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Abstract

Uterine leiomyoma rarely metastasizes to the lungs, and such occurrences are generally attributed either to intravenous leiomyomatosis or to benign metastasizing leiomyoma related to prior surgical manipulation. However, distinguishing between these two etiologies is not always straightforward. Cases reported as pulmonary metastases of intravenous leiomyomatosis often have a history of uterine surgery, while cases diagnosed as benign metastasizing leiomyoma without intravenous leiomyomatosis may not have undergone thorough pathological evaluation of the entire uterus, leaving the possibility of undetected intravenous leiomyomatosis. In cases where both intravenous leiomyomatosis, and a history of uterine surgery are present, determining the origin of pulmonary lesions requires comparative genomic analysis of each lesion to assess their clonality. To date, no such molecular studies have been conducted. The present case is a 47-year-old woman who underwent transvaginal myomectomy for submucosal leiomyoma 10 years earlier; computed tomography showed multiple nodules in both lungs, and thoracoscopic tumor resection was performed, with histopathology showing benign leiomyoma. A 40 mm leiomyoma-like mass was observed in the uterus, and histopathology of the removed uterus diagnosed intravenous leiomyomatosis. Comprehensive genomic profiling revealed that the submucosal leiomyoma and a metastatic leiomyoma in the lungs shared a single nucleotide variant in CSMD3, PIK3R1, and MAGEA1. The uterine intravenous leiomyomatosis also shared the same CSMD3 variant, but not the others. Taken together, these results indicate that the submucosal leiomyoma was actually a part of intravenous leiomyomatosis and surgical manipulation induced it to metastasize to the lungs. This suggests that the presence of intravenous leiomyomatosis and mechanical stimulation can act together to result in a metastatic leiomyoma, and a case diagnosed with benign metastatic leiomyoma should be carefully searched for intravenous leiomyomatosis.

Keywords

leiomyoma, uterine neoplasms, lung neoplasms, vascular neoplasms, genetic testing

Introduction

Benign tumors usually do not metastasize. However, when a metastatic leiomyoma develops that appears pathologically benign, without nuclear atypia or a significant number of mitoses, it is known as "benign metastatic leiomyoma" (BML). To date, approximately 500 cases of BML have been reported, and since more than 95% have a history of "uterine leiomyoma" [1-2], tumors of smooth muscle origin in the uterus are considered to be the primary site of BML. The smooth muscle of the uterus may give rise to tumors that do not meet histopathologic criteria for malignancy but may metastasize, i.e., smooth muscle tumors of uncertain malignant potential (STUMP); the distinction between STUMP and benign leiomyoma is difficult [3], and if diagnosed as leiomyoma by a pathologist, the metastasis may be diagnosed as BML. On the other hand, intravenous leiomyomatosis (IVL) is a rare disease in which a histopathologically benign leiomyoma extends into blood vessels [4] and can metastasize to the lungs and other organs, so metastases of IVL can be diagnosed as BML.

The differential diagnosis between BML and IVL carries important clinical implications, particularly in terms of recurrence risk, surveillance strategies, and therapeutic considerations. While BML generally follows an indolent course and is often incidentally detected, IVL is characterized by progressive intravascular extension, which may lead to sudden death and is associated with a higher risk of recurrence (4.8~30%) [5], warranting more aggressive and long-term surveillance.

Herein, we report a case of pulmonary metastasis of uterine leiomyoma 10 years after removal of a submucosal leiomyoma and subsequent diagnosis of IVL in the removed uterus. We also report the clonality analysis of these leiomyomas by comprehensive genetic profiling (CGP).

Case presentation

A 47-year-old Japanese woman, gravida 2 and parity 2, premenopausal. She had a history of irregular genital bleeding 10 years earlier and had undergone transvaginal myomectomy for submucosal leiomyoma of the uterus. This time, in the absence of any symptoms, a chest radiograph performed during routine medical checkup revealed multiple pulmonary nodules in both lung fields (Figure 1A). Chest computed tomography (CT) also showed multiple well-defined round nodules, 1-2 cm in size, diffusely distributed in both lungs (Figure 1B, 1C), and the patient underwent thoracoscopic resection of the masses. Histopathological examination revealed that the nodules were benign leiomyomas composed of ER+/PgR+/α-SMA+ spindle cells with well-defined borders. There was no nuclear atypia and mitosis, with a Ki67 index of 4.3% (Figure 1a-1i).

Transvaginal sonography and contrast-enhanced magnetic resonance imaging (MRI) revealed a 4-cm leiomyoma in the myometrium (Figure 1D, 2E). Contrast-enhanced CT showed no abnormal findings other than pulmonary nodules, and positron emission tomography CT showed no other abnormal findings. Total laparoscopic hysterectomy and bilateral salpingo-oophorectomy were performed for pulmonary leiomyoma and uterine leiomyoma for histologic diagnosis and castration. Histopathologic examination of the uterus revealed leiomyoma cell proliferation without nuclear atypia in the vein.

Immunostaining showed that the leiomyoma cells were ER+/PgR+/αSMA+, Ki-67 index 6% (Supplementary Table 1), and extended into the vein lined by CD31+ vascular endothelial cells, leading to the diagnosis of IVL. The pathological specimen of a submucosal leiomyoma 10 years earlier was reviewed, but there was no evidence of intravenous extension, and the immunohistochemical staining result was ER+/PgR+/αSMA+, leading to the diagnosis of benign leiomyoma. After hysterectomy and bilateral adnexectomy, the patient was followed up without treatment, with a slight shrinkage trend of the remaining lung nodules and no other new lesions (Supplementary Figure 1).

Figure 1. (A) Chest x-ray showed multiple well-defined circular nodules in both lung fields. (B, C) Chest computed tomography (CT) also showed multiple well-defined, circular masses in both lungs, without infiltrates or spicules. (D, E) Magnetic resonance imaging (MRI) of the pelvis showing a 4 cm mass on the right side of the uterus without hemorrhage. No abnormalities on diffusion weighted imaging or positron emission tomography CT (not shown). (a-i) Histopathology of benign metastasizing leiomyoma. CK7+, CK20-, TTF-1+, ER- and PgR-bronchioles are entrapped within a mass composed of spindle-shaped cells of smooth muscle origin, which were α-SMA+, caldesmon+, ER+ and PgR+. a: Hematoxylin-eosin (HE) stained image b: HE stained image on high power fields. (c) TTF-1 (d) caldesmon (e) ER (f) PgR (g) Ki67 (4.3%) (h) a-SMA (i) CD31 (j-o) Histopathology of recurrent uterine intraventricular myoma. α-SMA+, caldesmon+, ER+ and PgR+ smooth muscle cells are present in vessels lined by CD31-positive vascular endothelial cells. (j) HE-stained image (k) ER (l) PgR (m) Ki67 (6%) (n) α-SMA (o) CD31 (p-u) Histopathology of a submucosal leiomyoma removed 10 years earlier. It was composed of α -SMA+, ER+ and PgR+ spindle-shaped cells. (p) HE-stained image (q) ER (r) PgR (s) Ki67 (3.7%) (t) α-SMA (u) CD31

Figure 2. Developmental hypothesis of benign metastasizing leiomyoma in the present case. Clones with variant of uncertain significance (VUS) of CSMD3 were present in the submucosal leiomyoma removed 10 years earlier and the recurrent intravenous leiomyoma, while the submucosal leiomyoma removed 10 years earlier also had PIK3R1, MAGEA1 variant. These had surgically produced a pulmonary leiomyoma with similar variants and several more VUS.

Variant	Leiomyoma of 10 years earlier		Leiomyoma with uterus		Lung leiomyoma
Gene	Nucleotide change	Freq. (%)	Nucleotide change	Freq. (%)	Nucleotide change	Freq. (%)
CSMD3	c.4723T>C	7.5	c.4723T>C	16.4	c.4723T>C	4
PIK3R1	c.1538A>G	32.3			c.1538A>G	33
MAGEA1†	c.750G>A	37.4			c.750G>A	46.2
TPR					c.6110G>A	28.6
SGK1					c.1411G>A	25
SGK1					c.1365G>A	25
NOTCH1					c.4021G>A	22.2
KAT6B					c.5153G>A	19.4
TSC2					c.2053C>T	33.3
TML: Oncomine tumor mutation load assay (Thermo Fisher Scientific, Tokyo),†: Synonymous variants

Table 1. Results of comprehensive genomic profiling testing (TML)

CGP testing using the Oncomine tumor mutation load assay (TML, Thermo Fisher Scientific, Tokyo) was performed on the three types of leiomyomas and the fallopian tube as a normal control (Table 1) (Supplementary Text 1). Only one variant of uncertain significance (VUS) in CSMD3 was shared between the submucosal leiomyoma removed 10 years earlier and the IVL, and this variant was also found in the pulmonary leiomyoma. In addition to this VUS, the pulmonary leiomyoma shared the PIK3R1 and MAGEA1 variants with the submucosal leiomyoma removed 10 years earlier (Figure 2). MED12, which is frequently mutated in uterine leiomyoma, was not included in the TML panel, but when pulmonary leiomyoma was analyzed with FoundationOne CDx®, no MED12 variants were found (Supplementary Table 2).

Results and discussion

Clonality analysis of BML and uterine leiomyoma by next-generation sequencing (NGS) has been reported in five cases in three papers [5-7]. All were investigated by CGP. In two of the three cases reported by Wu et al, several SNVs (BCL11B, DNMT3A, FANCD2, MSH6, SYNE1) were found to be shared between uterine and lung tumors, but no MED12 variant was found, and in one case there was no shared SNV [5]. In one case reported by Jiang et al, the lung tumor showed marked nuclear atypia and responded to chemotherapy with epirubicin, ifosfamide, and dacarbazine. The lung tumor showed shared SNVs, including MED12, between the uterine and lung tumors that had been removed 8 years earlier with a diagnosis of uterine leiomyoma, but a new PTEN variant was detected in the lung tumor and the patient subsequently died of the primary disease, suggesting that the sarcoma component may have metastasized        in this case [7]. Ofori, et al. reported a case in which the lung tumor had a miliary nodular pattern and            histopathological evidence of focal pleomorphism. Although there were common SNVs between the uterine and lung tumors, including MED12, the tumor also had variants in ARID1A, and the patient died of the disease within a short time after presentation, suggesting that the case was not a benign leiomyoma but rather a sarcoma [8]. Therefore, two out of three true BML cases clonally analyzed by NGS so far     show shared SNVs between uterine tumor and lung metastasis. To the best of our knowledge, clonality analysis by NGS has never been performed for BML with IVL as in the present case.

In a systematic review of 385 cases of BML in 2023, the coexistence of 16 cases of IVL was reported [2]. In addition, there are other reports suggesting that IVL metastases may cause BML [9-12]. In the present case, the submucosal leiomyoma resected 10 years earlier was not pathologically diagnosed as IVL, and retrospective review of archival slides did not reveal intravenous extension. However, since IVL was found in the remaining uterus that was later removed, it is suggested that the submucosal leiomyoma removed 10 years earlier was also a leiomyoma that had the ability to extend into the veins. To our knowledge, there have been no studies of BML in which central pathologic review of the resected uterus has been performed. It is unknown whether common leiomyoma that are not STUMP or IVL have the potential to metastasize.

A history of total hysterectomy or myomectomy is commonly observed in patients with BML [1,2]. Notably, 14 out of 16 reported cases of BML associated with IVL had a documented history of uterine surgery [2]. In the present case, the SNVs common to pulmonary leiomyoma were found at three sites in the leiomyoma resected 10 years earlier, but at only one site in the IVL of the remaining uterus (Figure 2). Before performing the genomic analysis, we considered two hypotheses regarding the origin of the pulmonary lesions: (1) the uterine IVL metastasized to the lungs, and the myomectomy 10 years earlier was unrelated; or (2) surgical manipulation of the submucosal leiomyoma caused it to metastasize to the lungs (i.e., BML), and the uterine IVL was unrelated. The second hypothesis was considered much less likely because both BML and IVL are rare diseases and their coexistence in the same patient would be unexpected. Genomic analysis indicated that the uterine submucosal lesion resected 10 years earlier, the uterine IVL, and the pulmonary lesions were all clonally related, and the submucosal lesion and the pulmonary lesions were more closely related to each other than either was to the uterine IVL. The close genetic relationship of the uterine submucosal lesion and the pulmonary lesions certainly seemed to suggest a case of pulmonary leiomyoma due to surgical manipulation, but unexpectedly, these two lesions were also clonally related to the uterine IVL. A consistent interpretation would be that the lesion considered to be a submucosal leiomyoma was actually a part of IVL (although this could not be confirmed by pathological review), and the surgical manipulation of the IVL, not of the conventional leiomyoma, caused it to metastasize to the lungs. To our knowledge, this dual etiology has not been emphasized before, but it is consistent with the observation that a high proportion of IVL cases with lung metastases have a history of prior uterine surgery [2]. Furthermore, it underscores the need for molecular-level investigations—particularly in non-surgical cases of IVL—to better understand the pathogenesis of BML and determine whether true metastasis has occurred. The formation of leiomyoma within blood vessels has been observed in extra pelvic sites beyond the uterus, although such occurrences are rare [13]. This raises the possibility that a subset of lesions diagnosed as BML may in fact represent distinct pathological entities, and not true BML of uterine origin. Careful pathological and molecular evaluation is therefore essential to ensure accurate diagnosis in such atypical presentations.

Figure 2. Developmental hypothesis of benign metastasizing leiomyoma in the present case. Clones with variant of uncertain significance (VUS) of CSMD3 were present in the submucosal leiomyoma removed 10 years earlier and the recurrent intravenous leiomyoma, while the submucosal leiomyoma removed 10 years earlier also had PIK3R1, MAGEA1 variant. These had surgically produced a pulmonary leiomyoma with similar variants and several more VUS.

In this case, no MED12 mutation was found in BML. MED12 mutations are reported to be frequently found in leiomyoma but not in IVL [14]. The SNV of CSMD3 (c4723T>C) was found in all three leiomyoma with a low variant allele frequency, suggesting a subclonal variant. The SNV of CSMD3 (c4723T>C) has only been reported in one case of colorectal cancer, but its clinical significance is unknown [15]. In contrast, the SNV of PIK3R1 was found in BML and submucosal leiomyoma removed 10 years earlier. As PIK3R1 activation is associated with cell survival through enhanced PI3K signaling [16], it is possible that the mutation was a driver for the development of lung metastases. However, the SNV (c.1538A>G) found in the present case is not registered in the COSMIC database and its functional significance remains unresolved. Otherwise, no oncogenic driver mutations were detected in the CGP performed in this study. Comprehensive analyses, such as whole genome sequencing, are needed to clarify which genetic alterations are responsible for BML.

Conclusion

We experienced a case of a patient diagnosed with pulmonary leiomyoma 10 years after transvaginal myomectomy and IVL after removal of the uterus. Clonality analysis showed that removal of the submucosal leiomyoma was the cause of pulmonary leiomyoma, and the submucosal leiomyoma was clonally related to IVL. It is possible that the cases diagnosed with BML include those with latent IVL, and further studies based on the accumulation of BML cases and central pathologic review would be desirable in the future.

Informed consent

The patient provided informed consent.

Conflicts of interest

Dr. K. Sakai had honoraria for lectures from Qiagen, Inc., Takeda Pharmaceutical Co., Ltd. Nippon Kayaku Co., Ltd., Life Technologies Japan Ltd. Dr. K. Nishio had funding grants from Sysmex Corporation, Nichirei Biosciences Inc., Hitachi, Ltd., Otsuka Pharmaceutical, Thoracic Oncology Research Group, Eli Lilly Japan K.K., Japan Breast Cancer Research Group and Nippon Boehringer Ingelheim Co., Ltd. and speaking and lecture fees from Chugai Pharmaceutical Co Ltd., MSD K.K., Guardant Health Inc., DAIICHI SANKYO, SymBio Pharmaceuticals Limited., Ono Pharmaceutical Co Ltd, Janssen Pharmaceutical K.K., Novartis Pharma K.K., ELI LILLY JAPAN K.K., Otsuka Pharmaceutical Co., Ltd., Invitae Japan, AstraZeneca K.K., Nichirei Biosciences Inc. and Maruho Co., Ltd. The other authors declare no conflicts of interest.

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