Should MMMT still be treated with adjuvant taxane-based combination chemotherapy?

BACKGROUND: Malignant mixed Mullerian tumors of endometrial (MMMT-E) and ovarian (MMMT-O) origin are associated with poor prognosis. Suggestively epithelial-driven tumors, their treatment has shifted from anthracycline or ifosfamide-based towards taxane-based chemotherapy. It remains unclear whether this change associates with better outcomes. PATIENTS AND METHODS: A conjoined Australian and Swiss patient cohort of MMMT-E (N = 103) and MMMT-O (N = 17) was compared to patients with adenocarcinoma of the endometrium (EC, N = 172) and ovary (OC, N = 189). Clinicopathological characteristics, FIGO stage, first-line treatment, and patient outcomes were analyzed. The generated hypothesis was verified in an US-American cohort with high-grade serous ovarian cancer (HGSOC, N = 1290) and MMMT-O (N = 450) using immunohistochemistry and next-generation sequencing. RESULTS: Early stage I/II MMMT-E showed a survival plateau after 2.5 years, with no recurrence or death observed afterwards. Relapse-free survival was significantly worse in MMMT-E treated with platinum/taxanes (P = 0.024) compared to non-taxane regimen. Hypothesizing that also MMMT-O might benefit from an adjuvant non-paclitaxel regimen, a second independent cohort of MMMT-O and HGSOC patients was examined. p53 mutations dominated in both cancers with comparable frequency. PI3KCA and KRAS mutations were less frequent: they were more frequent in MMMT-O than in HGSOC (P = 0.015 and P = 0.018, respectively). MMMT-O responded better to a combination of carboplatin with anthracyclines than with taxanes (73.9% vs. 39.4%). CONCLUSION: Early stage I/II MMMT-E patients have excellent prognosis if no recurrence has appeared within the first 2.5 years. In MMMT-E, platinum/anthracycline or ifosfamide regimen associated with better outcomes than platinum/taxanes regimens. This might also apply to MMMT-O.

Primary peritoneal carcinosarcoma: A report of two cases.

OBJECTIVE: Carcinosarcomas also known as malignant mixed mullerian tumors (MMMTs) contain both carcinomatous and sarcomatous elements. Most MMMTs are arising from female genital tract, including ovaries, uterus and fallopian tubes. Extragenital carcinosarcomas are extremely rare, with an estimation less than 40 cases so far. CASE REPORT: We report two cases of primary peritoneal carcinosarcomas. An 81-year-old woman with pelvic peritoneal carcinosarcoma, heterologous type, was treated with incomplete surgery without further chemotherapy, and died of disease soon. The other one was a 76 year-old woman with abdominal peritoneal carcinosarcoma, homologous type. After optimal debulking surgery and subsequent 6 cycles of combination of paclitaxel and carboplatin chemotherapy, the patient is free of tumor half of year. CONCLUSION: Active therapy, including complete cytoreduction surgery and carboplatin-paclitaxel chemotherapy might offer a chance of disease control for these unusual primary peritoneal carcinosarcomas.

Metastasizing uterine mullerian adenosarcoma in a young female: Diagnostic enigma.

Uterine adenosarcomas are uncommon tumors. It is a biphasic tumor with both epithelial and mesenchymal component. The epithelial component is benign in nature, and the mesenchymal component is malignant. Metastasis is rare in adenosarcoma. We report a case of adenosarcoma with lymph nodal metastasis. A 20-year-old female presented with history of per vaginal bleeding for 1 month. Per vaginal examination revealed a fungating mass protruding through the cervical os. Ultrasonography and magnetic resonance imaging showed a large intrauterine mass. Biopsy of the mass done at an outside hospital was reported as rhabdomyosarcoma. Hence, she was given one cycle of neoadjuvant chemotherapy. Following this, she had profuse bleeding. Emergency hysterectomy with pelvic lymph nodal dissection was performed. The final histopathology was reported as adenosarcoma. One pelvic lymph node showed metastatic deposit of rhabdomyosarcomatous element. In young females presenting with polypoidal mass, uterine adenosarcoma can be considered in the differential diagnosis.

[Multimodal treatment of malignant mixed Müllerian tumor]. / Malignus kevert Müller-cso-eredetu tumor komplex kezelése.

INTRODUCTION AND AIM: The aim of our study was to evaluate the prognostic factors and treatment options of a very rare and highly aggressive type of uterine neoplasms, the malignant mixed Müllerian tumor, known as carcinosarcoma. METHOD: Between 2009 and 2017, 29 patients were treated with malignant mixed Müllerian tumor. At stage I, surgery and postoperative radiotherapy were performed. At stages II-IV, trimodal treatment (surgery, chemotherapy and radiotherapy) was administered. RESULTS: The average age of patients was 68.51 (49-90) years, mean body mass index was 30.22 (20.90-37.22). We have experienced recurrence of disease after complete resection in 6 cases (4 of 6 patients did not accept radiation therapy). Local recurrence has occurred after an average 15.52 (6-36) months, distant metastasis with an average 19.2 (8-32) months. Overall survival was 11.92 (1-75) months. Six patients are free of tumours at the moment. CONCLUSIONS: As overall survival has not increased in recent decades by using combined chemotherapy, there is no congruent consensus associated with the optimal treatment. The standard surgical treatment is total abdominal hysterectomy with bilateral oophorectomy, although due to high rates of recurrence and metastases, the necessity of lymphadenectomy and postoperative treatment is in the focus of recent studies. Though postoperative irradiation improves local control, the beneficial effect on overall survival is still not proven. Adjuvant chemotherapy decreases the rate of both pelvic and extrapelvic recurrence at the same time, although there is no recommendation for the optimal chemoterapeutic agent. Multimodal therapy should lead to better outcomes. Recently there are many ongoing studies with biologic and target therapies to improve efficiency, however, the relevant results will be disclosed in many years only, due to the small number of patients. Orv Hetil. 2018; 159(19): 741-7747.

Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives.

Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2-5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50-80%). Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms "uterine carcinosarcoma", "uterine Malignant Mixed Müllerian Tumors", "target therapies", "angiogenesis therapy", "cancer stem cell therapy", "prognostic biomarker", and "novel antibody-drug". Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes.

Mixed malignant mullerian tumor with neuroendocrine features in an irradiated uterus for cervical carcinoma. A unique association? A morphological, immunohistochemisty and ultrastructural study.

Chemo-radiation represents an effective therapy for carcinoma of the uterine cervix. The endometrium may however receive a consistent dose of mutagenic radiations and patients may have an increased risk of secondary malignancies. Endometrial mixed malignant mullerian tumor (MMMT) is a rare, highly aggressive disease, and neuroendocrine features are even rarer. A 68 years old woman underwent radio-chemotherapy for a squamous cell carcinoma of the cervix. Follow up was uneventful until, eight years after radio-chemotherapy, imaging exams detected a diffuse enlargement of the uterine body. Radical hysterectomy revealed a multiphasic lesion with both sarcomatous and mixed carcinomatous components. The carcinomatous, component presented neuroendocrine histologic and ultrastuctural features and an intense expression of neuroendocrine immunohistochemistry markers. No residual cervical carcinoma was documented (pR0). The patient died of disease after 9 months. Reported cases further demonstrate how the irradiation of the uterus for cervical cancer carries a not negligible risk of developing a second endometrial cancer. The second cancer may develop years after initial therapy and may have aggressive histologic and clinical features. This case underlines the importance for a long follow-up in women having received radio-chemotherapy alone.

Membrane associated cancer-oocyte neoantigen SAS1B/ovastacin is a candidate immunotherapeutic target for uterine tumors.

The metalloproteinase SAS1B [ovastacin, ASTL, astacin-like] was immunolocalized on the oolemma of ovulated human oocytes and in normal ovaries within the pool of growing oocytes where SAS1B protein was restricted to follicular stages spanning the primary-secondary follicle transition through ovulation. Gene-specific PCR and immunohistochemical studies revealed ASTL messages and SAS1B protein in both endometrioid [74%] and malignant mixed Mullerian tumors (MMMT) [87%] of the uterus. A MMMT-derived cell line, SNU539, expressed cell surface SAS1B that, after binding polyclonal antibodies, internalized into EEA1/LAMP1-positive early and late endosomes. Treatment of SNU539 cells with anti-SAS1B polyclonal antibodies caused growth arrest in the presence of active complement. A saporin-immunotoxin directed to SAS1B induced growth arrest and cell death. The oocyte restricted expression pattern of SAS1B among adult organs, cell-surface accessibility, internalization into the endocytic pathway, and tumor cell growth arrest induced by antibody-toxin conjugates suggest therapeutic approaches that would selectively target tumors while limiting adverse drug effects in healthy cells. The SAS1B metalloproteinase is proposed as a prototype cancer-oocyte tumor surface neoantigen for development of targeted immunotherapeutics with limited on-target/off tumor effects predicted to be restricted to the population of growing oocytes.

A phase II evaluation of pazopanib in the treatment of recurrent or persistent carcinosarcoma of the uterus: a gynecologic oncology group study.

OBJECTIVE: Carcinosarcomas of the female genital tract, also called malignant mixed müllerian tumors, are aggressive biphasic tumors. Second-line treatment options in the recurrent/persistent setting have yielded marginal responses. Given the potential role of angiogenesis in the gynecological carcinomas, pazopanib, a VEGFR inhibitor, was investigated in the management of patients with recurrent carcinosarcoma of the uterus. METHODS: Eligible patients had histologically confirmed carcinosarcoma of the uterus, a maximum of two prior lines of therapy, adequate renal, hepatic and hematologic function and a performance status of 0-2. Pazopanib was administered orally at 800mg. Two dose reductions were allowed. The primary objective was to ascertain the activity of pazopanib as measured by the proportion of patients who survive progression-free for at least six months and the proportion of patients that have objective tumor responses. Secondary objectives included the frequency and severity of adverse events as assessed by CTCAE v4.0. RESULTS: Of the 22 enrolled patients, 19 were eligible and evaluable for toxicity and survival. No patients had a partial or complete response (90% confidence interval [CI]: 0%, 14.6%). Three patients (15.8%) had PFS ≥6months (90% CI: 4.4%, 35.9%). The median PFS was 2.0months (first and third quartiles were 1.6 and 4.0months, respectively). The median overall survival was 8.7months (first and third quartiles were 2.6 and 14.0months, respectively). CONCLUSION: Pazopanib demonstrated minimal activity as a second or third line treatment for advanced uterine carcinosarcoma. Potential clinical trial participation should be discussed with the patients.

Malignant mixed Müllerian tumor of the fallopian tube: a case report.

Malignant mixed Müllerian tumor (MMMT) of the female genital tract is uncommon and extremely rare in the Fallopian tube. We describe a case of primary MMMT of the Fallopian tube with carcinomatous and heterologous mesenchymal components in a 60-year-old woman. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, pelvic and paraaortic lymph node dissection, and resection of intrapelvic metastases. The tumor formed a large polypoid mass within the right Fallopian tube and had penetrated the wall to the paraovarian space. Microscopic examination revealed two components of poorly differentiated adenocarcinoma and high-grade sarcoma with chondromatous differentiation. The patient received six courses of adjuvant chemotherapy with ifomide and cisplatin and is currently in remission. Although MMMT in the Fallopian tube shows poor prognosis, primary cytoreductive surgery with platinum-based combination chemotherapy may improve survival.

Collision of three histologically distinct endometrial cancers of the uterus.

A collision tumor is defined by the presence of two separate masses in one organ, which are pathologically distinct. We described a 70-yr-old patient who complained of abnormal vaginal bleeding with a collision tumor of the uterine corpus. The patient received total hysterectomy, bilateral salphingo-oophorectomy, bilateral pelvic-paraaortic lymphadenectomy, omentectomy, and intraperitoneal chemotherapy. The uterine corpus revealed three separate masses, which were located at the fundus, anterior and posterior wall. Each tumor revealed three pathologically different components, which were malignant mixed müllerian tumor, papillary serous carcinoma, and endometrioid adenocarcinoma. Among these components, only the papillary serous carcinoma component invaded the underlying myometrium and metastasized to the regional lymph node. Adjuvant chemotherapy and radiation therapy were performed. The patient is still alive and has been healthy for the last 8 yr. We have reviewed previously reported cases of collision tumors which have occurred in the uterine corpus.

Collision of Three Histologically Distinct Endometrial Cancers of the Uterus

A collision tumor is defined by the presence of two separate masses in one organ, which are pathologically distinct. We described a 70-yr-old patient who complained of abnormal vaginal bleeding with a collision tumor of the uterine corpus. The patient received total hysterectomy, bilateral salphingo-oophorectomy, bilateral pelvic-paraaortic lymphadenectomy, omentectomy, and intraperitoneal chemotherapy. The uterine corpus revealed three separate masses, which were located at the fundus, anterior and posterior wall. Each tumor revealed three pathologically different components, which were malignant mixed mullerian tumor, papillary serous carcinoma, and endometrioid adenocarcinoma. Among these components, only the papillary serous carcinoma component invaded the underlying myometrium and metastasized to the regional lymph node. Adjuvant chemotherapy and radiation therapy were performed. The patient is still alive and has been healthy for the last 8 yr. We have reviewed previously reported cases of collision tumors which have occurred in the uterine corpus.

Paclitaxel-ifosfamide-carboplatin combination chemotherapy regimen in advanced uterine and adnexal malignant mixed Mullerian tumours.

BACKGROUND: Malignant mixed Mullerian tumours (MMMTs) of the uterus and adnexa represent aggressive gynaecologic malignancies with a high rate of loco-regional and distant failure. For that reason, we evaluated the paclitaxel-ifosfamide-carboplatin (TICb) combination in patients with advanced MMMTs. METHODS: Female patients with advanced MMMTs, WHO-PS 0-2, no prior chemotherapy for systemic disease, unimpaired haemopoietic and organ function were eligible. Chemotherapy was administered at the following doses; paclitaxel: 175 mg m(-2) on day 1, ifosfamide: 2.0 g m(-2) day(-1)--days 1 and 2, and carboplatin at a target area under the curve 5 on day 2, with prophylactic G-CSF from day 3. RESULTS: Forty patients of a median age 61 (45-72) years, performance status 0-2 with advanced MMMTs of the uterus (n=34), tubes (n=2) or ovary (n=4) have entered and all were evaluable for response and toxicity. Responses were as follows: 27 out of 40 (67.5%) evaluable patients responded, with 11 complete responses and 16 partial responses, while 10 had stable disease, and 3 developed progressive disease. The median response duration was 9 months (range, 4-40 months), median progression-free survival 13 months (range, 3-42 months), while median overall survival 18 months (range, 4-48 months). Grade 3/4 neutropenia was recorded in 22 out of 40 (55%)--with 13 developing grade 4 (≤7 days) and 7 out of 40 (17.5%) of patients at least one episode of febrile neutropenia. CONCLUSION: In this study, it appears that the TICb combination, yielded important activity with manageable toxicity in females with advanced MMMTs warranting further randomised comparison with current standard regimens.

Cervical Mullerian adenosarcoma with heterologous sarcomatous overgrowth: a fourth case and review of literature.

BACKGROUND: Uterine sarcomas are relatively rare tumors that account for approximately 1-3% of female genital tract malignancies and between 4-9% of uterine cancers. Less than 8% of all cases are Mullerian adenosarcoma, a distinctive uterine neoplasm characterized by a benign, but occasionally atypical, epithelial and a malignant, usually low-grade, stromal component, both of which should be integral and neoplastic constituents of the tumor. Mullerian adenosarcoma with sarcomatous overgrowth (MASO) is a very aggressive variant, associated with post-operative recurrence, metastases, even when diagnosed in early stage. CASE PRESENTATION: We present a fourth MASO case derived from uterine cervix in a 72-year-old woman with metrorrhagia and a polypoid mass protruding through the cervical ostium. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, systematic pelvic lymph node dissection, omental biopsy and appendectomy were performed. Surgery treatment was associated with adjuvant whole-pelvis radiation (45 Gy) and adjuvant chemotherapy (cisplatin/ifosfamide). After nine months of follow up, the patient was free of tumor. CONCLUSIONS: The rarity of MASO of the cervix involves a management difficult. Most authors recommend total abdominal hysterectomy, usually accompanied by bilateral salpingo-oophorectomy. There is no common agreement on staging by lymphadenectomy during primary surgery and adjuvant chemo-radio therapy.

Malignant mixed Mullerian tumor of the ovary with two cases and review of the literature.

INTRODUCTION: Malignant mixed Müllerian tumor (MMMT) of the ovary is a rare and highly aggressive tumor. It accounts <1% of all ovarian carcinomas. It is characterized by the presence of both carcinomatous and sarcomatous components and tends to occur in low parity postmenopausal woman. These are mixed, mostly monoclonal tumors, and the predominance of the stromal component aggravates the prognosis. The staging system for ovarian and primary peritoneal cancer is also used for MMMT. After complete surgical staging, patient with stage II-IV at the time of surgery should have postoperative chemotherapy. Chemotherapy can be considered for stage I MMMT. Its optimal treatment is debatable. Taxane and platinum combination is standard for the epithelial ovarian carcinoma. There is very limited literature reporting this combination therapy in ovarian MMMTs. CASE 1 AND CASE 2: We presented two cases of stage III primary ovarian MMMT. The patients were treated with the taxane/platin combination, without adverse events following surgery, and remained in clinical remission in Case 1 at follow-up. Case 2 has progressed after first line taxane/platin regimen and treated like epithelial ovarian carcinoma. Case 1 was in complete remission in the follow-up visit 2 years later. Case 2 died 14 months later after the tumor was initially diagnosed. CONCLUSION: Predominating carcinomatous or sarcomatous component should be taken into consideration in predicting the response and planning the chemotherapy protocol.

Ovarian malignant Mullerian mixed tumor (heterologous) whose epithelial component is composed predominantly of signet ring cell carcinoma.

BACKGROUND: Ovarian malignant Mullerian mixed tumor (MMMT) (carcinosarcoma) is a relatively rare, very aggressive tumor. METHODS: Herein is presented an unusual case of heterologous MMMT with an epithelial element composed predominantly of signet ring cell carcinoma. RESULTS: A 60-year-old Japanese woman consulted our hospital because of a pelvic mass. Imaging modalities showed a huge tumor of the right ovary. Laparotomy was performed, and frozen section showed a malignant tumor. Therefore, hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, and omentectomy were performed. On gross examination, the right ovarian tumor was solid, measuring 12 × 13 × 12 cm. The surface was smooth but bosselated. Histologically, the tumor was composed of epithelial and sarcomatous elements. Curiously, the epithelial element was composed predominantly of signet ring cell carcinoma. A small area showed tubular adenocarcinoma and poorly differentiated carcinoma. The sarcomatous element was homologous with spindle cell sarcoma with many mitotic cells. The signet ring cells had mucins. Immunohistochemically, the epithelial element was positive for cytokeratins, EMA, p53, CEA, CA19-9, and Ki-67 (labeling = 75%). The sarcomatous element was positive for vimentin, α-smooth muscle actin, p53, and Ki-67 (labeling = 36%), indicating that it was a leiomyosarcoma. Metastases were found in many lymph nodes and intravascular spaces in the peritoneum; the metastases were composed of epithelial elements. CONCLUSION: To the best of our knowledge, there have been no descriptions in the English literature of MMMT composed predominantly of signet ring cell carcinoma. An MMMT in this case, should be differentiated from Krukenberg tumor, metastatic signet ring cell carcinoma, and signet ring stromal tumor.

Malignant mixed müllerian tumor with malignant neuroectodermal components (teratoid carcinosarcoma) of the ovary: Report of a case with clinicopathologic findings.

Malignant mixed müllerian tumor (MMMT) or carcinosarcoma of the female genital tract is a rare neoplasm. Malignant ovarian tumor composed of müllerian epithelial tumor and malignant germ cell tumor is also rare, with most cases composed of endometrioid adenocarcinoma and yolk sac tumor. Ovarian MMMT with malignant neuroectodermal components resembling immature teratoma is extremely rare. We report a case of teratoid carcinosarcoma of the ovary occurring in a 40-year-old female. The resected tumor measuring over 20 cm in diameter consisted of cystic and solid components and was very fragile. Microscopic examination showed a heterogenous mixed tumor composed of malignant epithelial, malignant mesodermal and malignant neuroectodermal components. The cells of ganglioneuroblastoma-like area were positive for neural markers (Synaptophysin, S-100 protein, neuron-specific enolase). There was no tumor immunoreactivity to alpha-fetoprotein, carcinoembryonic antigen, human chorionic gonadotropin, and inhibin. In spite of aggressive combination chemotherapy and three times of laparotomy, the patient died of disease 3 years 10 months after the initial treatment. This quite rare ovarian tumor closely resembled nasopharyngeal tumors described as 'teratoid carcinosarcoma' is biologically aggressive. We report the fourth case of ovarian teratoid carcinosarcoma. Further cases need to be accumulated to make diagnosis and to determine a successful treatment modality.

Oral progesterone treatment in a young woman with müllerian adenosarcoma whose ovary was preserved: a case report.

Müllerian adenosarcoma is a rare biphasic tumor in young women. These tumors can recur even after complete resection. We present a patient treated with oral progesterone after hysterectomy with ovary conservation. A 35-year-old woman had a diagnosis of adenosarcoma on hysteroscopic resection, which was estrogen and progesterone receptor positive. She underwent total hysterectomy with ovary conservation and has received oral medroxyprogesterone acetate treatment. At 15 months after surgery, there has been no disease recurrence. Oral medroxyprogesterone acetate therapy can be used effectively in young women with müllerian adenosarcoma whose ovaries are preserved.