-258, 1997.

9. Woodworth SH, Singh M, Yussman MA, et al: A prospective study on the association of between red hair color and endometriosis in infertile patients. Fertil Steril 64:651-652, 1995.

10. Zreik TG, Olive DL: The biologic principles of disease. Obstet Gynecol Clin N Am 24:259-268, 1997.

11. Oral E, Arici A: Pathogenesis of endometriosis. Obstet Gynecol Clin N Am 24:219-233 1997.

12. Keettel WC, Stein RJ: The viability of cast-off menstrual endometrium. Am J Obstet Gynecol 61:440-442, 1951.

13. Cornillie FJ, Oosterlynk D, Lauweryns JM, et al: Deeply infiltrating pelvic endometriosis: Histology and clinical significance. Fertil Steril 53:978-983, 1990.

14. Koninckx PR, Ide P, Vandenbroucke W, et al: New aspects of the pathophysiology of endometriosis and associated infertility. J Reprod Med 24:257-260, 1980.

15. Olive DL, Henderson DY: Endometriosis and mullerian anomalies. Obstet Gynecol 69(3Pt1):412-415, 1987.

16. Kempers RD, Dockerty MB, Hunt AB, et al: Significant postmenopausal endometriosis. Surg Gynecol Obstet 111:348-356, 1960.

17. Schrodt GR, Alcorn MO, Ibanez J: Endometriosis of the male urinary system: A case report. J Urol 124:722-723,1980.

18. Vessey MP, Villard-Mackintosh L, Painter R: Epidemiology of endometriosis in women attending family planning clinics. Br Med J 306:182-184, 1993.

19. Badawy SZ, Marshall L, Gabal AA, Nusbaum ML: The concentration of 13,14-dihydro-15-keto prostaglandin F2 alpha and prostaglandin E2 in peritoneal fluid of infertile patients with and without endometriosis. Fertil Steril 38:166-170, 1982.

20. Rock J, Dubin N, Ghodgaonkar R, et al: Cul-de-sac fluid in women with endometriosis: Fluid volume and prostanoid concentration during the proliferative phase of the cycle­­days 8 to 12. Fertil Steril 37:747-750, 1982.

21. Dawood M, Khan-Dawood F, Wilson L: Peritoneal fluid prostaglandins and prostanoids in women with endometriosis, chronic pelvic inflammatory disease, and pelvic pain. Am J Obstet Gynecol 148:391-395, 1984.

22. Ylikorkala O, Viinikka L: Prostaglandins and endometriosis. Acta Obstet Gynecol Scand Suppl 113:105-107, 1983.

23. Chauhan M, Barratt CLR, Cooke SMS, et al: Differences in the fertility of donor insemination recipients--A study to provide prognostic guidelines as to its success and outcome. Fertil Steril 51:815-819, 1989.

24. Dunphy BC, Kay R, Barratt CLR, et al: Female age: The length of involuntary infertility prior to investigation and fertility outcome. Hum Reprod 4:527-530, 1989.

25. Duleba AJ: Diagnosis of endometriosis. Obstet Gynecol Clin N Am 24:331-336, 1997.

26. Hoeger KM, Guzick DS: Classification of endometriosis. Obstet Gynecol Clin N Am 24:347-359, 1997.

27. Hornstein MD, Harlow BL, Thomas PP, et al: Use of a new Ca-125 assay in the diagnosis of endometriosis. Hum Reprod 10:932, 1995.

28. Hornstein MD, Thomas PP, Gleason RE, et al: Menstrual cyclicity of Ca 125 in patient with endometriosis. Fertil Steril 58:279-283, 1992.

29. Friedman H, Vogelzang RL, Mendelson EB, et al: Endometriosis detection by US with laparoscopic correlation. Radiology 157:217-220, 1985.

30. Volpi E, De Grandis T, Zuccaro G, et al: Role of transvaginal sonography in the detection of endometriomata. J Clin Ultrasound 23:163-167, 1995.

31. Togashi K, Nishimura K, Kimura I, et al: Endometrial cysts: Diagnosis with MR imaging. Radiology 180:73-78, 1991.

32. Kurjak A, Kupesic S: Scoring system for prediction of ovarian endometriosis based on transvaginal color and pulsed Doppler sonography. Fertil Steril 62:81-88, 1994.

33. Arrive L, Hrcak H, Martin MC: Pelvic endometriosis: MR Imaging. Radiology 171:687-692, 1989.

34. Kier R, Smith RC, McCarthy SM: Value of lipid- and water-suppression MR images in distinguishing between blood and lipid within ovarian masses. AJR Am J Roentgenol 158:321-325, 1992.

35. Ha HK, Lim YT, Kim HS, et al: Diagnosis of pelvic endometriosis: Fat suppressed T1 weighted vs conventional MR images. AJR Am J Roentgenol 163:127-131, 1994.

36. Gougoutas CA, Siegelman ES, Hunt J, Outwater E: Pelvic endometriosis: Various manifestations and MR Imaging findings. AJR Am J Roentgenol 175:353-358, 2000.

37. Sugimura K, Okizuka H, Imaoka I, et al: Pelvic endometriosis: Detection and diagnosis with chemical shift MR imaging. Radiology 188:435-438, 1993.

38. Bis KG, Vrachliotis TG, Agrawal R, et al: Pelvic endometriosis: MR imaging spectrum with laparoscopic correlation and diagnostic pitfalls. RadioGraphics 17:639-655, 1997.