Novel Subtype Classification of Diffuse Uterine Leiomyomatosis Based on a Nationwide Survey in Japan.

Hiroshi Ishikawa: conceptualization, methodology, data curation, investigation, validation, funding acquisition, writing – original draft, writing – review and editing, formal analysis. Ryoko Asano: validation, writing – original draft, writing – review and editing, investigation, data curation. Masanori Ono: validation, data curation, investigation. Mari Kitade: validation, supervision, data curation. Maki Kusumi: validation, data curation. Shunichiro Tsuji: data curation, validation, supervision. Tomoko Nakamura: validation, data curation, investigation, writing – review and editing. Ryo Maekawa: validation, data curation, investigation. Yuki Goto: data curation, validation, investigation. Akiyo Takada: validation, data curation, formal analysis. Kaori Koga: supervision, validation, funding acquisition.

This study was approved by the Ethics Committee for Observational Research at Chiba University Hospital (Study title: Nationwide Survey on the Diagnosis and Treatment of Diffuse Uterine Leiomyomatosis; Principal Investigator: Hiroshi Ishikawa; Approval number: HK202405 ‐06).

This work was supported by the Japan Society of Obstetrics and Gynecology, Japan Agency for Medical Research and Development (AMED): JP25gk0210042, and a Grant‐in‐Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), KAKENHI grant: 24K12574.

Of the 1080 institutions surveyed nationwide, responses to the web‐based questionnaire were obtained from 428 institutions. Among these, 128 institutions reported having clinical experience with DUL, 286 reported no experience, and 14 were unsure whether they had any such experience (Figure  1 ). A histogram of the number of DUL cases at each institution is shown in Figure  2 . Thirty‐eight institutions reported experience with five or more cases, with the highest‐volume institution managing up to 50 cases. In contrast, the majority of institutions had fewer than five cases, and 41 institutions had experience with only a single case. A total of 653 cases of DUL or DUL‐like multiple uterine leiomyomas were reported by the participating institutions. Overview of the study. A questionnaire was distributed to 1080 obstetrics and gynecology institutions nationwide, and responses were received from 428 institutions. *As of January 2025, MRI scans of 408 cases have been submitted to the subcommittee by 78 institutions. Histogram of the number of DUL cases experienced per institution. This histogram shows the number of DUL cases reported by institutions with clinical experience. DUL, diffuse uterine leiomyomatosis. MRI scans were requested from 119 institutions that reported having clinical experience with DUL and indicated the possibility of a case‐based investigation. MRI scans were obtained from 408 patients from 78 hospitals. The results of the central review of the MRI scans are shown in Figure  3 . In the initial evaluation, 283 cases (69%) were DUL, 75 (19%) were non‐DULs, and 49 (12%) were classified as indeterminate. One patient could not be evaluated due to poor image quality (Figure  3A,B ). After reviewing the indeterminate cases within the subcommittee, 307 cases were ultimately classified as DUL. The composition of the subcommittee members and the review process are presented in Figure  S1 . These cases were further subclassified based on MRI characteristics into the following three types: (1) Total replacement type, in which the JZ is disrupted and numerous leiomyomas are observed throughout the myometrium and toward the endometrial surface (Figure  4A,B ); (2) Myometrial replacement type, characterized by innumerable leiomyomas within the myometrium with minimal protrusion toward the endometrial surface, regardless of the preservation of JZ (Figure  4C,D ); and [ 3 ] Submucosal‐dominant type, in which multiple submucosal leiomyomas are present while the outer myometrium near the serosal surface remains relatively preserved (Figure  4E,F ). Of the 307 cases, 230 (75%) were classified as total replacement type, 49 (16%) as myometrial replacement type, and 27 (9%) as submucosal dominant type (Figure  3C ). One case could not be classified because the MRI was performed during pregnancy. Representative hysterectomies for each subtype are shown in Figure  5 . Additionally, representative cases that were initially judged as intermediate cases but ultimately classified as DUL are presented in Figure  S2 . Results of central review of MRI scans. (A) Initial evaluation (B) Final evaluation (C) Subtype classification. Representative MRI scans of DUL subtypes. (A and B) Total replacement type: Numerous leiomyomas are present both within the myometrium and beneath the endometrium (submucosal). (C and D) Myometrial replacement type: Numerous leiomyomas are present within the myometrium, but no submucosal leiomyomas are observed. (E and F) Submucosal‐dominant type: Multiple submucosal leiomyomas are present, whereas few or no leiomyomas are found in the outer myometrium near the serosal surface. DUL, diffuse uterine leiomyomatosis. Representative operative findings of DUL subtypes. (A and B) Cut surface of the uterus during extensive myomectomy for the total replacement type. Numerous leiomyomas are present on the endometrial surface and within the myometrium. (C and D) Cut surface of the uterus of the myometrial replacement type. (C) Hysterectomy specimen. (D) During extensive myomectomy. Numerous leiomyomas are observed within the myometrium, whereas no protrusion of leiomyomas is seen on the endometrial surface. (E and F) Cut surface of the uterus of the submucosal‐dominant type. (E) Hysterectomy specimen. (F) During extensive myomectomy. While innumerable leiomyomas originate from the junctional zone and extend toward the endometrial surface and into the myometrium, the outer myometrial layer remains structurally preserved. DUL, diffuse uterine leiomyomatosis.

To the best of our knowledge, this is the first nationwide survey to explore the diagnosis and treatment of DUL in Japan. No nationwide survey has been conducted within a single country on a global scale. We identified 653 cases of DUL or DUL‐like multiple uterine leiomyomas nationwide over the past 10 years. DUL can be classified into three types based on the location of leiomyoma development: total replacement, myometrial replacement, and submucosal dominance. These subtypes may influence the treatment strategies, surgical approaches, fertility treatments, and reproductive outcomes in affected women. For example, compared with the total replacement type, the myometrial replacement type may have a higher pregnancy rate despite uterine enlargement, as there is no protrusion of leiomyoma nodules into the uterine cavity. In contrast, in the submucosal‐dominant type, heavy menstrual bleeding tends to be the most severe, and transcervical resection (TCR) rather than open myomectomy is often performed to treat heavy menstrual bleeding and infertility. Our findings may significantly affect the development of treatment strategies for patients with DUL who wish to preserve their fertility. Although clinical experience in diagnosing and treating DUL, including pregnant cases, has been reported, most publications are limited to case reports or small case series. Consequently, large‐scale studies are essential to develop effective treatment strategies for patients with DUL. A recent systematic review of fertility‐preserving treatments identified only 13 case series and 28 case reports indexed in PubMed [ 6 ]. Reports that specifically addressed fertility‐preserving approaches remain limited. In our survey, more than half of the institutions reporting their experience with DUL had encountered only one case in the past decade. Considering the rarity of DUL, it is difficult for a single institution to accumulate a substantial number of cases. Therefore, our nationwide survey aimed to clarify the current treatment practices and perinatal outcomes of women with DUL at each institution, and the findings may help establish future treatment strategies for women affected by DUL. Diagnosis of DUL remains clinically challenging because of its nonspecific symptoms, which closely resemble those of conventional uterine leiomyomas and adenomyosis. However, image‐based differentiation is complex. Although transvaginal ultrasonography is commonly used for initial leiomyoma screening and can effectively depict localized nodules, DUL typically presents as a symmetrically enlarged uterus containing numerous, diffusely distributed leiomyoma nodules, making it difficult to distinguish individual lesions. Consequently, MRI is considered more effective for diagnostic evaluation [ 7 ]. The characteristic MRI appearance of DUL includes symmetrical uterine enlargement with countless small leiomyomas predominantly located around the JZ [ 8 ]. This includes cases in which the junctional zone disappears, and the innumerable leiomyomas extend into both the intramural and submucosal layers. However, through a central review of MRI scans collected from institutions nationwide, we found that some cases exhibited a myometrial replacement type, in which the JZ was preserved, but the entire myometrium was replaced, starting from the JZ region. A hallmark feature is the near‐complete absence of an intervening normal myometrium. Despite the presence of innumerable nodules, each lesion was individually small and the serosal contour remained smooth. Therefore, we diagnosed cases of DUL even when the JZ was preserved, provided the myometrium was replaced by innumerable leiomyomatous nodules. Moreover, we found cases in which most of the myometrium showed diffuse leiomyomatous changes but a small portion contained distinctly demarcated leiomyoma nodules. We also diagnosed such cases as DUL, even when a small portion of the uterus contained ordinary leiomyoma nodules. However, even when these diagnostic criteria were applied, there were cases in which it was difficult to clearly distinguish DUL from multiple uterine leiomyomas. In such cases, the final diagnosis of DUL is determined by majority vote among committee members. In the present survey, which asked each institution to report the number of DUL cases managed, several comments highlighted the diagnostic ambiguity between DUL and multiple uterine leiomyomas. These included: “We do not distinguish between multiple uterine leiomyomas and DUL in routine clinical practice;” “We have likely encountered cases suggestive of DUL but cannot accurately quantify them because of the difficulty in differentiating from multiple uterine leiomyomas;” and “We are not confident in making a definitive diagnosis of DUL at our institution,” making it difficult to identify such cases. Therefore, a central review of the MRI scans was conducted to determine whether each case met the definition of DUL. In cases in which the initial diagnosis was inconclusive, further discussions were conducted within the members of subcommittee. The criteria for DUL included whether the patient was likely to require a technically challenging myomectomy. The final classification of DUL or non‐DUL was based on a majority vote among committee members. Treatment strategies for DUL in patients desiring pregnancy often combine pharmacological, surgical, and noninvasive approaches. Hormonal therapies such as GnRH analogs have been reported to reduce uterine volume and support successful pregnancy outcomes. In one case, sustained disease control enabled two full‐term deliveries [ 5 ]. Fertility‐preserving surgeries, particularly hysteroscopic myomectomy (transcervical resection [TCR]), showed favorable results. Yen et al. reported pregnancies in all three patients who desired conception following TCR and postoperative hormonal therapy [ 9 ]. Zhao et al. described seven pregnancies following TCR, with six resulting in term deliveries [ 4 ], while Mazzon et al. reported three full‐term births after cold‐loop hysteroscopic resection [ 10 ]. Open myomectomy also led to successful deliveries [ 3 ]. In more complex scenarios, combining laparoscopy, hysteroscopy, laparotomy, and medical therapy has proven effective [ 1 , 11 ]. Noninvasive modalities, such as high‐intensity focused ultrasound, are emerging as potential options. Gong et al. reported successful pregnancies and deliveries in three patients treated with high‐intensity focused ultrasound [ 12 ], while one case of pregnancy following uterine artery embolization has also been described [ 13 ]. These reports suggest that tailored multimodal management, often combined with surgical intervention and hormonal control, may improve reproductive outcomes in patients with DUL. However, further prospective studies are needed to establish the long‐term safety, fertility outcomes, and optimal treatment sequences. In this study, a novel finding was obtained: DUL can be classified into three distinct subtypes. This was made possible by conducting a nationwide survey and analyzing many cases of this rare condition. The most common subtype was the total replacement type, accounting for 75% of all cases, followed by the myometrial replacement (16%) and submucosal‐dominant types (9%). To the best of our knowledge, no studies, to date, either in Japan or internationally, have classified DUL into subtypes. By clarifying the treatment outcomes of ART, implementation and effectiveness of uterus‐preserving surgeries, pregnancy outcomes, and perinatal prognoses for each DUL subtype, it may be possible to propose new treatment strategies for DUL, a condition for which hysterectomy has traditionally been considered the only therapeutic option. This study had some limitations. First, the present study was an analysis based solely on imaging data, and information such as patient background and treatment outcomes was neither collected nor analyzed. Therefore, it would be interesting to clarify in future studies whether treatment strategies, prognoses, and reproductive outcomes differ among these subtypes. In addition, a consensus process, such as Cohen's kappa, was not used to reach an agreement on cases judged as “intermediate”. This was because of the complexity of the classification process, which involved multistep consensus discussions rather than independent binary evaluations. Furthermore, even when applying strict diagnostic criteria, distinguishing DUL from multiple uterine leiomyomas is complicated by the ambiguous and unstandardized definition of “innumerable” nodules, a central yet unresolved element of DUL diagnosis. In summary, a nationwide survey was conducted to assess the clinical experience of DUL at obstetrics and gynecology institutions in Japan, targeting 1080 facilities participating in the Obstetrics and Gynecology Specialist Training Program of the Japanese Medical Specialty Board. Responses were obtained from more than 40% of the institutions. In total, 653 cases of DUL or DUL‐like multiple uterine leiomyomas managed over the past 10 years (since 2013) were reported by the participating institutions. In addition, the subcommittee conducted a central review of the MRI scans of patients diagnosed with DUL at each institution. DULs can be classified into three subtypes based on the location of leiomyoma development: total replacement, myometrial replacement, and submucosal dominance. Further research is required to clarify the status of DUL management in Japan.

In this study, a large number of participants were recruited from multiple institutions. Because obtaining individual informed consent from all participants would require an extremely large amount of time and cost, the study information will be publicly disclosed, thereby providing potential participants with an opportunity to opt out of participation. If any individual requests to withdraw from the study, their data will not be included. However, if the study results have already been published at the time of the request, this restriction will not apply. Each participating institution, including those that only provided existing samples or data, will post the study information in locations accessible to potential participants or on their institutional websites to ensure the opt‐out process.

Diffuse uterine leiomyomatosis (DUL) is a rare condition characterized by the presence of numerous uterine leiomyomas (fibroids), most of which are < 3 cm in diameter, arising within the myometrium near the endometrial surface and diffusely replacing the uterine muscle [ 1 , 2 ]. Many patients present with heavy menstrual bleeding and associated iron‐deficiency anemia at a young age. In patients who wish to conceive, DUL can cause refractory infertility even after assisted reproductive technology (ART). However, the rarity of DUL, lack of standardized diagnostic criteria, and insufficient awareness of the disease concept among obstetricians and gynecologists have resulted in diagnostic ambiguity regarding multiple uterine leiomyomas. Moreover, the clinical management of DUL in Japan has not been fully elucidated. Although there have been reports of patients with DUL achieving pregnancy and live birth following surgery or hormonal therapy [ 3 , 4 , 5 ], no studies have broadly compared the effectiveness of fertility‐preserving surgery, hormonal therapy, and ART on pregnancy outcomes. This study aimed to elucidate the current status of the diagnosis of DUL in obstetrics and gynecology practices across Japan. We first inquired about the number of DUL cases managed at each institution. Subsequently, assuming that the ambiguity of the diagnostic criteria for DUL may make it difficult to distinguish DUL from multiple uterine leiomyomas in several cases, we collected magnetic resonance imaging (MRI) scans of patients diagnosed with DUL at each institution and conducted a central review.

Masanori Ono is a member of the editorial board of the Journal of Obstetrics and Gynaecology Research and a co‐author of this article. To minimize bias, he was excluded from all editorial decision‐making related to the acceptance of this article for publication. The remaining authors declare no conflicts of interest.

This survey was conducted as a part of the activities of the Subcommittee on the Nationwide Survey on the Diagnosis and Treatment of Diffuse Uterine Leiomyomatosis under the Reproductive Endocrinology Committee of the Japan Society of Obstetrics and Gynecology. Between December 2023 and January 2024, a web‐based questionnaire survey was administered using Google Forms and distributed with identifiable responses to 1080 Obstetrics and Gynecology training facilities registered in the Obstetrics and Gynecology Specialist Training Program of the Japanese Medical Specialty Board. These facilities include most institutions in Japan that offer obstetric and gynecological services, excluding private clinics. The survey asked whether the institutions had any clinical experience with DUL or DUL‐like multiple uterine leiomyomas that were difficult to differentiate from DUL during the 10‐year period from January 2013 to December 2022. In this study, DUL was defined using the following criteria: (1) the presence of numerous leiomyomas of varying sizes within the myometrium replacing the normal myometrial tissue; (2) disappearance of the endometrial–myometrial junction (i.e., the junctional zone [JZ]) because of the presence of leiomyomas, or the JZ was preserved but innumerable small leiomyomas diffusely replaced the myometrium; and (3) relatively few leiomyomas protruding toward the serosal surface with generalized uterine enlargement. Representative imaging findings were provided in the questionnaire [ 1 ]. Given the limited awareness of the disease concept of DUL and the potential for diagnostic ambiguity with multiple uterine leiomyomas, institutions that indicated the ability to provide imaging data were asked to submit the MRI scans of patients diagnosed with DUL. The images were centrally reviewed by members of the subcommittee. Whether each case represented the DUL was determined using sagittal T2‐weighted MRI. The initial evaluation was conducted by two reviewers (Ishikawa and Goto) who classified the cases into three categories: clearly consistent with DUL based on the aforementioned criteria, clearly inconsistent with DUL, and indeterminate. The second round of evaluation was conducted by the subcommittee, during which indeterminate cases were reviewed and classified as DUL or non‐DUL cases. Whether the intermediate type was classified as DUL was determined by a majority vote among subcommittee members. The review process conducted by the subcommittee is illustrated in Figure  S1 . Cases determined to be DUL were further subclassified based on imaging characteristics into specific DUL subtypes. We used JMP 15.0 (SAS Institute Inc., Cary, NC, USA) for descriptive statistics and figure generation. This study was approved by the Ethics Committee for Observational Research at Chiba University Hospital (Study title: Nationwide Survey on the Diagnosis and Treatment of Diffuse Uterine Leiomyomatosis; Principal Investigator: Hiroshi Ishikawa; Approval number: HK202405 ‐06). In this study, no clinical information, including patient age, was collected from the participating institutions, and the diagnosis of DUL was determined solely based on MRI scans.

Figure S1: Consensus‐building process within the subcommittee members. A consensus process within the subcommittee members regarding the intermediate type and its outcomes is presented. Among the 49 cases initially classified as the intermediate type, 23 were ultimately judged to be DUL. Figure S2: Representative MRI scans that were initially judged as intermediate and were ultimately classified as DUL. (A and B) Because a relatively well‐defined 7‐cm leiomyoma nodule was present near the internal os in the posterior uterine wall, the case was initially judged as intermediate, but was ultimately classified as DUL. (C and D) Although innumerable uterine leiomyomas were observed in the submucosal and intramural layers, the uterine serosal surface was irregular owing to the presence of some subserosal leiomyomas; therefore, the case was initially judged as intermediate but was ultimately classified as DUL. (E and F) Although innumerable submucosal leiomyomas were present and the junctional zone had disappeared, one of them showed a well‐defined border. Therefore, the case was initially judged as intermediate but was ultimately classified as DUL.