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Abstract

Objective:

Adenosarcoma is an uncommon cancer of the female genital system that consists of malignant mesenchymal and benign epithelial components. In this article, we evaluated the clinical, investigational, diagnostic, and oncological data of such a rare disease.

Methods:

In this retrospective descriptive study, the data of the patients treated between January 2011 and October 2024 have been reviewed. The current investigation documented clinicopathological features, treatment, and outcomes.

Results:

A total of 15 patients have been included. The mean age was 59.4 years, and the mean body mass index was 33.64 kg/m². All patients reported abnormal uterine bleeding. In 14 patients (93.3%), pelvic MRI was used as an imaging modality. Neoadjuvant treatment was not administered to any of the patients. Eight patients (53.3%) underwent a hysterectomy and bilateral salpingo-oophorectomy only, whereas the remaining patients underwent, in addition, an omentectomy, lymphadenectomy, or both. Eleven patients (73.3%) had an immunohistochemical staining confirming their pathological diagnosis. In 9 individuals (60%), sarcomatous overgrowth was observed. Adjuvant therapy was administered to 11 patients (73.3%). The mean follow-up duration was 11.7 months, with 7 patients (46.6%) experiencing relapses. The median disease-free survival was 12 months, and overall survival was 13 months.

Conclusion:

Adenosarcoma of the uterus is a rare condition with a low prevalence. Surgical resection is the standard of care. There is little evidence to support treatment choices; hence, the oncologist’s clinical judgment must be used.

Keywords

adenosarcoma sarcomatous overgrowth survival rate hysterectomy prognosis

Introduction

Uterine adenosarcoma (UAS) was first named by Clement and Scully in 1974, defining it as a combination of benign glandular tissue and malignant stromal elements. By 1979, with the reporting of several cases, the term Müllerian adenosarcoma gained acceptance.¹ Five to ten percent of all uterine sarcomas are UAS, an uncommon form of cancer.²

UAS affects females of all ages. While premenopausal patients, including teenagers, account for around 30% of cases, the majority occur in postmenopausal women.³ It seldom affects the ovary or cervix, but it commonly affects the uterine body. Myometrial invasion, extrauterine metastases, high mitotic rate, and sarcomatous overgrowth are associated with poorer outcomes.^4,5

The most common presentation of UAS is vaginal bleeding; however, pelvic pain, vaginal discharge, and pelvic compression symptoms are all possible.⁶ Although there are still debates about lymphadenectomies and postoperative care, hysterectomy and bilateral salpingo-oophorectomy are the conventional therapies for UAS.⁷

Objective

This study aims to present the epidemiological, clinical, diagnostic, and prognostic features of patients. The results will provide important insights that could guide future research directions and clinical decision-making.

Methods

Ethical statement

Institutional Research Board (IRB) approval was obtained from the Mansoura Faculty of Medicine Ethics Committee under the number R.24.12.2922.

Study design

This is a retrospective observational study.

Setting

The study included all patients with pathologically proven UAS who presented to our center—which is a tertiary referral university center—from January 2011 to October 2024. The data were retrieved from the center’s prospectively maintained database, and any patients with missing or incomplete data were excluded from the study. Fifteen patients were included in the final analysis.

Inclusion criteria

Pathologically proven UAS, either by preoperative biopsy or after hysterectomy.

Exclusion criteria

The patients with missing data or recurrent disease at the time of presentation.

Study variables

The following variables were analyzed for each of the included patients:

Patient data: age, body mass index (BMI), medical comorbidities.

Investigations: radiological (type of imaging, endometrial plate thickness, depth of myometrial invasion, ovarian involvement, ascites, lymph node involvement, peritoneal deposits, distant metastasis, and provisional radiological diagnosis), pathological (type, result), and laboratory (CA 125) tests.

Surgery: neoadjuvant (preoperative) therapy, surgery type: laparotomy or laparoscopy, surgical resection: hysterectomy, lymphadenectomy, omentectomy, operative time, perioperative complications, and hospital stay.

Pathology: FIGO stage,⁸ immunohistochemical (IHC) studies, sarcomatous overgrowth, presence of heterologous elements, myometrial invasion, ovarian infiltration, extension to the cervix, omental infiltration, lymph node deposits (number and distribution), and tumor grade.

Adjuvant therapy: type of adjuvant therapy, chemotherapy protocol.

Follow-up and prognosis: follow-up period, recurrence, mortality, disease-free survival (DFS), and overall survival (OS).

Outcomes

The primary endpoint is DFS, while OS is the secondary endpoint.

Study size

All the patients who presented to our department in the study period have been included.

Statistical analysis

The Statistical Package of Social Sciences (SPSS 25, IBM/SPSS Inc., Chicago, IL) was used for statistical analysis. This included descriptive and inferential statistics. Descriptive statistics used the mean (X) and standard deviation (SD) for normally distributed data or the median (Med) and range for skewed data. For qualitative data, frequency with percentage was used. Regarding analytical or inferential statistics, univariate analysis was used to evaluate the dependent and independent risk predictors for binary dependent variables, while in all applied tests, p values ≥0.05 were statistically nonsignificant, p values <0.05 were significant, and p values <0.01 were highly significant.

Results

Participants

Sixteen patients were identified with UAS. One patient was excluded due to missing data. A total of 15 female patients with UAS were included in the final analysis.

Main results

The mean age of the included patients was 59.4 years, while the mean BMI was 33.64 kg/m². Nine patients had medical comorbidities.

All the patients presented with abnormal uterine bleeding. In addition, 2 patients also complained of pelvic pain. The most used imaging modality was pelvic MRI (Fig. 1A–D) in 14 patients (93.3%), while CT was mainly used as a metastatic workup (Fig. 1E, F). Minimal ascites was described in 1 patient, and pelvic lymphadenopathy in another one. Dilatation and curettage was performed for 10 patients (66.6%), revealing the diagnosis of adenosarcoma in 6 patients only (60%). The demographic and preoperative clinical data are summarized in Table 1.

FIG. 1.

Imaging of patients with adenosarcoma: (A–D) MRI of a patient with adenosarcoma. MRI of a 56-year-old female with uterine adenosarcoma and sarcomatous overgrowth. (A) Sagittal T2-weighted imaging and (B) postcontrast fat-suppressed T1-weighted imaging showed a heterogeneously enhancing large polypoidal intrauterine mass distending both endometrial cavity and cervical canal with myometrial invasion (arrow) and ovarian involvement (asterisk). (C) Axial T2-weighted imaging and (D) high b-value DWI (b = 1000 s/mm²) revealed a heterogeneous T2 signal of the mass with cystic changes and focal areas of high DWI signal intensity (arrowheads) reflecting sarcomatous overgrowth. (E–F) CT of two patients with recurrent adenosarcoma. CT of two different cases with pulmonary, peritoneal, and nodal recurrence. (E) Axial CT (pulmonary window) revealed marked right pleural effusion and multiple left pulmonary metastatic nodules. (F) Postcontrast axial CT revealed a heterogeneously enhancing bulky necrotic left common iliac LN (asterisk) and peritoneal deposit at the right paracolic gutter (arrow).

Table 1.

Preoperative Demographic and Clinical Data

Variables	Study cases, N = 15
Variables	Number	Percent
Complaint
Bleeding	15	100
Pelvic pain	2	13.3
Medical comorbidities^a	9	60
Hypertension	6	40
Diabetes mellitus	4	26.6
Ischemic heart disease	3	20
Radiology
Ultrasound	8	53.3
CT	6	40
MRI	14	93.3
Provisional diagnosis by imaging
N/A	1	6.6
Cervical fibroid	1	6.6
Endometrial carcinoma	10	66.6
Normal (after polypectomy)	1	6.6
Pathologically proven	2	13.3
D&C
Not done	5	33.3
Done	10	66.6
D&C results (n = 10)
Adenosarcoma	6	40
Not diagnostic	1	6.6
Necrotic	1	6.6
Serous endometrial carcinoma	1	6.6
Sarcoma	1	6.6
	Mean ± SD	Median (range)
Age (years)	59.4 ± 13.25
BMI	33.64 ± 7.53
CA-125 (n = 8)		29.5 (9–157)

Continuous data expressed as mean ± SD and median (range).

Categorical data are expressed as numbers (percent).

Two patients had synchronous three medical comorbidities.

BMI, body mass index; D&C, dilatation and curettage.

None of the included patients received neoadjuvant therapy. Eight patients (53.3%) underwent hysterectomy and bilateral salpingo-oophorectomy, while the remaining patients underwent, in addition, an omentectomy, lymphadenectomy, or both. Most of the operations (14 patients) were performed through the open approach. The median operative time was 120 (80–190) minutes. Intraoperative complications occurred only in 1 patient, while postoperative complications occurred in 4 patients.

Histopathology for all tumors was composed of biphasic proliferation formed of bland epithelial elements and atypical sarcomatous proliferation (Figs. 2 and 3). In 1 case, there was squamous metaplasia in the epithelial component. Leaf-like projections were present more prominently in low-grade cases and focally in high-grade cases. The sarcomatous component exhibited periglandular condensation and cuffing with cytological atypia and frequent mitotic figures (≥2 mitoses/10 high-power fields). In high-grade cases, the degree of cytological atypia was high, equivalent to pleomorphic sarcoma, and easily seen at low-power magnification. Sarcomatous overgrowth was reported in 9 patients. Heterologous elements were present in 7 cases. The most frequent rhabdomyosarcomatous differentiation (5 cases) was followed by chondrosarcomatous differentiation (3 cases). IHC was used to confirm the pathological diagnosis in 11 patients (73.3%) (Table 2). Only 1 patient (out of 6) showed pelvic lymph node metastasis.

FIG. 2.

Microscopic examination of low-grade adenosarcoma. A case of low-grade adenosarcoma showed leaf-like projections covered by a bland epithelium (H&E, 100×) (A), with prominent periglandular cuffing by the stromal sarcomatous component (H&E, 100×) (B). A higher view of the stromal sarcomatous component exhibited cytological atypia with frequent mitotic figures (H&E, 400×) (C, D).

FIG. 3.

Microscopic examination of high-grade adenosarcoma. (A) High degree of cytological atypia and heterologous chondrosarcomatous elements (H&E, 100×). (B) The same case exhibiting areas of sarcomatous overgrowth and heterologous chondrosarcomatous and rhabdomyosarcomatous elements (H&E, 100×). (C) Another case of high-grade adenosarcoma exhibiting heterologous rhabdomyosarcomatous elements (H&E, 100×), closer view of these in picture (H&E, 400×) (D).

Table 2.

Treatment and Outcomes of the Cases Included in the Study

Variables	Study cases,N = 15
Variables	Number	Percent
Neoadjuvant therapy	0	0
Surgery type
Laparotomy	14	93.3
Laparoscopy	1	6.6
Surgical resection extent
Hysterectomy and bilateral salpingo-oophorectomy	8	53.3
Hysterectomy + lymphadenectomy	3	20
Hysterectomy + lymphadenectomy + omentectomy	3	20
Hysterectomy + omentectomy	1	6.6
Intraoperative complications (posterior vaginal tear)	1	6.6
Pathological FIGO stage
N/A	2	13.3
IA	6	40
IC	3	20
IIA	2	13.3
IIIA	1	6.6
IIIC	1	6.6
IHC use
No	4	26.6
Yes	11	73.3
Hormonal receptors
N/A	7	46.6
Negative	2	13.3
Positive	3	20
Weak	1	6.6
Desmin
N/A	7	46.6
Focal	4	26.6
Negative	3	20
Positive	1	6.6
CD10
N/A	8	53.3
Focal	3	20
Positive	4	26.6
CD34	1	6.6
Myogenin
N/A	9	60
Focal	2	13.3
Negative	2	13.3
Positive	2	13.3
WT1
N/A	13	86.6
Focal	1	6.6
Negative	1	6.6
Vimentin	1	6.6
Sarcomatous overgrowth	9	60
Myometrial invasion
N/A	1	6.6
Not involved	2	13.3
Less than half	6	40
More than half	6	40
Involved sites
Right ovary	1	6.6
Left ovary	2	13.3
Cervix	3	20
Omentum	2	13.3

	Mean ± SD	Median (range)
Operative time (min)		120 (80–190)
Total lymph nodes (n = 6)		10 (0–24)
Hospital stay (n = 9)		3 (1–9)
	Number	Percent
Positive pelvic lymph nodes	1	6.6
Postoperative complications (all are late)	4	26.6
Type of postoperative complications
Delayed wound healing	1	6.6
Seroma	2	13.3
Wound infection	1	6.6
Adjuvant therapy	11	73.3
Chemotherapy	6	40
Chemotherapy + brachytherapy	1	6.6
Chemotherapy + external beam radiotherapy	3	20
Hormonal therapy	1	6.6
Chemotherapy protocol
N/A	2	13.3
Adriamycin	1	6.6
Dacarbazine, adriamycin	1	6.6
Gemzar, Taxotere	1	6.6
H/A	3	20
T/C	4	26.6
	Mean ± SD	Median (range)
Follow-up (months)		6 (2–71)
Recurrence
No recurrence	8	53.3
Recurrence	7	46.6
Site of recurrence
Brain	1	6.6
Local	1	6.6
Nodal	1	6.6
Peritoneal	3	20
Pulmonary	1	6.6
Status at time of last follow-up
Alive	8	53.3
Dead	7	46.6

Continuous data expressed as mean ± SD and median (range).

Categorical data are expressed as numbers (percent).

IHC, immunohistochemical.

Eleven patients (73.3%) received adjuvant therapy, with the majority (10 patients) receiving chemotherapy either alone (6 patients) or in combination with external beam radiotherapy (3 patients) or brachytherapy (1 patient), while hormonal therapy was received by 1 patient only.

The mean follow-up was 11.7 (2–71) months. At the date of last follow-up, 8 patients were alive and disease-free. Seven patients (46.6%) presented with a relapse. The most frequent site of relapse was the peritoneum, which occurred in 3 cases. All the patients who presented with a relapse did not survive. The median DFS was 12 (2–58) months, while the median OS was 13 (4–71) months. Multivariate analysis showed that only the presence of preoperative medical comorbidities contributed significantly to mortality in our cohort (Table 3).

Table 3.

Univariate Analysis for the Prediction of Mortality

Predictors	p Value	Odds ratio	95% CI for odds ratio
Predictors	p Value	Odds ratio	Lower	Upper
Age	0.250	0.950	0.871	1.036
BMI	0.216	1.111	0.940	1.313
Comorbidities	0.035 ^*	7.500	1.223	10.357
CA-125	0.694	1.005	0.979	1.032
FIGO—classification	0.902	1.178	0.673	1.510
Sarcomatous overgrowth	0.215	4.000	0.447	5.788
Grade	0.522	0.417	0.029	6.064
Heterologous elements	0.594	0.563	0.068	4.672
Myometrial invasion	0.624	1.163	0.819	1.507
Postoperative complications	0.378	1.540	0.766	3.052

Bold data indicates statistically significant p values.

Statistically significant (p < 0.05).

CI, confidence interval.

Discussion

UAS is an uncommon neoplasm^9,10 that is more likely to develop in postmenopausal women. Based on three retrospective analyses, the age range of patients diagnosed with UAS was 14–89 years, with median ages of 54, 56, and 58 years, respectively. A total of 51.5% of the patients in 544 instances from the Surveillance, Epidemiology, and End Results database were between the ages of 40 and 65, while less than 10% were younger than 40.² The mean age of the included patients was 59.4 years, ranging from 29 to 78 years. Table 4 summarizes the studies published in the literature.

Table 4.

Summary of Previously Mentioned Cases of Adenosarcoma in Literature

Author/year	Number of cases	Mean age/range	Presentation	Findings	Treatment	Outcomes
Clement et al.1990¹¹	100	58 years old (14–89 years old).	Abnormal vaginal bleeding.	Sarcomatous overgrowth was present in 10 cases. LVSI : NA Heterologous elements were present in 22 cases. Myometrial Invasion was present in 15 cases, but was deep in only 4.	TAH and SO in 57 cases. TAH in 11 patients. TAH + SO + postoperative radiation in 11 cases. Vaginal hysterectomy in 5 cases. TAH + BSO + pelvic lymphadenectomy in 5 cases. Preoperative radiation + TAH + BSO in 4 cases. TAH + BSO + pelvic lymphadenectomy + postoperative radiation and chemotherapy in 4 cases. Local excision in 4 cases.	Three patients were lost to follow-up immediately after the diagnosis. The median follow-up interval is 5.9 years.Alive and no evidence of tumor in 53 cases.Dead with no evidence of tumor in 12 patients. Recurrence occurred in 23 patients.After recurrence, 10 cases died of tumor.One case is dead with a tumor.Eight cases are alive with no evidence of tumor.Three cases are dead with no evidence of tumor.One case is lost to further follow-up. DFS: NA OS: NA
Bernard et al. 2013¹²	64	61 years old (29–94 years old).	NA	Sarcomatous overgrowth was present in 30 cases. LVSI : NA Heterologous elements: NA Myometrial Invasion was documented, but the number of cases was unknown.	TAH + BSO in 31 cases.TAH + BSO + staging (LND) in 12 cases.TAH + BSO + omentectomy in 11 cases.TAH + BSO + debulking in 1 case.Subtotal hysterectomy in 2 cases.D&C in 1 case. Unknown in 6 cases.Adjuvant chemotherapy in 3 cases. Radiotherapy in 10 cases.Chemo + radiotherapy in 1 case.	The median follow-up was 1.98 years for the 59 patients for whom clinical follow-up data were available. Recurrence occurred in 16 cases of the 59.Median time to recurrence was 21.2 months.Eleven patients with recurrence have died of their disease, 3 are alive on active treatment or observation, and 2 are disease-free as of last follow-up. Five-year OS is 69.3% for patients with AS.60.7% for those with AS + sarcomatous overgrowth. Within stage I was 83.3% for those with stage IA and 66.3% for IB. DFS: NA
Tanner et al. 2013¹³	19	AS only: 57 years old (27–76 years old).AS + sarcomatous overgrowth: 53 years old (44–72 years old).	NA	Sarcomatous overgrowth was present in 5 patients. LVSI : NA Heterologous elements were present in 3 of the 5 patients with AS + sarcomatous overgrowth. Myometrial Invasion was present in 3 of 14 cases of AS only and in 2 of 5 cases of AS + sarcomatous overgrowth.	All patients underwent surgical resection, either laparoscopic-assisted vaginal hysterectomy in 3 patients or TAH in 16 patients.Sixteen patients underwent BSO.Pelvic lymphadenectomy and para-aortic lymphadenectomy were performed in 58% and 26% of patients, respectively.Adjuvant radiation was administered to 3 patients.	The median follow-up was 72.9 months. Recurrence occurred in 5 patients. The 5-year PFS and OS rates were 77% and 82%, respectively.In 5 patients with AS + sarcomatous overgrowth, t he 2-year PFS and OS rates were both 20% vs. 100% for 14 patients without sarcomatous overgrowth.
Taga et al. 2014¹⁴	1	59 years old.	Abnormal vaginal bleeding.	Sarcomatous overgrowth : NA LVSI : NA Heterologous elements: NA Myometrial Invasion was absent.	TAH + BSO and pelvic lymphadenectomy.	The patient remains alive without disease 6 months after the surgery, but there are no further data.
Carroll et al. 2014¹⁵	74	54 years old (15–84 years old).	Abnormal vaginal bleeding in 48 cases and pelvic pain in 9 patients.	Sarcomatous overgrowth was present in 31 cases. LVSI was present in 7 cases. Heterologous elements were present in 15 cases. Myometrial Invasion : NA.	Chemotherapy + radiation in 1 patient.Surgery alone in 47 patients. Surgery + radiation in 14 patients.Surgery + chemotherapy in 5 patients. Surgery + chemotherapy + radiation in 3 patients.Surgery + hormones in 4 patients.	The median follow-up was 56.5 months. Recurrence occurred in 34 patients. The median time to first recurrence was 18.3 months. One patient without 6 months of follow-up who died of disease progression 3.3 months after initial treatment. Median PFS and OS were 29.4 and 55.4 months for patients with sarcomatous overgrowth, compared with 105.9 and 112.4 months for patients without sarcomatous overgrowth.
Kandaz et al. 2016¹⁶	1	39 years old.	Abnormal vaginal bleeding.	Sarcomatous overgrowth : NA LVSI : NA Heterologous elements: NA Myometrial Invasion : There was 1/3 myometrial invasion into the middle part.	TAH + BSO + adjuvant chemotherapy.	She was followed up, but the period and the results were not mentioned.
Lee et al. 2017¹⁷	31	44.5 years old (21–81 years old).	NA	Sarcomatous overgrowth was present in 10 patients. LVSI : NA Heterologous elements: NA Myometrial Invasion : NA	Uterine preservation surgery was performed in 7 of the nulliparas. Laparoscopy-assisted vaginal hysterectomy was performed in 13 patients.Total abdominal hysterectomy was performed in 11 patients. Thirteen patients had BSO at the time of hysterectomy. Eleven patients underwent pelvic lymphadenectomy, while 3 patients underwent para-aortic lymphadenectomy.Five patients received adjuvant chemotherapy	The median follow-up was 32 months.Of 7 patients receiving uterine preservation surgery, 3 showed NED, 2 had persistent disease confined to the uterus, and 2 were alive with disease after recurrence. One patient with an NED status had a vaginal delivery at term. Recurrence: In the uterine preservation group, 1 patient had sarcomatous overgrowth at the time of diagnosis and experienced disease recurrence. In the hysterectomy group, 3 of 24 patients had tumor recurrence. OS: NA DFS: NA
L’Heveder et al. 2019⁶	1	18 years old.	Abnormal vaginal bleeding.	Sarcomatous overgrowth was absent. LVSI : NA Heterologous elements: NA Myometrial Invasion was absent.	She was advised to undergo TAH + BSO + pelvic lymphadenectomy, but she wanted to preserve her fertility and underwent conservative management.	After a total of 20 years of follow-up, she finally underwent an uncomplicated laparoscopic hysterectomy with ovarian conservation. There was no histological evidence of disease recurrence.
I. García Mendoza et al. 2022¹⁸	1	48 years old.	Abnormal vaginal bleeding.	Sarcomatous overgrowth was present. LVSI was absent. Heterologous elements were present with grade 2 chondrosarcoma. Myometrial Invasion : NA	TAH + BSO + adenectomy.	Three months after the surgery, a tumor adhered to the pelvic and abdominal cavity was identified.No further data about the follow-up.
Wang et al. 2023²	1	38 years old.	Abnormal vaginal bleeding.	Sarcomatous overgrowth wasabsent. LVSI was absent. Heterologous elements: NA Myometrial Invasion: There was focal invasion to the superficial myometrium.	TAH + BSO + pelvic lymphadenectomy and postoperative chemotherapy.	The patient has been followed up for more than 15 months after chemotherapy and has no signs of recurrence.
Mancari et al.2024¹⁹	32	61.5 years old (17–88 years old).	Abnormal vaginal bleeding was present in 27 patients, while 5 patients were asymptomatic.	Sarcomatous overgrowth was available in only 3 cases but not considered in this study. LVSI was available in only 12 patients and was always reported as negative. Heterologous elements: NA Myometrial Invasion: NA	All patients underwent a total hysterectomy. Twenty-nine patients also underwent BSO. Omentectomy was done in 2 cases and appendectomy in 1 case. Complete cytoreduction was achieved in 31 patients. Seven patients underwent pelvic lymphadenectomy, 1 of them with an additional para-aortic dissection.Adjuvant treatment was administered in 15 cases, radiotherapy in 13 patients, and chemotherapy in 2 patients.	The median follow-up was 48 months. The 5-year DFS was 85.3%. The 5-year OS was 89.5%. Recurrence: Five patients relapsed, 2 with pelvic recurrence, 2 with pelvic and distant disease, and 1 with distant metastasis only. Three of them relapsed within 1 year of follow-up.
Rafiq et al. 2025⁹	1	52 years old.	Abnormal vaginal bleeding.	Sarcomatous overgrowth was present. LVSI: NA Heterologous elements: NA Myometrial Invasion: NA	TAH + BSO and adjuvant chemotherapy.	No evidence of metastatic disease at the 6-month follow-up. At her most recent evaluation, 18 months postsurgery, there were no signs of recurrence, and she remains under observation with plans for continued surveillance every 6 months.
Camejo et al. 2025²⁰	1	77 years old.	Abnormal vaginal bleeding.	Sarcomatous overgrowth was absent. LVSI: NA Heterologous elements: NA Myometrial Invasion: There was less than half the uterine wall and focal extension to the uterine isthmus, sparing the endocervix.	TAH + BSO + adjuvant therapy with anastrozole.	She was followed up, but the period and the results were not mentioned.

LVSI, lymphovascular space invasion; TAH, total abdominal hysterectomy; SO, salpingo-oophorectomy; BSO, bilateral salpingo-oophorectomy; DFS, disease-free survival; OS, overall survival; LND, lymph node dissection; D&C, dilatation and curettage; AS, adenosarcoma; PFS, progression-free survival; NED, no evidence of disease.

Endometriosis appears to be a significant risk factor; however, a specific correlation has not yet been proven. Adenosarcoma, clear cell carcinoma, and endometrioid carcinoma have been shown to account for 5.5% of the cancer incidence in a cohort of 1000 individuals with confirmed endometriosis.²¹ Uncertainty surrounds the molecular pathway causing this malignant change. Iron overload resulting from oxidative stress brought on by menstruation may induce recurrent damage to DNA. An additional risk factor for adenosarcoma could be previous irradiation of the pelvis plus treatment with antiestrogens, possibly because of the endometrial partial estrogen agonist action.²² No risk factors could be identified in our cases. This can be attributed to the lack of verification of these data.

A polypoid mass inside the uterine cavity is the usual presentation of UAS. This mass bleeds readily. As a result, most individuals exhibit irregular vaginal bleeding. Pelvic pain or the appearance of a pelvic mass is the second most frequent presenting symptom or sign, occurring in 12.3%–33.3% of cases. Patients may also exhibit an irregular vaginal discharge. Upon assessment, individuals may show signs of endocervical polyps, cervical polyps, or an enlarged uterus. In rare cases, Pap smear abnormalities can result in the diagnosis of UAS. Ultimately, UAS is discovered by coincidence in certain patients having a hysterectomy for uterine fibroids.²³ In all our patients, there was bleeding, but only 2 of them additionally experienced abdominal pain.

Ultrasonography is the first choice for imaging due to its affordability, noninvasiveness, and reproducibility, despite having limited diagnostic accuracy. MRI is preferred over CT to detect the local pelvic extent with good sensitivity and even greater specificity.²⁴ Furthermore, patients should perform a chest CT scan to exclude pulmonary metastases. Imaging results are usually not specific enough to diagnose adenosarcoma. A regular, well-defined swelling that is heterogeneous and hypointense on T1, cyst-like with multiple septae on T2, and a low signal on DWI are characteristics that are indicative of UAS. However, MRI features of UAS can overlap with other uterine malignancies.^23,25–27 In this rare situation, hysteroscopy may offer an additional tool to describe the tumor, especially if curettage is not able to reach a diagnosis.⁷ MRI in our study was the preferred imaging method in 14 of the 15 cases. Ultrasound was used in 8 cases out of 15. Imaging revealed that endometrial cancer was the provisional diagnosis in 10 cases and cervical fibroid in 1. This copes with the present literature in which the imaging modalities can only expect malignancy but can never be specific to predict UAS.

Under the microscope, adenosarcoma is composed of two components: a malignant mesenchymal component and a benign glandular epithelial component. The malignant one is defined by periglandular cuffs of spindled cells. They are marked by strong mitotic activity and cellular atypia. According to the WHO guidelines, adenosarcoma diagnosis requires a mitotic rate of at least 2 per 10 high-power fields. The Ki67 index is typically less than 5%; in periglandular cuffs, it can reach 20%. In 35% of instances, necrosis, myometrial invasion, and lymphovascular invasion can be noted.²²

Histomorphological examination with hematoxylin and eosin staining is the foundation for the pathological diagnosis of UAS. IHC assays have also been used because morphological investigations of adenosarcomas do not always yield the expected results. CD10, WT1, and vimentin are the most often found IHC markers for the sarcomatous element of UAS. Patients with sarcomatous overgrowth have been observed to have decreased CD10 positivity. SMA, desmin, CD34, and cytokeratin are further indicators of adenosarcomas.²⁸ Coping with such data, in 11 cases, IHC was used. The results showed the following: focal positivity of desmin in 4 cases, a positive reaction in 1 case, and a negative reaction in 3 cases. CD10 showed a focal positive reaction in 3 cases and a positive reaction in 4 cases. One case showed a positive reaction to CD34, and another showed a positive reaction to vimentin. Two cases showed a positive reaction to myogenin, as well as two focal positive reactions. WT1 showed a focal reaction in 1 case and a negative reaction in another case. Similar to endometrial stromal cells or tumors, UAS often exhibits hormone receptors (estrogen, progesterone, and androgen receptors). However, the nature of dedifferentiation is reflected in the loss of hormone receptor expression in adenosarcomas with sarcomatous overgrowth.²⁸ In our study, 3 cases showed positive reactions to ER and PR; 1 showed a weak reaction, and 2 showed a negative reaction.

An adenosarcoma with sarcomatous overgrowth is identified when the tumor has at least 25% high-grade sarcomatous tissue. These tumors, which can fill the uterine cavity, are usually polypoid. Sarcomatous overgrowth increases the risk of myometrial invasion and is associated with bigger, fleshy, hemorrhagic, and necrotic-cut tumors.²⁹ In 9 cases, sarcomatous overgrowth was observed. Myometrial invasion has been observed in 12 cases; in 6 of these cases, the tumor involved less than half of the myometrium, whereas in the remaining cases, it involved more than half. However, lastly, this did not lead to a statistically significant contribution to the prognosis.

The endometrium is where UAS usually arises (87%), but they can also be limited to the internal os (9%), myometrium (4%), or both. Comparable tumors may start in the pelvis, cervix, ovaries, or vagina. Adenosarcomas ranged in diameter from 1 mm to >20 cm, with an average of 5 cm.² In our cohort, the tumor involved the cervix in 3 patients, the left ovary in 2 patients, and the right ovary in 1 patient, while it involved the omentum in 2 patients.

Hysterectomy and bilateral salpingo-oophorectomy are the standard treatments for UAS, while there is still debate over lymphadenectomies and postoperative care.⁷ According to our cohort, the main treatment option is surgery. Hysterectomy only was performed in 8 patients, while, in addition, omentectomy, lymphadenectomy, or both were performed in the remaining patients. Since lymph node involvement occurs in 0%–6% of patients, lymph node dissection (LND) might not be required in women whose illness is restricted to the uterus. However, LND must be taken into consideration in patients with enlarged lymph nodes in imaging studies or palpated intraoperatively.^6,30 In our study, only 1 case showed positive lymph nodes out of the 6 patients who underwent lymphadenectomy.

Regarding adjuvant treatment, due to the scarcity of cases and the absence of prospective clinical trials, the management of UAS is based on an individual patient and institutional basis, and usually, the guidelines for the management of endometrial carcinoma or sarcoma are applied. Adjuvant radiotherapy is mainly used for patients who exhibit an elevated risk for recurrences, such as advanced stages and sarcomatous overgrowth. It can be delivered in the form of external beam irradiation or brachytherapy. Meanwhile, there is no consensus regarding the use of adjuvant hormonal treatment or chemotherapy. Also, the role of neoadjuvant therapy is not well established.^1,5,23,31,32 In our cohort, 11 patients received adjuvant therapy, with the majority (10 patients) receiving chemotherapy either alone (6 patients) or in combination with external beam radiotherapy (3 patients) or brachytherapy (1 patient), while hormonal therapy was received by 1 patient only. The heterogeneity in adjuvant therapy protocols can be attributed to the long study period and the absence of uniform local and international treatment guidelines.

Adenosarcoma patients frequently get a stage I diagnosis and show a 60%–80% 5-year OS rate.¹⁹ As in our study, there were 6 cases in stage IA and 3 in the FIGO stages IC, 2 in stage IIA, and 1 patient with stages IIIA and IIC. In our patients, OS varied between 4 and 71 months, and the range of DFS in our patients was 2–58 months.

On the contrary, the 2-year progression-free survival (PFS) and OS can reach 100% without sarcomatous overgrowth and only 20%–50% with it.² Increased age at diagnosis is linked to a worse PFS, and cardiovascular disease is linked to a worse OS rate.³⁰ However, age did not contribute to survival in our patients.

The prognosis for adenosarcomas is generally favorable, with recurrence rates of 26%–46%. Several prognostic variables are linked to worse outcomes. Sarcomatous overgrowth, for instance, has been linked to a 45%–70% greater risk of recurrence. Heterologous elements, lymphovascular invasion, deep myometrial invasion, and the patient’s age are additional high-risk characteristics.^5,19,33 Within our study, the outcomes were different from reported in the literature; 7 (46.6%) of the 15 patients reported recurrences in various sites: one was a local recurrence, while three were peritoneal, and there was one recurrence in each of the brain, lung, and lymph nodes.

Our study has limitations: First, it is retrospective. Second, the limited number of patients is due to being a single-center study. Meanwhile, it represents a yield of more than 13 years. Third, the possible risk factors (tamoxifen use, endometriosis, radiation therapy, and genetics) were missing for our patients and so could not have been evaluated for such a rare disease.

To conclude, UAS is an extremely rare disease with a limited incidence. It has no specific imaging criteria. Upfront surgery is the mainstay of treatment. Adjuvant treatment may have a role in the management approach. Further studies, including a large number of patients in many centers, are recommended to help plan international guidelines for the management of such a disease.

Authors’ Contributions

All authors have read and approved the article. R.A., R.A.E., R.E., and M.T.: Data collection and editing. O.H. and G.A.S.: Conceptualization and writing and revision. G.A.S.: Preparation and editing of the radiology part. A.E. and A.H.: Preparation and editing of the pathology part. S.E. and B.R.: Revision and editing. All authors read and approved the final version of the article.

Footnotes

Author Disclosure Statement

All authors declare that they have no conflict of interest.

Funding Information

No funding was received.

Ethics Approval and Consent to Participate

The authors received IRB approval for the study from the Medical Research Ethics Committee at Mansoura University Faculty of Medicine under the number R.24.12.2922. All procedures performed in the study involving human participants followed the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All the patients signed informed consent for the surgical maneuvers whenever indicated. This is a retrospective study. Consent for participation in the study itself is not applicable.

Availability of Data and Material

All the clinical, radiological, and pathological data used in this article are available on the Mansoura University medical system (Ibn Sina Hospital management system). .

Abbreviations

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