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.
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.
Imaging of patients with adenosarcoma:
Preoperative Demographic and Clinical Data
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.
Microscopic examination of low-grade adenosarcoma. A case of low-grade adenosarcoma showed leaf-like projections covered by a bland epithelium (H&E, 100×)
Microscopic examination of high-grade adenosarcoma.
Treatment and Outcomes of the Cases Included in the Study
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).
Univariate Analysis for the Prediction of Mortality
Bold data indicates statistically significant p values.
Statistically significant (p < 0.05).
CI, confidence interval.
Discussion
UAS is an uncommon neoplasm9,10 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.
Summary of Previously Mentioned Cases of Adenosarcoma in Literature
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.
