A case report of uterine adenosarcoma with sarcomatous overgrowth and pulmonary metastasis

Clinical History and Presentation: The patient was a 56-year-old woman who presented on January 13, 2024, with stabbing pain in the left inguinal region for half a month. She had been postmenopausal for 2 years and reported no abnormal vaginal bleeding. Her past medical history was notable for hypertension of 2 years’ duration, for which she was on regular oral antihypertensive medication. She had no history of prior surgeries or other chronic diseases. Family history was noncontributory for malignancy or other hereditary disorders, and she had no significant smoking, alcohol consumption, or occupational exposure history. On physical examination, vital signs were stable. The abdomen was flat, soft, and non-tender. Gynecological examination revealed a palpable mass approximately 5 cm in diameter in the left adnexal region; the mass was moderately firm, mobile, and non-tender, with no abnormalities detected in the right adnexa. The uterus was normal in size and consistency. Transabdominal ultrasonography revealed an endometrial thickness of 7 mm and multiple hypoechoic nodules in the myometrium. A cystic-solid mass measuring 43 × 32 mm was identified in the left adnexal region, and a teratoma was considered in the differential diagnosis ( Figure 1A ). The patient was initially diagnosed preoperatively with uterine leiomyoma and teratoma. The preoperative differential diagnosis also included ovarian sex cord–stromal tumors (e.g., fibrothecoma) and ovarian malignancy, although the latter was considered less likely given the absence of abnormal vaginal bleeding and the imaging characteristics suggesting a benign process. Radiological findings of the patient. (A) Transvaginal ultrasound showing multiple hypoechoic nodules in the myometrium and a cystic-solid mass in the left adnexal region measuring approximately 43 × 32 mm. (B) Chest CT demonstrating multiple bilateral pulmonary nodules with well-defined margins, suggestive of metastatic lesions. Initial Clinical and Pathological Diagnosis: On January 23, 2024, the patient underwent laparoscopic total hysterectomy with bilateral salpingo-oophorectomy. Intraoperatively, the uterus was enlarged, corresponding to approximately 2positive months of gestation, with multiple surface protrusions. The left adnexa were congested and enlarged, with no obvious ovarian tissue identified. Intraoperative Frozen Section of the Left Adnexa: The specimen measured 8 × 6 × 2.5 cm, with focal gray-yellow and soft areas ( Figure 2A ). Microscopically, spindle-shaped and oval cells were observed, with pale cytoplasm, Microscopically, spindle-shaped and oval cells were identified, with pale cytoplasm, hyperchromatic chromatin, prominent nucleoli, and rare mitotic figures. Focal hemorrhage was noted. The intraoperative preliminary diagnosis was a sex cord-stromal tumor, favoring fibrothecoma with hemorrhage ( Figure 3B ) Immunohistochemistry: Calretinin (-), CK/P (-), Desmin (+ focal), Ki-67 (+ 8%), Inhibin-α (-). Gross pathological findings of the surgical specimens. (A) Gross appearance of the left adnexal mass measuring approximately 8 × 6 × 2.5 cm, showing a gray-yellow soft cut surface with focal hemorrhage. (B) Gross section of the uterus revealing a gray-white multinodular mass within the uterine cavity measuring approximately 6 × 5.5 × 5 cm, with areas of hemorrhage, cystic degeneration, and focal myxoid change. Histopathological features of uterine adenosarcoma and metastatic lesion (HE staining, ×200). (A) Characteristic periglandular stromal condensation forming a cuff-like pattern around endometrial-type glands. (B) Tumor stromal component infiltrating ovarian tissue. (C) Tumor emboli identified within vascular spaces, indicating lymphovascular invasion. (D) Area of osseous metaplasia within the tumor. (E) Lung biopsy showing proliferation of spindle tumor cells consistent with metastatic uterine adenosarcoma. Total Uterus and Right Adnexa: The uterus measured 12 × 6.5 × 5.5 cm. A 6 × 5.5 × 5 cm gray-white multinodular mass was identified within the uterine cavity. The cut surface showed hemorrhage and cystic degeneration, with partially myxoid areas ( Figure 2B ). Microscopic Findings: The tumor exhibited endometrioid, tubular, and semi-tortuous glandular structures. The glands were separated by abundant stroma, and the periglandular stromal cells were densely arranged, forming a characteristic “cuff-like” pattern ( Figure 3A ). Mitotic figures ranged from 5–8 per 10 high-power fields (HPF). Focal osseous metaplasia ( Figure 3D ), hemorrhage, and lymphovascular tumor emboli ( Figure 3C ) were observed. The tumor invaded the myometrium. Immunohistochemistry: Caldesmon (-), CD10 (+ focal), Ki-67 (+ 40%), WT-1 (-), ER (+ focal), PR (+ focal) ( Figure 4 ). Based on the histomorphological features and immunohistochemical findings, a diagnosis of uterine adenosarcoma with sarcomatous overgrowth was established. The tumor was noted to invade the ovarian tissue. Immunohistochemical findings of the primary uterine tumor (IHC, ×200). (A) Tumor cells CD10 (+). (B) Tumor cells Desmin (+, focal). (C) Tumor cells WT-1 (−). (D) Tumor cells ER (+, focal). (E) Tumor cells PR (+, focal). (F) Ki-67 proliferation index approximately 40%. Postoperative Adjuvant Therapy and Disease Progression: From February to June 2024, the patient received six cycles of adjuvant chemotherapy with gemcitabine plus docetaxel. In September 2024, contrast-enhanced chest CT revealed multiple bilateral pulmonary nodules ( Figure 1B ), with more than five nodules and the largest measuring11mm×9mm.No subsequent PET/CT examination was performed. Percutaneous lung biopsy confirmed metastatic uterine adenosarcoma ( Figure 3E ). Immunohistochemistry of the metastatic lesion: ER (+), PR (-), Ki-67 (+ 20%), TTF-1 (-), Napsin A (-), Desmin (+ focal), CD10 (+ focal), CK/P (-). RNA sequencing for fusion gene detection revealed no abnormalities ( Figure 5 ). Immunohistochemical findings of the pulmonary metastatic lesion (IHC, ×200). (A) Tumor cells CD10 (+). (B) Tumor cells Desmin (−). (C) Tumor cells TTF-1 (−). (D) Tumor cells ER (+, focal). (E) Tumor cells PR (−). (F) Ki-67 proliferation index approximately 20%. In December 2024, the treatment regimen was changed to doxorubicin combined with toripalimab and anlotinib for four cycles, followed by maintenance therapy with toripalimab plus anlotinib. Follow-up CT in July 2025 demonstrated progression of multiple metastatic lesions in both lungs compared with previous imaging. The disease progression process is shown in Table 1 . Clinical timeline of diagnosis, treatment, and follow-up.

Uterine adenosarcoma (UAS), also known as Müllerian adenosarcoma, was first reported in 1974 ( 1 ). It accounts for approximately 5%–10% of all uterine sarcomas and about 1% of all gynecologic malignancies ( 2 , 3 ). Histologically, it is characterized as a biphasic tumor composed of benign epithelial elements and malignant stromal components. UAS predominantly occurs in postmenopausal women, with the uterine fundus and cervix being the most common sites of involvement. Most UAS are low-grade tumors with relatively indolent behavior, with a 5-year disease-specific survival rate of approximately 48%–79%. Although both the incidence and distant metastasis rate are low, the lung is the most common metastatic site; in a Japanese nationwide case series of 110 cases, Tate et al. found that 75% of distant recurrences were pulmonary ( 4 ). At the molecular level, the epithelial and stromal components have distinct clonal origins, and the genetic alterations are primarily confined to the stromal component ( 5 ). UAS exhibits complex and heterogeneous molecular features, commonly including amplification of MDM2, CDK4, HMGA2, and TERT, as well as alterations in the PIK3CA/AKT/PTEN signaling pathway. Tumors with sarcomatous overgrowth or high-grade transformation more frequently harbor TP53 mutations, ATRX mutations, and MYBL1 amplification ( 6 ), which are associated with increased aggressiveness and an unfavorable prognosis.

According to the 5th edition of the WHO Classification of Female Genital Tumours ( 7 ), UAS is categorized as a mixed epithelial and mesenchymal tumor. The epithelial component is benign or atypical, whereas the stromal component is typically low-grade sarcomatous. When the sarcomatous component accounts for more than 25% of the total tumor volume, is often high-grade, and lacks glandular structures or demonstrates marked cytological atypia, a diagnosis of uterine adenosarcoma with sarcomatous overgrowth (MASO) can be established ( 8 ). This variant indicates highly aggressive biological behavior and significantly impacts prognosis. Based on currently published case reports, the clinical manifestations of UAS are generally nonspecific, most commonly presenting with abnormal vaginal bleeding, a pelvic mass, or lower abdominal discomfort ( 3 ). In some patients, the lesion may be detected incidentally on imaging studies, which can easily lead to delayed diagnosis. The pathogenesis of UAS remains unclear. Some studies have suggested that adenomyosis and endometriosis may be associated with the development of UAS. A possible mechanism is that bleeding from endometriotic lesions may induce persistent oxidative stress and DNA damage ( 9 , 10 ). In the present case, after extensive sampling of the specimen, endometriotic foci were identified in the right ovarian tissue, further supporting a potential association between endometriosis and the occurrence and progression of uterine adenosarcoma, and providing clinical evidence for exploring its underlying pathogenic mechanisms. In terms of pathological diagnosis, UAS is generally of low malignant potential. The characteristic histopathological feature is densely cellular stromal proliferation surrounding the glands in a cuff-like pattern, often forming slit-like spaces. A multivariate analysis demonstrated that the presence of sarcomatous overgrowth, heterologous elements, myometrial invasion, and lymphovascular invasion are associated with a higher risk of recurrence and metastasis ( 11 ). In the present case, the tumor exhibited a prominent cuff-like architecture, with the sarcomatous component constituting the majority of the lesion. Mitotic figures ranged from 5–8 per 10 high-power fields (HPF), and osseous metaplasia, myometrial invasion, and lymphovascular tumor emboli were observed. Pulmonary metastasis occurred eight months after surgery, indicating highly aggressive biological behavior and further supporting the correlation between the aforementioned high-risk pathological features and poor prognosis. Regarding differential diagnosis, UAS is extremely rare, and there are limited immunohistochemical markers available to aid in its diagnosis, making differentiation challenging. In the intraoperative frozen section of this case, the tumor was predominantly composed of malignant stromal elements without an identifiable benign epithelial component. Due to the limited sampling inherent to frozen section examination and the absence of apparent mitotic figures, it was easily confused with fibrothecoma. However, immunohistochemistry plays a crucial role in differential diagnosis. In most adenosarcomas, the stromal component shows diffuse or multifocal expression of CD10, ER, PR, and WT-1. In contrast, fibrothecoma typically expresses markers such as Inhibin, Calretinin and SF-1. In this case, the left adnexal tumor was negative for Inhibin-α and Calretinin, with focal positivity for CD10 and Desmin. Combined with the characteristic morphological features of the primary uterine lesion, these findings ultimately supported the diagnosis of UAS involving the left adnexa. Preoperative diagnosis of uterine adenosarcoma (UAS) remains challenging due to its nonspecific clinical presentation and overlapping imaging features with benign uterine pathologies. Transvaginal ultrasound serves as the initial screening tool; however, its ability to distinguish UAS from benign entities such as endometrial polyps or leiomyomas is limited. In a large multicenter retrospective study of 195 uterine sarcomas, Ludovisi et al. summarized the clinical and ultrasound characteristics of uterine sarcomas and found that uterine sarcomas typically present as solid masses with inhomogeneous echogenicity, sometimes with irregular cystic areas ( 12 ). Magnetic resonance imaging (MRI), with its superior soft-tissue resolution, holds significant value in the preoperative evaluation of UAS. In a case-control study, Harada et al. identified key MRI features distinguishing UAS from endometrial polyps, including larger tumor volume, larger cystic lesions, and gross intratumoral hemorrhage; these features may also aid in predicting the presence of sarcomatous overgrowth (SO) ( 13 ). In the present case, although MRI was not performed preoperatively, the ultrasound finding of a 43 × 32 mm cystic-solid mass with heterogeneous echogenicity was consistent with the ultrasound features of uterine sarcomas described in the study by Ludovisi et al., highlighting the potential clinical value of dedicated imaging workup, including MRI, in suspected cases ( 12 ). Differential diagnosis of uterine adenosarcoma (UAS) is challenging due to its rarity and the limited availability of specific immunohistochemical markers for this entity. First, UAS must be distinguished from endometrial stromal sarcoma (ESS). ESS is characterized by a pure stromal component without glandular elements. In contrast, the present case exhibited a distinct biphasic architecture—benign endometrioid glands admixed with sarcomatous stroma, with the stroma forming characteristic periglandular “cuff-like” aggregations, a feature incompatible with ESS. Immunohistochemically, although the stromal component in our case showed focal CD10 positivity, ESS typically demonstrates diffuse and strong CD10 expression and is frequently associated with specific fusion genes (eg JAZF1-SUZ12, YWHAE-FAM22). Genetic testing in this case did not identify any of these fusion genes, further supporting the exclusion of ESS. Second, the differential diagnosis from uterine carcinosarcoma should be considered. Uterine carcinosarcoma typically exhibits a frankly malignant epithelial component along with a high-grade sarcomatous stroma, which differs morphologically from UAS ( 14 ). In our case, the glandular epithelial component was morphologically benign without significant atypia, and only the stromal component was malignant (sarcomatous overgrowth). This “benign epithelium with malignant stroma” biphasic pattern is the key feature distinguishing adenosarcoma from carcinosarcoma. Third, ovarian sex cord–stromal tumors should be excluded. In this case, the intraoperative frozen section of the left adnexal mass favored fibrothecoma because the tumor was predominantly composed of spindle cells without identifiable glandular components. However, after comprehensive sampling of the permanent paraffin sections, a distinct biphasic architecture (benign glandular epithelium with sarcomatous stroma) and “cuff-like” changes were identified in the primary uterine lesion. Immunohistochemically, the tumor cells in the left adnexa were negative for Calretinin and Inhibin-α, whereas sex cord–stromal tumors typically show positivity for these markers. Moreover, the immunophenotype of the ovarian lesion (CD10 focal+, Desmin focal+, ER focal+) was completely consistent with that of the stromal component of the primary uterine tumor, indicating that both lesions represent local regional extension from the same clonal origin rather than an independent ovarian sex cord–stromal tumor. Additionally, UAS should be differentiated from atypical polypoid adenomyoma (APA). APA is characterized by atypical endometrial glands and a cellular myofibromatous stroma, lacking the phyllodes-like architecture and cuff-like stromal arrangement seen in UAS. The epithelial component in APA shows varying degrees of atypia and is often accompanied by prominent squamous metaplasia ( 15 ). Compared with ESS, UAS demonstrates a prominent glandular component and lacks the characteristic fusion genes seen in ESS. In summary, based on the integrated histomorphological and immunohistochemical findings, the final diagnosis of uterine adenosarcoma with sarcomatous overgrowth was established, and the above major differential diagnoses were excluded. Regarding the determination of clinical stage and the nature of ovarian involvement in this case, according to the FIGO 2009 staging system for uterine sarcomas ( 16 ), the tumor had extended to the pelvic adnexa at the time of initial surgery, corresponding to Stage II(tumor beyond the uterine corpus but confined to the pelvis). After the detection of pulmonary metastases, the stage was updated to Stage IV(distant metastasis). As for the mechanism of ovarian involvement, anatomically, the involved ovary was located ipsilateral to the primary tumor, and intraoperative findings demonstrated close proximity and ill-defined borders between the two, consistent with direct extension from the uterine serosal surface to the adjacent ovarian cortex. This is supported by GOG multicenter studies ( 17 , 18 ), which have shown that extrauterine spread of uterine adenosarcoma may manifest as ovarian involvement or parametrial invasion. Histologically, microscopic examination revealed sarcomatous stromal components infiltrating from the uterine wall into the ovarian cortex ( Figure 3B ), with no independent benign or malignant glandular epithelial components within the ovary. If it were a primary ovarian adenosarcoma, a complete biphasic architecture would be expected ( 19 ); however, in the present case, the ovarian lesion represented merely an extension of the stromal component. Moreover, the right adnexa contained only endometriotic foci without tumor involvement, suggesting that the left-sided lesion was not an independent malignant transformation arising from endometriosis bilaterally. Immunophenotypically, the immunophenotype of the tumor cells within the ovary was completely consistent with that of the stromal component of the primary uterine tumor, supporting that both lesions represent local regional extension from the same clonal origin. In summary, the ovarian involvement in this case should be interpreted as direct invasion from the uterine primary tumor. Molecular studies have demonstrated that the pathogenesis of UAS is complex due to its pathological heterogeneity. Different studies have reported a variety of gene mutations, amplifications, or deletions. Common alterations include amplification of MDM2, CDK4, HMGA2, and TERT, as well as abnormalities in the PIK3CA/AKT/PTEN signaling pathway ( 5 , 20 ). Cases with sarcomatous overgrowth (MASO) or high-grade transformation are more likely to harbor TP53 and ATRX mutations, as well as MYBL1 amplification ( 6 , 21 ). In the present case, no fusion genes with clear diagnostic or therapeutic significance were identified, suggesting the possible presence of driver alterations that remain undetected by current testing technologies. This finding also reflects the molecular heterogeneity of metastatic UAS. The absence of actionable genetic alterations means that treatment still primarily relies on conventional chemotherapy and endocrine therapy strategies, underscoring the necessity of further molecular subtyping studies and the exploration of potential targets for precision therapy. With regard to treatment, surgical resection remains the mainstay of therapy for UAS. For patients with localized disease, total hysterectomy combined with bilateral salpingo-oophorectomy is considered the standard approach. According to large-scale published studies ( 4 ), high-risk patients (such as those with sarcomatous overgrowth, deep myometrial invasion, metastasis, or recurrence) should receive postoperative adjuvant chemoradiotherapy and undergo long-term regular follow-up. In the present case, despite receiving adjuvant chemotherapy with gemcitabine plus docetaxel after surgery, the patient rapidly developed pulmonary metastases. Subsequent treatment with doxorubicin combined with a PD-1 inhibitor and anlotinib targeted therapy still resulted in disease progression. These findings indicate that metastatic UAS, particularly aggressive subtypes, has limited responsiveness to current systemic treatment regimens, highlighting the urgent need to explore more precise molecular classification and individualized therapeutic strategies. The prognosis of UAS largely depends on the presence of myometrial invasion and sarcomatous overgrowth ( 22 ). Reported 2-year overall survival and progression-free survival rates for patients with low-grade uterine adenosarcoma are both 100%. Tumors with myometrial invasion have a survival rate of approximately 60%, whereas patients with distant metastases often have survival rates below 50% ( 23 ). Sarcomatous overgrowth is a well-established poor prognostic factor. In the case series of 12 cases reported by Seidman et al., 60% of the tumors exhibited sarcomatous overgrowth, which was significantly higher than the previously reported rate of 16% ( 24 ). Zhang et al. specifically analyzed 3 cases of adenosarcoma with sarcomatous overgrowth ( 25 ) and found that the pure sarcomatous component exceeded 25% in all cases, with one patient dying 1 month after surgery, suggesting the highly aggressive nature of this subtype. These domestic and international case series collectively confirm that sarcomatous overgrowth is an important factor affecting prognosis. Notably, most studies have reported ( 3 , 26 ) that in cases of distant metastasis, the metastatic lesions are almost entirely composed of malignant stromal components, while the glandular epithelial component is typically absent or present only as residual non-neoplastic glands. The comparative study by Omi et al. on 7 cases of primary and recurrent adenosarcoma ( 27 ) provided further confirmation of this phenomenon: among 3 evaluable patients who developed recurrence or metastasis, biopsy revealed that the metastatic lesions consisted exclusively of stromal components with no benign epithelial elements, and their immunophenotype was largely identical to that of the primary tumor. These findings suggest that the stromal component constitutes the key biological basis driving tumor invasion, recurrence, and distant metastasis. This indicates that even when the glandular component of the primary tumor appears morphologically benign, the biological behavior of the stromal component can still dictate disease progression and prognosis. The prognostic significance of FIGO staging in uterine adenosarcoma has been further validated by the SARCUT study. SARCUT (SARComa of the UTerus) is a retrospective international multicenter study involving 46 European centers ( 28 ). In the subanalysis of 32 uterine adenosarcoma cases, FIGO stage II–III was identified as one of the most significant factors affecting overall survival, along with age and tumor size at diagnosis. The study concluded that the most important prognostic factors for uterine adenosarcoma are age and FIGO stage, as well as, indirectly, tumor size at diagnosis. These findings corroborate the staging assessment in the present case—in which the tumor had extended to the pelvic adnexa (Stage II) at initial surgery and progressed to Stage IV upon detection of pulmonary metastases—and further underscore the central role of FIGO staging in prognostic evaluation of uterine adenosarcoma.

This case report presents a uterine adenosarcoma with sarcomatous overgrowth that exhibited a highly aggressive clinical course, characterized by early postoperative pulmonary metastasis and poor response to multi-line systemic therapies. The findings further confirm that sarcomatous overgrowth, myometrial invasion, and lymphovascular involvement are important pathological indicators of unfavorable prognosis. Molecular testing did not identify any targetable driver gene mutations, suggesting that the pathogenesis of such tumors may involve complex molecular events not captured by current assays, including rare fusion genes, copy number variations, or epigenetic alterations. Given the rarity of uterine adenosarcoma, especially the subtype with sarcomatous overgrowth and distant metastasis, standardized treatment protocols remain lacking. There is an urgent need for multicenter collaborative efforts and molecular profiling studies to establish more precise prognostic stratification biomarkers and to develop individualized therapeutic strategies.