Adjuvant Treatment Modalities, Prognostic Factors, and Outcome of the Uterine Carcinosarcoma.

OBJECTIVE: To determine the impact of adjuvant therapy and other factors associated with the recurrence and survival of patients with uterine carcinosarcoma (UCS). METHODS: A total of 102 patients who underwhent surgery for UCS from 1998 to 2017 were included in the analysis. Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. RESULTS: At 240 months, the actuarial recurrence rate was 34.3%. Distant recurrence was the most common recurrence pattern. Patients with higher CA 125 levels, sarcoma dominance, cervical involvement, advanced stage, no lymphadenectomy, and residual tumour had a significiantly higher risk of recurrence. Five-year disease-free survival (DFS) and overall survival (OS) were 67% and 77%, respectively. FIGO stage was found to be an independent prognostic factor for DFS and OS. Sarcoma dominance was independently associated with decreased OS. CONCLUSION: Sarcoma dominance is associated with poor survival in UCS. Adjuvant treatment was not found to affect recurrence or survival. Given this finding, more effective postoperative strategies are needed.

Management and clinical outcomes in uterine malignant mixed Müllerian tumor: Lessons from a single-institution series.

Malignant mixed Müllerian tumor remains an important contributor to morbidity and mortality in women with uterine cancer. Surgery is the primary treatment modality, followed by chemotherapy and/or radiation for advanced disease or high-risk patients. Clinico-epidemiologic characteristics and outcomes in older versus younger women with Malignant mixed Müllerian tumor may differ. We analyzed and now report on 15 consecutive patients with uterine Malignant mixed Müllerian tumor treated at our institution from 2000 to 2018. The mean age at diagnosis was 65 years; 60% (9/15) patients were overweight/obese. Forty-six percent (7/15) had hypercholesterolemia, an association not previously linked with Malignant mixed Müllerian tumor in the literature. All patients but one had surgical excision of the tumor. A third of patients received adjuvant radiation therapy. A majority of patients received chemotherapy; the preferred regimen was carboplatin-paclitaxel. The patients older than 70 had a tendency towards a more advanced disease stage at diagnosis and a significantly shorter cancer-specific survival than their younger counterparts (6 months vs. 102 months (hazard ratio 1.32, p = 0.02)). Our study's conclusions are restricted due to its relatively small size, retrospective design, and some variation in the chemotherapy doses administered in individual patients. Larger studies are needed to confirm the significance of our findings.

Uterine Carcinosarcomas - Diagnosis and Management.

Uterine carcinosarcomas are rare tumors that account for less than 5% of all uterine malignancies. These tumors (previously called malignant mixed Müllerian tumors) are dedifferentiated carcinomas that comprise carcinomatous and sarcomatous elements and arise from a single malignant clone. They are considered a high-risk variant of endometrial adenocarcinoma because carcinosarcomas share more similarities in epidemiology, risk factors, and clinical behavior with endometrial carcinoma than with uterine sarcomas. The clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma will be discussed in this review.

Primary malignant mixed Müllerian tumors of the fallopian tube with cervix metastasis: A rare case report and literature review.

RATIONALE: Primary malignant mixed mullerian tumors of the fallopian tube is very rare and has only 1 case in the current literature with cervix metastasis. PATIENT CONCERNS: We reported a 49-year-old woman sufferring from primary malignant mixed mullerian tumors of the fallopian tube with cervix metastasis, and the imaging examination found a strip of solid mass in the right fallopian tube and a nodular mass in cervical canal, which were both hyperintense on T2 weighted image (T2WI) and diffusion weighted image (DWI) and continuous moderate enhancement on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DIAGNOSES: The diagnosis was confirmed according to the specific anatomical location and pathological examination which was proved as primary malignant mixed mullerian tumors of the fallopian tube with cervix metastasis. INTERVENTIONS: The patient underwent radical hysterctomy, bilateral adnexectomy, pelvic lymph node dissection, omentum majus excision and intravenous chemotherapy. OUTCOMES: Her posttreatment condition was good. LESSONS: Primary malignant mixed mullerian tumors of the fallopian tube can be located by magnetic resonance image examination, which may also offer several diagnostic tips according to changes in signal and enhancement. When combined with pathological findings, qualitative diagnosis can be determined. Surgery and adjuvant chemotherapy are considered as effective methods. Our paper discussed its epidemiology, clinical symptoms, pathologic characters, therapeutic method as well as magnetic resonance imaging findings suggesting the diagnosis and differential diagnosis, including precontrast scan, contrast scan and diffusion weighted image and provided magnetic resonance imaging characteristics of primary malignant mixed mullerian tumors of the fallopian tube described in other literatures.

PD-L1 Expression in Carcinosarcomas of the Gynecologic Tract: A Potentially Actionable Biomarker.

BACKGROUND: Carcinosarcomas of the gynecologic tract, also known as malignant mixed Müllerian tumors, are aggressive neoplasms with a high recurrence rate and poor prognosis. Despite advances in adjuvant therapies in recent years, the prognosis of these tumors has not improved. In fact, there are currently no consensus guidelines for the treatment of these neoplasms and the search for targetable biomarkers has not been successful so far. Programmed death-ligand 1 (PD-L1) has emerged as a potential target for therapeutics in a number of malignant tumors, including melanoma, lung, and colorectal cancer. In normal conditions, PD-L1 is thought to promote immune homeostasis via a number of pathways, but mainly through downregulation of cytotoxic T cells. In some human neoplasms, however, overexpression of PD-L1 by tumor cells has been observed, which can modulate the immune system to allow cancer cells to evade host response. As this marker could potentially be a therapeutic target for these tumors, the immunohistochemical expression of PD-L1 in a group of carcinosarcomas was evaluated in the present study. MATERIAL AND METHODS: Twenty-nine cases of gynecologic carcinosarcomas were analyzed, corresponding to tumors originating from the uterus (25), ovary (2), fallopian tube (1), and pelvic epithelium (1). Immunohistochemistry for PD-L1 was performed on paraffin sections and the staining results were assessed semiquantitatively in both epithelial and mesenchymal components of each tumor. RESULTS: Positive membranous staining for PD-L1 was detected in 25/29 tumors (86%). The epithelial components were strongly positive in 19/29 (65%) and weakly positive in 6/29 tumors (21%). The mesenchymal elements were strongly positive in 8/29 (27%) and weakly positive in 3/29 tumors (10%). With exception of 1, all tumors with positive sarcomatous components had staining of the carcinomatous element. Four tumors were negative for PD-L1 in both components. CONCLUSIONS: This study shows that PD-L1 is expressed by the majority of carcinosarcomas, predominantly in the epithelial components. This is particularly important as most locoregional recurrences and distant metastases are of epithelial origin. This finding may serve as a basis for possible therapeutic approaches using antibodies that have already shown significant value in a number of other malignant tumors.

Carcinosarcomas and Related Cancers: Tumors Caught in the Act of Epithelial-Mesenchymal Transition.

In this review, we outline the biology and management of patients with carcinosarcomas and related malignancies, which are often included under the broader concept of sarcomatoid carcinomas. Carcinosarcomas are unusual tumors that are commonly gynecologic in origin, where they are referred to as malignant mixed Müllerian tumors, but may appear in any anatomic site. Although a variety of hypotheses have been presented as to the biphasic nature of these tumors, carcinosarcomas seem to represent the best example in human cancers of the concept of epithelial-mesenchymal transition (EMT), in which the two parts of the tumor are genomically related to one another, as opposed to the mesenchymal component that represents a second neoplasm or (benign) reactive process. In general, patients with carcinosarcomas fare worse than patients with carcinomas of the same anatomic site. Treatment paradigms for carcinosarcomas generally follow those of carcinomas of the same organ site, except where clinical trials provide more specific options. Agents that block or reverse EMT are worth examination in patients with carcinosarcoma and arguably may be even more effective in carcinomas, given evidence of dependence on EMT to generate successful metastases. Information about EMT may also inform other phase transitions in cancer, such as those between prostate or lung carcinoma and more aggressive tumors with neuroendocrine differentiation.

Extremely Locally Advanced Ovarian Malignant Mixed Mullerian Tumor in 37-Years-Old Female.

Ovarian carcinosarcomas, rare variant of ovarian carcinoma, composed of both carcinomatous and mesenchymal components, solid and/or cystic, fleshy and hemorrhagic, frequently spreading beyond the ovary, are treated with surgery and adjuvant chemotherapy according to the treatment principles of ovarian carcinomas due to the small number of reported cases and lack of randomized studies. We report a case of a 37-year-old woman with clinical signs of extremely locally advanced tumor of ovarian origin, infiltrating the lower left quadrant of the abdominal wall with necrosis of the covering skin. Prior biopsy of the left ovary and omentum confirmed poorly differentiated serous adenocarcinoma. Bulky tumor the size of a child's head, originating from the left ovary and infiltrating into the lower left quadrant abdominal wall was debulked with wide excision of the abdominal wall and creation of wide defect of the lower left part of abdominal wall covered with Dexon mesh. After the recovery, the medial part of the defect with exposed mesh was closed with pedicled tensor fasciae latae fasciomyocutaneous flap, while the lateral part of the defect was covered with split thickness skin graft. Optimal surgical cytoreduction and adjuvant chemotherapy in case of extremely locally advanced ovarian malignant Müllerian tumor provide satisfactory recurrence-free survival period.

Malignant Mixed Müllerian Tumour of the Uterus: Analysis of 44 Cases.

OBJECTIVES: The aim of our study was to evaluate the clinicopathological features and prognostic factors of uterine carcinosarcoma. PATIENTS AND METHODS: In this retrospective study, the clinical characteristics of 44 patients with uterine MMMT were evaluated. Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Forty-four patients with uterine carcinosarcoma were referred to our unit between 1995 and 2015. Their median age was 66.5 years. All women underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Twenty-five percent had omental resection. Pelvic lymphadenectomy was performed in 18.2% of the cases. Twenty-six of the patients presented with stage I/II disease, 17 with advanced stages. In 20.5% of the cases there were metastases at diagnosis. Forty women received adjuvant chemotherapy, with complete remission in 67.9% of the cases. Recurrences were observed in 27.3% of the women. Disease-free and overall survival was 27 and 103 months, respectively. The FIGO stage, histological type, tumour size, chemotherapy regimen, pelvic lymphadenectomy, and myometrial invasion did not affect survival. CONCLUSIONS: Uterine MMMT is an aggressive tumour, often diagnosed at an advanced stage and with a high rate of metastases or recurrences. Because of its rarity, its management is controversial and fixed prognostic factors cannot be defined.

Heterogeneous Appearance of Central Nervous System Involvement in Malignant Mixed Müllerian Tumors.

Involvement of the central nervous system (CNS) is rarely described in malignant mixed Müllerian tumors (MMMTs). Only four intracranial and two spinal cases have been published to date. Here we report two more cases with heterogeneous clinical, radiologic and pathologic features and summarize the available contemporary literature. One patient presented with aphasia due to an intra-axial contrast-enhanced left temporal lesion with marked perifocal edema. After surgical resection, histology showed collections of small uniform tumor cells embedded in a myxoid matrix and compartmentalized by connective tissue septations, consistent with an MMMT. The other patient presented with trigeminal/tongue hypesthesia and double vision accompanied by left radiculopathy and paresis. Magnetic resonance imaging MRI revealed an extraaxial lesion at the petrous tip with mild perifocal edema and multiple small intradural contrast-enhancing lesions of the conus and cauda medullaris. Histologic examination of the intracranial lesion showed a mainly papillary architecture, also consistent with MMMTs. The spinal lesions were not excised, and both patients received adjuvant radiochemotherapy. The first patient died 3 months and the second patient 12 months after surgery. As illustrated by the heterogeneous clinicopathologic features of our two cases as well as the reviewed literature, CNS metastasis of MMMTs is diagnostically challenging, shows a variable outcome, and thus requires individualized treatment. In the present cases and CNS metastases reported to date, a higher histologic ratio of sarcomatous to epithelial components portends a worse outcome.

Outcome and prognosis in uterine sarcoma and malignant mixed Mullerian tumor.

PURPOSE: There is low evidence regarding the optimal treatment in patients with uterine sarcomas and malignant mixed Mullerian tumors (MMMTs). This study provides an overview of experience at our center with patients diagnosed with uterine sarcoma and MMMT, in relation to the clinical management and outcome. METHODS: The medical records for 143 patients with low-grade endometrial stromal sarcoma (ESS), leiomyosarcoma (LMS), and high-grade (undifferentiated) endometrial sarcoma (UES) and MMMT were reviewed. All available clinical and pathological data were collected and analyzed. Putative prognostic factors were entered into a multivariate analysis using a Cox proportional hazards ratio model, and survival data were calculated. RESULTS: The 5-year overall survival rates were significantly different between patients with ESS, LMS, and UES and MMMT (86 vs. 40 vs. 57 vs. 45 %; P < 0.001). The multivariate analysis showed that the patients' age, higher FIGO stage (III-IV), a history of smoking, prior pelvic radiation, diabetes, and residual tumor after surgery were associated with a poorer overall survival. Histological subtypes of LMS (HR 4.68; 95 % CI 1.35-16.17), UES (HR 1.21; 95 % CI 0.26-5.77) and MMMT (HR 1.63; 95 % CI 0.42-6.43) were also associated with a poorer overall survival than ESS (P = 0.008). Adjuvant therapies showed no associations with overall survival. CONCLUSIONS: Adjuvant therapy has so far not shown any overall survival benefit, and the focus is therefore on primary surgery. In future studies, the entities should be investigated separately in relation to prognostic factors and effective therapeutic management.

Synchronous malignant mixed Müllerian tumor of the uterus with transitional cell carcinoma of the ovary.

A 55-year-old woman presented with a complaint of post-menopausal bleeding per vaginum. Local examination revealed a mass, protruding from the cervical os, which detached spontaneously. An adnexal mass was felt through the pouch of Douglas on per vaginum examination. Histopathological examination of the avulsed specimen revealed a diagnosis of malignant mixed Müllerian tumor. The patient underwent surgical staging with total abdominal hysterectomy, bilateral salpingo-oophorectomy, left pelvic lymphadenectomy, infracolic omentectomy, and peritoneal wash cytology. Pathological examination revealed a second primary tumor, that is, a transitional cell carcinoma of the ovary. Both the uterine malignant mixed Müllerian tumor and the ovarian transitional cell carcinoma were staged as IA. Subsequently, the patient was treated with adjuvant chemotherapy followed by radiotherapy. The patient is in complete remission at 1 year following the treatment. Synchronous genital tract neoplasms constitute a therapeutic challenge and necessitate an effective multimodality therapeutic approach based on meticulous pathological examination and tumor staging.

Tratamiento conservador del adenosarcoma mülleriano de cérvix uterino / Conservative treatment of a müllerian adenosarcoma of the uterine cervix

El adenosarcoma mülleriano de cérvix es un tumor muy poco frecuente que aparece generalmente en mujeres jóvenes, como un pólipo cervical sangrante, con tendencia a la recurrencia local debido a su bajo potencial de malignidad. No está claro cuál es su tratamiento óptimo, pero en casos seleccionados se puede realizar tratamiento conservador para preservar la fertilidad de la mujer, destacando la importancia del seguimiento clínico prolongado. Presentamos el caso de un adenosarcoma mülleriano de cérvix en una mujer de 19 años tratada con una conización extensa (AU)

Müllerian adenosarcoma of the cervix is a rare tumor that usually presents in young women as a bleeding cervical polyp. There is a tendency for local recurrence due to their low malignant potential. The optimal therapy for these tumors is uncertain but conservative treatment can be provided in selected patients to preserve female fertility. Long-term follow-up is of paramount importance. We present the case of a 19-year-old girl who was diagnosed with a Müllerian adenosarcoma of the uterine cervix treated with a wide cervical conization (AU)

Osteoid differentiation in mesodermal (mullerian) adenosarcoma of ovary.

A 55-year-old female presented with abdominal pain and 10 cm mass per abdominal examination. Computerized tomography scan of abdomen and pelvis revealed a heterogeneously enhancing solid cystic mass right ovarian mass and mild ascites. Surgery was performed. Specimens were sent for examination. Microscopic examination revealed an admixture of benign but occasionally atypical appearing mullerian type glands with sarcomatous stroma. Solid area showed undifferentiated tumour cells. Atypical mitoses and necrosis were also seen. Areas with extensive benign osteoid surrounded by fibroblastic stroma were also present. Glandular component showed positivity for CK-7, AE-1 and EMA while sarcomatous areas showed positivity for vimentin only. Mullerian adenosarcoma of ovary with sarcomatous overgrowth (SO) having heterologous component was confirmed. Postoperative 3 cycles of chemotherapy was given and the patient was well till date (three months after surgery).

Uterine malignant mixed Müllerian tumor after adjuvant tamoxifen treatment for breast cancer.

BACKGROUND: Uterine malignant mixed Müllerian tumor (MMMT), also known as carcinosarcoma, is a biphasic tumor of the female genital tract and demonstrates both malignant epithelial (carcinoma) and mesenchymal (sarcoma) components. The authors present two cases of uterine MMMT after adjuvant tamoxifen (TAM) treatment for breast cancer and a review of the current literature. CASES: The patients presented with a complaint of abnormal uterine bleeding. They both had a history of breast cancer Stage IIB previously treated with modified radical mastectomy, at 51 and 78 months, respectively. They also had history of tamoxifen treatment 20 mg daily for seven and 73 months respectively. They underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and total omentectomy. Histopathology revealed a uterine MMMT. Postoperatively, they received adjuvant chemotherapy and radiotherapy. One of the patients died 26 months after initial surgery due to uterine MMMT. CONCLUSION: Uterine MMMT is a rare, highly-aggressive, and rapidly-progressing tumor associated with a poor prognosis. Postmenopausal patients, with prolonged adjuvant TAM treatment for breast cancer, are at increased risk for the development of uterine MMMT.

Clinico-pathological spectrum of primary ovarian malignant mixed mullerian tumors (OMMMT) from a tertiary cancer institute: A series of 27 cases.

AIMS AND OBJECTIVES: To study the clinico-pathological characteristics of primary ovarian malignant mixed mullerian tumor (OMMMT) and assess the prognostic factors associated with treatment outcome and survival. MATERIALS AND METHODS: The pathology database was searched for primary ovarian carcinosarcoma diagnosed and/or managed at our institute from period of January 2004 to July 2010. The histological sections were reviewed, with emphasis on type and grade of epithelial and sarcomatous components. The medical records were retrospectively analyzed for clinical details and follow up. RESULTS: A total of 27 cases of primary ovarian carcinosarcoma were identified. The median age at diagnosis was 51 years. Fourteen patients had advanced stage (stage III and IV) at presentation. Cytoreductive surgery was done in 18 cases, and 7 had received upfront chemotherapy. Histologically, 10 cases had epithelial predominance (> 50% epithelial component) and 11 had sarcoma predominance. The most frequent epithelial component was endometroid type, and most common sarcoma component was rhabdomyosarcomatous. Hyaline droplets within sarcomatous stroma were seen prominently in 15 cases. Three cases showed germ cell /yolk sac-like areas. Eighteen cases had follow up with a median of 15 months (4-40 months). The recurrence-free survival in advanced stage and sarcoma predominant was 10.5 months in comparison to 13 months in early stage and epithelial predominant OMMMT. CONCLUSION: Primary ovarian carcinosarcoma is a rare biphasic malignancy with variable proportions of epithelial and spindle elements. Presence of hyaline droplets within spindle sarcoma in a biopsy from ovarian mass should alert the pathologists regarding MMMT. Advanced stage, suboptimal cytoreduction, and sarcoma predominant tumors are likely to have a worse outcome in ovarian MMMT.

Prognostic factors and treatment outcomes in 93 patients with uterine sarcoma from 4 centers in Turkey.

INTRODUCTION: Uterine sarcomas are a group of heterogenous and rare malignancies of the female genital tract and there is a lack of consensus on prognostic factors and optimal treatment. OBJECTIVE AND METHODOLOGY: To perform a retrospective evaluation of clinicopathological characteristics, prognostic factors and treatment outcomes of 93 patients with uterine sarcomas who were diagnosed and treated at 4 different centers from November 2000 to October 2010. RESULTS: Of the 93 patients, 58.0% had leiomyosarcomas, 26.9% malignant mixed Mullerian tumors, 9.7% endometrial stromal sarcomas, and 5.4% other histological types. According to the last International Federation of Gynecology and Obstetrics (FIGO) staging, 43.0% were stage I, 20.4% were stage II, 22.6% were stage III and 14.0 % were stage IV. Median relapse free survival (RFS) was 20 months (95% confidence interval (CI), 12.4-27.6 months), RFS after 1, 2, 5 years were 66.6%, 44.1%, 16.5% respectively. Median overall survival (OS) was 56 months (95% CI, 22.5-89.5 months), and OS after 1, 2, 5 years was 84.7%, 78%, 49.4% respectively. Multivariate analysis showed that age≥60 years and high grade tumor were significantly associated with poor OS and RFS; patients administered adjuvant treatment with sequential chemotherapy and radiotherapy had longer RFS time. Among patients with leiomyosarcoma, in addition to age and grade, adjuvant treatment with sequential chemotherapy and radiotherapy after surgery had significant effects on OS. CONCLUSION: Uterine sarcomas have poor progrosis even at early stages. Prognostic factors affecting OS were found to be age and grade.

Uterine müllerian adenosarcoma with sarcomatous overgrowth and lung metastasis in a 25-year-old woman.

Uterine müllerian adenosarcoma with sarcomatous overgrowth (MASO), uncommon in premenopausal women, is a rare variant of uterine adenosarcomas characterized by a sarcomatous portion constituting >25% of the tumor. Uterine MASO often appears as a benign, protruding cervical polyp. However, in contrast to typical müllerian adenosarcomas (MAs), MASO is a highly aggressive tumor, frequently associated with a fatal outcome. Though very rare in premenopausal women, because of the high aggressiveness and malignant potential, uterine MASO should be considered, even in women of a young age with benign-appearing polypoid masses, and treated aggressively at the time of initial diagnosis without delay. We present herein a case of uterine MASO in a 25-year-old woman with lung metastasis who was lost to follow-up for one month after the initial diagnosis had been established.

Primary mixed mullerian tumor of the vagina--a case report with review of the literature.

Malignant mixed mullerian tumor (MMMT) is a rare entity. The commonest site of this tumor in the female genital tract is the uterus followed by cervix. Primary MMMT of vagina is extremely rare. We are reporting this rare entity, with a brief review of the literature, in a 48-year-old perimenopausal female who presented with a history of passage of urine per vagina. On pelvic examination, a polypoidal mass arising from the anterior wall of the vagina was identified. Histopathological examination revealed the biphasic nature of the tumor. Immunohistochemistry confirmed the diagnosis of MMMT of vagina. To conclude, although rare, clinicians, oncologists, and pathologists should identify this malignant tumor for appropriate treatment and management.

Malignant mixed müllerian tumor of primary peritoneal origin.

The aim of this study was to describe 2 cases of primary peritoneal malignant mixed müllerian tumor (MMMT). Two patients with primary peritoneal MMMT were examined for their clinical and pathologic features. We describe 2 cases of primary peritoneal MMMT in which the carcinomatous and mesenchymal components were readily identifiable, predominantly involving the peritoneum, with no ovarian involvement. The peritoneum and ovaries, with their common embryologic origin, likely account for the peritoneum's ability to undergo a similar malignant transformation, with the resultant genesis of an MMMT of peritoneal origin.